IASLC Lung Cancer News - V5, N2 by IASLC

GLOBAL EDITION

LUNG CANCER

V5 / N2 / APRIL 2020

FOR THORACIC SPECIALISTS Read online at LungCancerNews.org g & Visit IASLC.org

INSIDE 2

Grappling with Coronavirus (SARS-CoV-2)

Partnering With Oncogene-Focused Patient Groups to Propel Research

Decade of Progress Timeline: U.S. Drug Approvals

Decade of Progress Timeline: Milestones in Lung Cancer Treatments

Artificial Intelligence in Lung Cancer

Deeper Dive: Disparities in Meeting Eligibility Criteria for Lung Cancer Screening

A Cloud-Based Computerized System for the Korean Lung Cancer Screening Project

PD-L1 Testing for Lung Cancer in 2019: Perspective From the IASLC Pathology Committee

Liquid Biopsy’s Role in Marker Identification: An Interview With Dr. Martin Filipits

Time to End the Debate on Genomic Testing in NSCLC

NEWS

I N T E R N AT I O N A L A S S O C I AT I O N F O R T H E S T U D Y O F L U N G C A N C E R E V O LV I N G S TA N D A R D S O F C A R E

Stunning Progress Achieved in Lung Cancer Treatment Over the Last Decade By Kara Nyberg, PhD

After decades of failed clinical trials and persistently dismal lung cancer survival outcomes, the 2010s breathed new life into the beleaguered field of lung cancer research. Treatment progress gained momentum and finally reached a tipping point in the mid-2010s, with the number of advances over the last 5 years outweighing all the advances in the 5 decades leading up to that point. As the field continues to race forward into the 2020s, it seems fitting to reflect back on how much the treatment of lung cancer has evolved over the past decade.

Surgery Surgical oncologists worldwide increasingly turned to video-assisted thoracic surgery (VATS) in the 2010s to manage early-stage lung cancer, with many centers now favoring this minimally invasive approach over open thoracotomy to reduce surgical morbidity.1 Multiple

observational studies and meta-analyses pointed to fewer postoperative complications and better short- and long-term survival with VATS lobectomy compared with open lobectomy. However, data from a large randomized trial supporting the advantage of this approach were heretofore lacking—that is, until the British VIOLET study, the largest randomized trial ever to compare clinical outcomes following VATS versus open surgery in patients with early-stage disease. At the end of 2019, the VIOLET investigators reported that patients who underwent VATS lobectomy experienced significantly fewer in-hospital complications compared with those who underwent open lobectomy (32.8% vs. 44.3%; p = 0.008), as well as a shorter length of stay (4 vs. 5 days; p = 0.008).2 Importantly, these benefits were attained without compromising early oncologic outcomes (i.e., R0 resection rates or lymph node upstaging) or increasing serious adverse events in the early postoperative period. Results

for patient-reported pain, quality of life, and disease recurrence at 1 year are still awaited.

Given its success in treating inoperable lung cancer, ongoing research is now focused on whether SABR can be used in lieu of surgery in early-stage disease. Some centers have explored other techniques to further decrease the invasiveness of surgery, including segmentectomy, single-port VATS, and roboticassisted thoracic surgery, with promising signals of success.

Radiotherapy For patients with early-stage NSCLC that is unsuitable for surgery, stereotactic ablative radiotherapy (SABR) offers an alternative. Both the American Society for Radiation Oncology3 and the European Society for Radiotherapy and continued on page 4

TA R G E T E D T H E R A P Y

Histologic Transformation From NSCLC to SCLC: A Mechanism of Resistance to Osimertinib and Other Agents Targeting EGFR Mutations By Denis Moro-Sibilot, MD, MSc

EGFR tyrosine kinase inhibitors (TKIs) are the standard of care for mutated EGFR NSCLC. Today, one of the burning questions is whether to select the most recent third-generation agent or to combine a first- or second-generation TKI with chemotherapy or antiangiogenic agents and reserve third generation inhibitors for patients who exhibit acquired resistance due to T790 mutations. Regardless of the first-line treatment chosen, resistance is, unfortunately, a nearly universal occurrence. The primary mechanism of resistance to first- and second-generation TKIs is represented by the appearance of the secondary resistance mutation T790M. This occurs approximately

50% to 60% of the time of circulating tumor DNA after treatment with first often limits the decision or second generation to re-biopsy, which is TKIs, but is extremely more complex to orgarare after treatment nize. Liquid biopsies with osimertinib in obviously do not allow the first-line setting. the diagnosis of SCLC Among other mechatransformation, which nisms, transformation requires tissue. Dr. Denis Moro-Sibilot into SCLC is a relatively Transformation to SCLC uncommon event, but it may occur at any time during occurs regardless of the generathe course of the disease, from the tion of TKI used, including osimertinib. first few months to several years after SCLC transformation occurs in 3% to the diagnosis of metastatic EGFR mt 10% of EGFR TKI‒resistant cases1,2; how(+) NSCLC, but the average transforever, this incidence is possibly underestimation time is approximately 13 to 18 mated due to the absence of or inability months after the start of TKI treatment.5,6 3,4 to re-biopsy at the time of progression. Although these tumors have the usual Moreover, the simplicity of the analysis histologic criteria of small cell carcino-

mas such as neuroendocrine differentiation, they differ from conventional SCLCs in that they occur in non-smokers or light smokers and frequently retain the original EGFR mutation, which is virtually never seen in de novo SCLC. More than two-thirds of SCLC transformations were observed in patients with EGFR exon 19 mutations (Table 1, page 3), whereas T790M resistance mutation is rarely observed in transformed SCLCs, even if it was present in the patient’s previous specimens, suggesting that this mutation may appear in a clone that is distinct from the clone that transforms to SCLC. Losses of P53 and RB1 with inactivation of the two key alleles were identified in a majority of transformed SCLCs. A continued on page 3

IASLC LUNG CANCER NEWS / APRIL 2020

JOURNAL RADAR

Grappling with Coronavirus (SARS-CoV-2) date, no antiviral has shown any efficacy, and vaccines are thought to be 12 to 18 Michele Carbone MD, Ph.D and col- months off. So, at this point, scrupulous leagues have penned a far-ranging hygiene (proper hand-washing), screeneditorial, now published online in the ing at-risk individuals, and minimizing Journal of Thoracic Oncology (JTO), contact between those who have tested on the “Facts, Myths, and Hypotheses” positive and the outside world until the behind this pandemic and global public disease has run its course are the optimal health crisis, which was first documented measures available. in Hubei Province in China. The Finally, Carbone reviews the advent of COVID-19 has early pulmonary patholclear cut implications for ogy observed in those our patients with thowith fulminant disracic cancer, many of ease, which has all the whom are immuneearmarks of SARS compromised or (severe acute respielderly, as well as ratory syndrome). for all of us in the In the early phase, health care profession. patients exhibit fever, Carbone points out that dry cough, and dyspnea. Dr. Corey J. Langer the current incidence rates Like the 1918 Flu pandemic, “barely scratch the surface” SARS-CoV-2, can lead to and that the real rates are likely far higher rapid alveolar damage, which even since testing material is not uniformly ventilation and assisted oxygenation available. Nations that have made a major may not be able to overcome. Tian et al. effort to test their citizens, unsurprisingly, in the JTO have documented the early are documenting much higher incidence pathology observed in two patients who than those, like the United States, that do had undergone lobectomies and who not. In addition, early testing has been had GGOs in their lungs with COVIDcompromised by the faulty science in 19 documented on RT-PCR. Both patients ultimately became extremely In the early phase, patients exhibit fever, dry ill, and one died. cough, and dyspnea. Like the 1918 Flu pandemic, Edema and proteinSARS-CoV-2, can lead to rapid alveolar damage, aceous exudate were which even ventilation and assisted oxygenation noted in the surgimay not be able to overcome. cal specimens. In one case, abundant the design of some of the early PCR kits, intra-alveolar pulmonary macrophages leading potentially to “under-detection.” were present; alveolar walls or septa Recent ELISA kits have proven far more were expanded by proliferating fibroreliable and sensitive, and are now being blasts with type II pneumocyte hyperused routinely in China and elsewhere. To plasia. Lung damage is not caused by the By Corey J. Langer, MD, ILCN Editor

Figure. 84-Year-Old Female Patient with Lung Cancer and COVID-19

Post-op Day 1 scans revealed post-resection changes and bilateral GGO in the lower lobes.

According to Tian et al., tumor sections revealed evident alveolar damage, including alveolar edema and proteinaceous exudates (A), and prominent inspissated spherical secretions or globules (B) were noted. Mononuclear inflammatory were mixed with focally fibrin clusters with multinucleated giant cells were noted in the airspaces (C). Suspected viral inclusions were also noted in some cells (D).

accumulation of granulocytes and fibrin, but by intra-alveolar organization and fibrosis. Radiographically, these patients

IN REFERENCE TO: Carbone M, Green JB, Bucci EM, and Lednicky JJ. Editorial: Coronaviruses: Facts, Myths and Hypotheses. J Thoracic Onc. 2020;doi: https://doi.org/10.1016/j.jtho.2020.02.024. Tian S, Hu W, Niu L, Liu H, Xu H and Xiao S-Y. Pulmonary pathology of early phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thoracic Onc. 2020; doi: https://doi.org/10.1016/j.jtho.2020.02.010.

SHARE YOUR COVID-19 EXPERIENCES

Names and News Fred Hutchinson’s New President, Director Dr. Thomas J. Lynch Jr. has been named the new president and director of the Fred Hutchinson Cancer Research Center. Most recently Dr. Lynch was chief scientific officer at BristolMyers Squibb, where he oversaw research and development for oncology, cardiovascular disease, fibrosis, and immunoscience. Previously chairman and CEO of Massachusetts General Physicians Organization, director of Yale Cancer Center, physician-in-chief of Yale’s Smilow Cancer Hospital,

will often first manifest peripheral GGOs near the pleura before more extensive consolidation occurs. ✦

and professor of medicine at Yale School of Medicine, Dr. Lynch is known for his research on targeted therapies for EGFR-mutated lung cancer while chief of HematologyOncology at Massachusetts General Hospital. ✦

IASLC is collecting member and patient experiences with COVID-19 as a way to pool knowledge and connect our members during this public health crisis.

Dr. Thomas J. Lynch Jr.

Visit LungCancerNews.org and click the COVID-19 banner to access the latest research and IASLC statements, as well as to submit your story.

LUNGCANCERNEWS.ORG / APRIL 2020

Transformation From NSCLC to SCLC

Table 1. Survival, Objective Response to Chemotherapy, and Molecular Characteristics of Transformed SCLC in Different Retrospective Cohorts

from page 1

recent study compared 43 patients with the triple mutation (EGFR, P53, and RB1) to 142 controls with an EGFR mutation and wild-type P53 and RB1. Seven cases of SCLC were observed, all carrying the triple mutation, though only 18% of the triple mutants transformed, which shows that the P53 and RB1 mutations are necessary, but not sufficient, for transformation into SCLC.7 In sharp contrast, no transformation to SCLC was noted among patients whose tumors harbored the EGFR mutations alone.

Treatment Options: More Data Needed The appearance of brain metastases is a frequent event, observed in two-thirds of patients during the evolution of SCLC.5 As with conventional SCLCs, retrospective data show sensitivity to standard chemotherapy combining etoposide and cisplatin (Table 1); other agents such as taxanes are also active.5 The continuation of TKI with chemotherapy is reported in a few retrospective cases; however, the value of such an association has not been demonstrated by clinical studies. Immunotherapy, which is disap-

Time to transf (med, months)

Overall survival (med, months)

Ref

Ex 19/21/other %

40/60

77/23

Overall survival from SCLC (med, months)

SCLC with EGFR mut

OR to PE

3/4

71/29

69/25/6

17.8

31.5

10.9

100%

8/10

75/21/4

84%

9/20

80/20

Abbreviations: ref, reference; n , number of patients; time to transf, time to transformation into SCLC (time from the onset of TKI to the diagnosis of SCLC); med, median; mut, mutation; OR to PE, objective response to platinum etoposide; NR, not reported.

pointing in mutated EGFR tumors, is also disappointing in these transformed tumors.5,10 As with mutated EGFR tumors, checkpoint inhibitors have had only limited activity in this setting. Based on the recent positive results of the CASPIAN and IMpower133 trials, the combination of etoposide and platinum with either durvalumab or atezolizumab may emerge, but it should be noted that neither trial included patients with transformed SCLC. Clinical trials in this group of patients are desirable, even if the relative rarity of these transformations will make it difficult to carry out such trials. After transformation, clinical behavior mimics the behavior of “classic SCLCs,” with a median overall survival of approximately 10 to 11 months, which confirms the poor prognosis of these transformed SCLCs. ✦

About the Author: Dr. Moro-Sibilot is with the Thoracic Oncology Unit, CHU Grenoble-Alpes, Grenoble, France. References: 1. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;23;3(75):75ra26. 2. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240-2247. 3. Bosc C, Ferretti GR, Cadranel J, et al. Rebiopsy during disease progression in patients treated by TKI for oncogene-addicted NSCLC. Target Oncol. 2015;10(2):247-253. 4. Redig AJ, Costa DB, Taibi M, et al. Prospective Study of Repeated Biopsy Feasibility and Acquired Resistance at Disease Progression in Patients With Advanced EGFR Mutant Lung Cancer Treated With Erlotinib in a Phase 2 Trial. JAMA Oncol. 2016;2(9):1240-1242. 5. Marcoux N, Gettinger SN, O’Kane G, et al. EGFR-Mutant Adenocarcinomas That

Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes. J Clin Oncol. 2019;37(4):278-285. 6. Ferrer L, Giaj Levra M, Brevet M, et al. A Brief Report of Transformation from NSCLC to SCLC: Molecular and Therapeutic Characteristics. J Thorac Oncol. 2019;14(1):130-134. 7. Offin M, Chan JM, Tenet M, et al. Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes. J Thorac Oncol. 2019;14(10):1784-1793. 8. Niederst MJ, Sequist LV, Poirier JT, et al RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun. 2015;11;6:6377. 9. Lee JK, Lee J, Kim S, et al. Clonal History and Genetic Predictors of Transformation Into SmallCell Carcinomas From Lung Adenocarcinomas. J Clin Oncol. 2017;35(26):3065-3074. 10. Tokaca N, Wotherspoon A, Nicholson AG, et al. Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer. Lung Cancer. 2017;111:65-68.

ADVOCACY AND SURVIVORSHIP

Disrupting the Paradigm: Partnering With Oncogene-Focused Patient Groups to Propel Research By Amy C. Moore, PhD, and Upal Basu Roy, PhD, MPH

Genomic alterations drive more than 60% of adenocarcinoma cases of NSCLC.1 Approximately 25% of these cases will have an oncogenic driver (EGFR, ALK, ROS1, BRAF, or NTRK) that can be treated with approved targeted therapy drugs, and more (such as MET, RET, and exon 20 insertions) have clinical trial options.1 Patients and caregivers dealing with these cancers have organized globally into oncogene-focused groups (Table) and are building partnerships that

seek to provide support, increase awareness and education, accelerate funding and research, and improve access to effective diagnosis and treatment (including access to clinical trials).2 The GO2 Foundation for Lung Cancer, its sister organization the Addario Lung Cancer Medical Institute (ALCMI), and the LUNGevity Foundation are effectively working in partnership with several of these oncogene groups, including the ROS1ders, the EGFR Resisters, and ALK Positive, to collaborate on research to address ongoing needs in the lung cancer community. Together with these

Table. Oncogene-Focused Groups† Group

Focus

Email Address

ROS1ders

ROS1+ cancer

ros1cancer.patient@gmail.com

ros1cancer.com

ALK Positive

ALK+ NSCLC

info@alkpositive.org

alkpositive.org

Exon 20 Group

EGFR and HER2; exon 20 insertions

exon20@exon20group.org

exon20group.org

EGFR Resisters

EGFR+ NSCLC and cancers resistant to EGFR TKIs

egfrresisters@gmail.com

egfrcancer.org

RET Renegades

RET+ NSCLC

retrenegades@gmail.com

ALK Fusion

ALK+ NSCLC

info@alkfusion.org

alkfusion.org

Abbreviation: NA, not available. † Presented at the IASLC 2019 World Conference on Lung Cancer

Website

groups as well as the Exon 20 to collaborate successfully Group, we recently prewith clinicians, researchsented our findings at ers, advocacy organizathe 2019 IASLC World tions such as ours, and Conference on Lung industry partners to generate ideas for next Cancer in Barcelona, where we shared the steps in research for key characteristics their disease, forge new studies and clinical trials required for building Dr. Amy C. Moore effective research collabofor a specific oncogenic rations: driver, create new patient1. Include patients from the start, derived models of oncogene-driven in all aspects; cancers to study acquired resistance, conduct studies to collect real-world data, 2. Address questions meaningful to and guide patients to clinical trials. Here patients; 3. Develop patient-centered we highlight ongoing efforts across the various groups to address unmet needs measurements; in the lung cancer community. 4. Accommodate patients’ clinical realities; Developing Oncogene-Specific 5. Leverage social media and patient Cancer Models groups; 6. Share progress with participants Together with GO2 Foundation for Lung Cancer, ALCMI, Dr. Christine Lovly, frequently; and Dr. Robert Doebele, and Champions 7. Make results rapidly and freely Oncology, the ROS1ders are creating available. new ROS1 cell lines and patient-derived Adherence to these seven key charac- xenograft (PDX) mouse models from teristics has enabled the patient groups continued on page 8

IASLC LUNG CANCER NEWS / APRIL 2020

Decade of Progress

Lung Cancer Screening

from page 1

Oncology 4 established guidelines to standardize SABR delivery to patients with peripherally located, early-stage, node-negative NSCLC who are not candidates for surgery or who refuse to undergo surgery, cementing this modality as a standard of care over conventional external beam radiotherapy. Given its success in treating inoperable lung cancer, ongoing research is now focused on whether SABR can be used in lieu of surgery in early-stage disease. Two large randomized trials, the Joint Lung Cancer Trialist’s Coalition STABLEMATES trial (NCT02468024) and the Veterans Affairs Lung Cancer Surgery or Stereotactic Radiotherapy (VALOR) trial (NCT02984761), were launched during the last 5 years to compare SABR versus surgery in patients with operable stage I NSCLC.

Molecular Testing Following the discovery of oncogenic drivers in lung cancer in the early 2000s and initial forays into developing tyrosine kinase inhibitors (TKIs) to target those mutations, the field has embraced molecular testing as a fundamental tool to guide and individualize treatment selection for patients. The first ringing endorsement of molecular testing came in 2013 when the College of American Pathologists, the IASLC, and the Association of Molecular Pathologists jointly released guidelines recommending EGFR and ALK analysis of either the primary tumor or a metastatic lesion for all patients with advanced-stage adenocarcinoma, regardless of clinical risk factors.5 The associations since expanded

In 2010, the National Lung Cancer Screening Trial (NLST) became the first study ever to document improvements in lung cancer mortality through use of a specific screening approach.1 Among 53,454 ever-smokers aged 55 to 74 years who had at least a 30 pack-year history and who quit no more than 15 years previously or who still smoked, the individuals randomly assigned to screening

via low-dose chest CT demonstrated a 20% reduction in lung cancer mortality and a 6.7% reduction in overall mortality when compared with individuals randomly assigned to screening with a plain chest x-ray. Following the publication of these results, the US Preventive Services Task Force officially recommended yearly low-dose CT screening for patients aged 55 to 77 with at least a 30 pack-year his-

tory who had smoked within the last 15 years; however, community uptake of this approach has been slow and rates of low-dose CT screening remain low.2 ✦ References: 1. The National Lung Screening Trial Research Team. The National Lung Screening Trial Research. N Engl J Med. 2011;365:395-409. 2. Okereke IC, Nishi S, Zhou J, Goodwin JS. Trends in lung cancer screening in the United States, 2016–2017. J Thorac Dis. 2019;11(3):873-881.

Table 1. Estimated Prevalence of Lung Cancer Screening, 2010 and 1015a 2010

2015

Weighted % (95% CI)

p-valueb

1,085

3.8 (2.7, 5.2)

1,228

4.4 (3.0, 6.6)

0.52

Met USPSTF criteria and reported a chest x-ray

1,085

7.7 (6.1, 9.7)

1,246

111

8.5 (6.5, 11.1)

0.60

Did not meet USPSTF criteria and reported a chest x-ray

13,937 310

2.1 (1.8, 2.4)

18,606 440

2.3 (2.0, 2.6)

0.24

Did not meet USPSTF criteria and reported a chest CT scan 13,936 164

1.1 (0.9, 1.3)

18,439 242

1.3 (1.1, 1.5)

0.23

Variable Consistent with USPSTF recommendations Met USPSTF criteria and reported a chest CT scan Inconsistent with USPSTF recommendations

Respondents are adults aged ≥ 40 years without lung cancer. Lung cancer screening categories are not mutually exclusive. The p-values are for the differences in prevalences from 2010 to 2015 using linear contrast procedures and t-tests (p < 0.05). CT, computed tomography; USPSTF, U.S. Preventive Services Task Force.

In 2015, the estimated prevalence of lung cancer screening with chest CT was about 4% among individuals meeting USPSTF smoking status and age criteria (55−80 years; Table 1). Source: Am J Prev Med. Author manuscript; available in PMC 2020 Jan 1. Published in final edited form as: Am J Prev Med. 2019 Jan; 56(1): 66–73. Published online 2018 Nov 19. doi: 10.1016/j.amepre.2018.07.030

the guidelines in 2018 to include ROS1, BRAF, MET, RET, HER2, and KRAS, underscoring the wide breadth of targets and corresponding therapies now available for lung cancer treatment.6 A study conducted by the Lung Cancer Mutation Consortium in the United States elegantly illustrated the importance of screening for driver mutations as a standard component of the diagnostic workup for NSCLC.7 Of 733 patients with adenocarcinoma who underwent genotyping for 10 oncogenic drivers,

64% harbored a targetable driver mutation. Notably, patients with an oncogenic driver who received targeted therapy survived a median of 3.5 years, whereas patients with a driver mutation who did not receive targeted therapy survived a median of 2.4 years. Median OS for patients without a driver mutation was 2.1 years. A nationwide study conducted by the French Cooperative Thoracic Intergroup that included more than 17,600 patients with advanced NSCLC subsequently reported similar findings,

bolstering the clinical benefit and prognostic utility of molecular profiling.8

Systemic Therapy In 2010, only approximately 20% of patients with lung cancer were expected to live 5 years beyond their initial diagnosis, largely owing to the late onset of disease. Moreover, only two targeted therapies, gefitinib and erlotinib, were available to target just one driver mutation, EGFR. As of 2020, nearly 20 new agents— continued on page 5

INDUSTRY AND REGULATORY NEWS

In early January 2020, the American Cancer Society (ACS) released a statement noting that the cancer mortality rate had dropped 2.2% between 2016 and 2017. This was the most notable decline ever recorded and, according to an NPR interview with Rebecca Siegel, MPH, scientific director for surveillance research at the ACS, “It seems to be driven by accelerating declines in lung cancer mortality.” New therapies could have contributed (see the Decade in Review article on page 1), along with declining smoking rates. However, it is yet to be determined how the dramatic increase in vaping rates, especially among youth, will offset the decline in smoking rates. Long-term risks for vaping also need to be parsed out from the more immediate risks. ✦

Death Rates, 2013-2017 – By State, All Cancer Types Combined Average annual rate per 100,000, age adjusted to the 2000 US standard population. Rates for Puerto Rico are for 2011-2015 116.1 - 131.8

131.9 - 147.6

147.7 - 163.3

163.4 - 179.1

179.2 - 194.8

CancerStatisticsCenter.cancer.org

Sharp Decline of Cancer Death Rates Partially Due to Lung Cancer Advances

LUNGCANCERNEWS.ORG / APRIL 2020

Decade of Progress

U.S. Drug Approvals: 2010 – 2020

from page 4

targeted therapies, checkpoint inhibitors, and anti-angiogenic agents—have transformed the treatment landscape (see the Drug Approvals timeline), and OS rates are beginning to creep upward as a result. In 2016, the 5-year OS rate had reached 23.5%, and it is expected to continue to its climb as an increasing number of patients hit the 5-year mark since the initial introduction of novel therapies. Targeted therapy The field of lung cancer research intensified the pace of targeted therapy development in the 2010s, rolling out agents directed against new oncogenic drivers and iteratively introducing more potent agents with higher barriers to genetic resistance. Five first-line EGFR-targeted agents reflecting three generations of development have come to market since the identification of EGFR sensitizing mutations more than 15 years ago. The newest of these, osimertinib, has emerged as the frontrunner in the first-line setting in NSCLC in many regions of the world based on both efficacy and safety, displacing erlotinib, afatinib, gefitinib, and dacomitinib as a preferred standard of care. This is largely based on the results of the phase III FLAURA trial, which documented significant improvements in median progression-free survival (PFS; 18.9 vs. 10.2 months; p < 0.001) and median overall survival (38.6 vs. 31.8 months; p = 0.046) with osimertinib compared with erlotinib or gefitinib, in tandem with a milder toxicity profile, less frequent central nervous system progression, and improved post-progression outcomes.9,10 An array of treatment options likewise now exist for patients with ALK rearrangements. These include the first-generation ALK TKI crizotinib; the second-generation agents ceritinib, alectinib, and brigatinib; and the thirdgeneration agent lorlatinib. In the phase II study supporting lorlatinib approval for second- or later-line treatment of ALK-positive disease, objective response rates in patients previously treated with at least one ALK TKI reached 47%.12 Notably, among 81 patients with measurable brain lesions at baseline, lorlatinib yielded an objective intracranial response in 63%, with a median duration of response of 14.5 months. Inhibitors of ROS1-rearranged NSCLC entered the scene in 2016 with the approval of crizotinib for ROS1-positive tumors. This has since been followed by the approval of entrectinib for ROS1continued on page 6

2011

Crizotinib label expansion approved for ALK-rearranged advanced NSCLC

2013 Erlotinib approved for EGFR-mutated advanced NSCLC

2016

Crizotinib approved for ROS1-positive metastatic NSCLC Afatinib approved supplemental NDA for metastatic squamous NSCLC progressing after platinum-based chemotherapy

Atezolizumab approved for metastatic NSCLC progressing on/after platinum-containing chemotherapy/TKI if EGFR/ALK+

Afatinib approved for EGFR-mutated advanced NSCLC

Pembrolizumab approved in first line for metastatic PD-L1expressing (TPS ≥ 50%) NSCLC with no EGFR or ALK genomic tumor aberrations

2018

continued Larotrectinib granted accelerated approval for advanced solid tumors with an NTRK gene fusion and no known acquired resistance mutations for which no satisfactory treatment alternatives exist

Durvalumab approved for unresectable stage III NSCLC that has not progressed following concurrent platinumbased chemotherapy + RT Nivolumab approved for metastatic SCLC that progressed after platinumbased chemotherapy + ≥1 other line of therapy

2014 Ramucirumab approved in combination with docetaxel for metastatic NSCLC progressing on/ after platinum-based chemotherapy

Alectinib approved as first-line treatment of ALKpositive advanced NSCLC

Ceritinib granted accelerated approval for ALK-positive metastatic NSCLC

Necitumumab approved in combination with gemcitabine/cisplatin for metastatic squamous NSCLC

2017

Brigatinib granted accelerated approval for ALKrearranged NSCLC progressing on or intolerant to crizotinib

Gefitinib granted Orphan Drug Designation for EGFR mutation-positive advanced NSCLC

2015

Gefitinib approved for EGFR-mutated advanced NSCLC

Osimertinib granted accelerated approval for EGFR T790M+ advanced NSCLC progressing on/after EGFR TKI

Alectinib approved for ALK-rearranged advanced NSCLC progressing on or intolerant to crizotinib Nivolumab approved for metastatic NSCLC progressing on/after platinum-containing chemotherapy Pembrolizumab approved for metastatic PD-L1–expressing (TPS ≥ 1%) NSCLC progressing on/after platinum-containing chemotherapy

Pembrolizumab approved as first-line treatment in combination with (nab-) paclitaxel/carboplatin for metastatic squamous NSCLC

Pembrolizumab approved for metastatic PD-L1-expressing (TPS ≥ 1%) NSCLC progressing on/after platinum-containing chemotherapy

Ceritinib approved for ALKpositive metastatic NSCLC Dabrafenib/trametinib approved for BRAF V600E mutation-positive metastatic NSCLC Pembrolizumab approved as first line in combination with pemetrexed/carboplatin for metastatic nonsquamous NSCLC Osimertinib granted full approval for EGFR T790M+ advanced NSCLC progressing on/after EGFR TKI

2018

Osimertinib approved for metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations

Dacomitinib approved for metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations Lorlatinib approved for ALK-positive metastatic NSCLC progressing on crizotinib + ≥1 other ALK inhibitor or progressing on 1L alectinib or ceritinib

Atezolizumab approved in combination with paclitaxel/ carboplatin + bevacizumab for metastatic nonsquamous NSCLC with no EGFR or ALK mutations Afatinib supplemental NDA approved for first-line metastatic EGFR-mutated NSCLC

2019

Entrectinib approved for ROS1positive metastatic NSCLC and granted accelerated approval for advanced solid tumors with an NTRK gene fusion and no known acquired resistance mutations for which no satisfactory treatment alternatives exist Pembrolizumab approved as monotherapy for stage III, PD-L1-expressing (TPS ≥1%) NSCLC unsuitable for surgery or definitive CRT and with no EGFR or ALK mutations

Pembrolizumab approved for metastatic SCLC that progressed after platinumbased chemotherapy + ≥1 other line of therapy Atezolizumab approved as first line in combination with carboplatin/etoposide for extensive-stage SCLC Atezolizumab approved as first line in combination with nab-paclitaxel/carboplatin for metastatic nonsquamous NSCLC with no EGFR or ALK mutations

Abbreviations: 1L, first line; CRT, chemoradiation; NDA, New Drug Application; RT, radiation therapy; TPS, tumor proportion score.

IASLC LUNG CANCER NEWS / APRIL 2020

Decade of Progress

Milestones in Lung Cancer Treatment

from page 5

positive metastatic NSCLC based on an integrated analysis of three ongoing phase I and II trials (ALKA-372-001, STARTRK-1, and STARTRK-2). The analysis showed that entrectinib yielded an objective response in 77% of patients with ROS1 fusion–positive NSCLC and maintained that response for a median of 24.6 months.13 Other targeted therapies approved for metastatic NSCLC in just the last few years include dabrafenib/trametinib for patients with BRAF V600E mutation– positive disease, along with larotrectinib and entrectinib for patients with disease harboring the NTRK gene fusion who lack viable treatment options. Immunotherapy The introduction of immune checkpoint inhibitors in 2015 represents a major milestone in lung cancer treatment. At that time, nivolumab, pembrolizumab, and atezolizumab monotherapy each demonstrated the ability to prolong survival by approximately 2 to 3 months when pitted against the prior standard, docetaxel, in previously treated squamous and nonsquamous NSCLC in randomized trials.14-17 After becoming established for second- or later-line treatment, efforts quickly escalated to move immunotherapy into the first-line setting, along with routine testing for tumor PD-L1 expression, where the effects of checkpoint inhibitor therapy appeared to be more pronounced. Pembrolizumab was the first to break this new ground by demonstrating superior median PFS and OS compared with platinum-based chemotherapy in patients with high (≥ 50%) PD-L1 expression (10.3 vs. 6.0 months; p < 0.001).18 Since that time, frontline use of a checkpoint inhibitor, either alone for tumors with high PD-L1 expression or in combination with chemotherapy regardless of PD-L1 tumor expression, has now become a standard of care for patients with advanced NSCLC lacking a driver mutation, followed thereafter by continuation of immunotherapy for at least 2 years in an effort to maintain response. The checkpoint inhibitor breakthroughs do not stop there. Durvalumab first established a new standard of care in unresectable stage III NSCLC based on evidence that use of the immunotherapy as consolidation following the completion of chemoradiotherapy significantly prolonged both OS (2-year OS: 66.3% vs 55.6%; p = 0.005) and PFS (median: 16.8 vs 5.6 months; p < 0.001) as compared with placebo.19 in 2018, checkpoint inhibitors made headway in extensivecontinued on page 8

The National Lung Screening Trial (NLST) shows that annual screening with low-dose helical CT vs. chest x-ray reduces the risk of lung cancer mortality by 20% among current and former heavy smokers

2010

An Intergroupe Francophone de Cancerologie Thoracique trial shows that platinum-based doublet chemotherapy should be offered to older patients (≥70 years) with advanced NSCLC, based on significant OS improvements vs. monotherapy A head-to-head trial shows that adding palliative care to standard chemotherapy significantly extends OS and improves patient QOL

2011

ALK-targeted therapy first enters the NSCLC treatment landscape with the approval of crizotinib

New AJCC lung cancer staging system adopted, based on expanded clinical data IASLC 7th edition of the TNM Classification for Lung Cancer adopted by the AJCC and the UICC

CAP, IASLC, and AMP release guidelines promoting routine molecular testing in lung cancer

2013

2015

ROS1-targeted therapy first enters the NSCLC treatment landscape with the approval of crizotinib

Immunotherapy first enters the NSCLC treatment landscape, with three agents (pembrolizumab, nivolumab, and atezolizumab) showing the ability to extend OS and cause fewer AEs vs. chemotherapy in metastatic NSCLC

2016

IASLC 8th edition of the TNM Classification for Lung Cancer released

2017

BRAF V600E-targeted therapy first enters the NSCLC treatment landscape with the approval of dabrafenib/trametinib ASTRO and ESTRO publish guidelines to standardize SABR delivery to patients with inoperable, peripherally located, early-stage, node-negative NSCLC

Durvalumab becomes the first immunotherapy approved for unresectable stage III NSCLC following concurrent platinum-based chemotherapy + RT

UICC adopts IASLC 8th edition of the TNM Classification for Lung Cancer released

2018

Nivolumab becomes the first immunotherapy approved for metastatic SCLC, specifically for patients whose disease progressed after platinum-based chemotherapy + ≥1 other line of therapy NTRK-targeted therapy first enters the NSCLC treatment landscape with the approval of larotrectinib AJCC adopts IASLC 8th edition of the TNM Classification for Lung Cancer released

2019

VIOLET trial supports benefit of VATS over open lobectomy for early-stage lung cancer Atezolizumab + carboplatin/etoposide becomes the first immunotherapy-chemotherapy combination approved for extensive-stage SCLC

Abbreviations: AEs, adverse events; AJCC, American Joint Committee on Cancer; AMP, Association for Molecular Pathology; ASTRO, American Society for Radiation Oncology; CAP, College of American Pathologists; CT, computed tomography; ESTRO, European Society for Radiotherapy; IASLC, International Association for the Study of Lung Cancer; QOL, quality of life; OS, overall survival; RT, radiotherapy; SABR, stereotactic ablative radiotherapy; VIOLET, Vitamin D to Improve Outcomes by Leveraging Early Treatment; VATS, video-assisted thoracic surgery.

LUNGCANCERNEWS.ORG / APRIL 2020

E V O LV I N G S TA N D A R D S O F C A R E

Artificial Intelligence in Lung Cancer: Opening New Avenues for Detection, Diagnosis, and Prognostication achieve better outcomes. The detailed analyses of imaging-derived information Artificial intelligence (AI) approaches can be particularly beneficial to facilitate have emerged as promising tools to detection and improve diagnostic accuracy of lung cancer screening, address important unmet needs across different as delineated in the recent specialties in medicine, article, “End-to-end lung including oncology, cancer screening with radiology, and patholthree-dimensional ogy. Recent studies deep learning on have described the low-dose chest comutility of AI in lung puted tomography,” by cancer to improve Ardila et al., published detection, diagnosis, and in Nature Medicine.1 Dr. Mizuki Nishino prognostication. Many of In this study, Ardila et the AI studies in lung cancer al. aimed to build an endinvolve computational analyses of imag- to-end approach that performs both ing data, most commonly CT scans, to lesion localization and lung cancer risk By Mizuki Nishino, MD, MPH

Fig. 1. Overall Modeling Framework

For each patient, the model uses a primary low-dose CT (LDCT) volume and, if available, a prior LDCT volume as input. The model then analyzes suspicious and volumetric ROIs as well as the whole-LDCT volume and outputs an overall malignancy prediction for the case, a risk bucket score (LUMAS), and localization for predicted cancerous nodules. Reprinted by permission from Springer Nature: Springer Nature, Nature Medicine, End-to-end lung cancer screening with three-dimensional deep learning on low-dose chest computed tomography, Diego Ardila et al, 2019.

categorization based on the input CT data, in order to simulate a complete workflow of radiologists for lung cancer CT screening. The workflow included a full assessment of CT volume, region-ofinterest detection, comparison to prior imaging, and correlation with biopsyderived results (Fig 1).1 The “end-toend” design is particularly important when considering AI application in lung cancer because the human workflow consists of multiple steps, and these steps can interact with each other, which adds further complexity to the process. Replicating the entire workflow using the AI model, although challenging, has the potential to provide more robust solutions to improve efficiency and performance of lung cancer CT screening, g, rather than providing separate tools forr individual steps. The models in the study were builtt using deep convolutional neural net-works (CNN), a powerful way to learn n useful representations of images and d other structured data, which formed d a basis of the current trends of the AII application in medical imaging.2 Usingg CNN, the models can learn useful fea-tures automatically and directly from m n the raw data, which has been shown to be superior to hand-engineered fea-tures.1,2 Using the state-of-the-art AII approaches, the authors built a three-dimensional (3D) CNN model for the whole-CT volume analyses using screening CT.1 Then, a model for CNN region-of-interest (ROI) detection was

Fig. 2. Illustration of the Architecture of the End-to-End Cancer Risk Prediction Model

The model is trained to encompass the entire CT volume and automatically produce a score predicting the cancer diagnosis. In all cases, the input volume is first resampled into two different fixed voxel sizes as shown. Two ROI detections are used per input volume, from which features are extracted to arrive at per-ROI prediction scores via a fully connected neural network. The prior ROI is padded to all zeros when a prior is not available. Reprinted by permission from Springer Nature: Springer Nature, Nature Medicine, End-to-end lung cancer screening with three-dimensional deep learning on low-dose chest computed tomography, Diego Ardila et al, 2019.

trained to detect 3D cancer candidate regions in the CT volume. Finally, a CNN cancer risk-prediction model was developed, which operated on the outputs from the other two models (Fig 2).1 The risk prediction model can also incorporate regions of interest from the prior scans by assessing the regions corresponding to the cancer candidate regions on the current scan. This particular feature of the model integrating information from the prior scans is notable and can be a key component of AI applications in lung cancer specifically and in oncologic imaging in general because much of the workflow in oncologic imaging includes the evalu-

In deep learning, a convolutional neural network (CNN) is a class of deep neural networks, most commonly applied to analyzing visual imagery. CNNs were inspired by biologic processes: neuron connectivity patterns resemble the organization of the animal visual cortex. Cortical neurons respond to only the stimuli in the receptive field part of the visual field, but receptive fields of numerous neurons can partially overlap, covering the entire visual field. The “fully-connectedness” of these networks makes them prone to overfitting data. Source: Wikipedia.org

ation of serial scans over time in each patient. The models focusing on single timepoint analyses can address only a limited portion of the clinical questions. In the test dataset consisting of 6,716 cases (86 cancer-positives) from the National Lung Screening Trial (NLST), this model achieved an area under the receiver operating characteristic (AUC) of 94.4% for lung cancer risk prediction, which is considered to be a state-of-theart performance. The model performed similarly with an AUC of 95.5% on an independent clinical validation set of 1,139 cases, demonstrating a step toward automated image evaluation for lung cancer risk estimation using AI. Furthermore, the two-part retrospective reader study was performed to compare the model performance with that of six U.S. board-certified radiologists. In the first part, each of the six radiologists and the model evaluated a subset of the test dataset consisting of 507 participants (83 of whom with cancer) from NLST, without access to previous continued on page 9

IASLC LUNG CANCER NEWS / APRIL 2020

Oncogene-Focused Patient Groups from page 3

patient donations of excess fresh tumor tissue or pleural fluid. The ROS1 Cancer Model Project has already created four cell lines that have been distributed to researchers conducting research on ROS1 lung cancer.

Funding OncogeneSpecific Research The ALK Positive group has partnered with LUNGevity Foundation to fund grants related to “improving the life expectancy and quality of life” for patients with ALK-positive NSCLC. Together with LUNGevity Foundation and leading thoracic oncology experts, the ALK Positive team selected the studies to be funded. These studies aim to understand how immunotherapy can be applied to ALKpositive lung cancer after progression on TKIs. The ALK Positive team is also funding another research project with GO2 Foundation focusing on using combination targeted therapies for ALK-positive tumors to delay or prevent drug resistance.

Decade of Progress from page 6

stage SCLC, with atezolizumab being the first to significantly prolong median OS when combined with carboplatin/ etoposide, as compared with carboplatin/etoposide alone (12.3 vs. 10.3 months; p = 0.007).20 Anti-angiogenic therapy In 2014, ramucirumab became the second anti-angiogenic agent to enter the NSCLC treatment landscape after bevacizumab, which was originally approved for NSCLC in 2006. Authorization of the VEGFR-2 inhibitor was based on the phase III REVEL trial conducted in more than 1,200 patients with squamous and nonsquamous NSCLC whose disease progressed during or after a first-line platinum-based regimen. Patients who received docetaxel plus ramucirumab realized superior outcomes compared with patients who received docetaxel plus placebo, both for median OS (10.5 vs. 9.1 months; p = 0.023) and median PFS (4.5 vs. 3.0 months; p <0.0001).21

Supportive/Palliative Care The importance of early palliative care for ambulatory patients with metastatic NSCLC first came to light in 2010. In a randomized trial that included 151 patients, the many benefits of combining early palliative care with standard

Treatment Sequencing

concerns regarding risk factors, sympThe Exon 20 Group has just initiated toms, and side effects of treatments. the Resistance Mutation Study Preliminary results of the study and the Immune Cell Study, have already been presented which aim to understand at the 2019 IASLC World the resistance landConference on Lung scape for EGFR exon Cancer and the 2019 20 insertions and IASLC North America HER2 exon 20 inserConference on Lung tions. The project, Cancer. Additionally, which was funded by the ROS1ders have worked wit h GO 2 the Exon 20 group, will Dr. Upal Basu Roy work with patients and Foundation to look at key families to focus on more characteristics of patients effective sequencing of therapies. with ROS1-positive NSCLC using a patient-designed, global, pan-cancer Collecting Patientdata repository.3 Reported Data As scientists working within lung The EGFR Resisters’ Project PRIORITY cancer advocacy organizations, we know (Patient Reported Initiative On firsthand the progress that has been made in recent years in the treatment Resistance, Incidence, Treatment studY) is a survey-based project in collaboraof this disease. Indeed, because of these tion with LUNGevity Foundation. It advances, scientists recently reported aims to understand the treatment expethe largest single-year drop in cancer rience of patients with EGFR-positive mortality, driven largely by a decline in lung cancer, specifically, to identify lung cancer deaths.4 Yet, we have been areas for improvement in diagnosis unable to significantly move the needle and treatment and give voice to patient on overall survival, and lung cancer

oncologic care, compared with standard oncologic care alone, included better patient quality of life on the Functional Assessment of Cancer Therapy–Lung scale (98.0 vs. 91.5; p = 0.03), fewer depressive symptoms (16% vs. 38%; p = 0.01), and longer median OS (11.6 vs. 8.9 months; p = 0.02) despite a lower likelihood of aggressive end-of-life care (33% vs. 54%; p = 0.05).22 Following corroboration by subsequent studies, concurrent palliative care is now recommended as a standard component of disease management in tandem with active treatment for all patients with advanced lung cancer.23 ✦ References: 1. Cao C, Frick AE, Ilonen I, et al. European questionnaire on the clinical use of video-assisted thoracoscopic surgery. Interact Cardiovasc Thorac Surg. 2018;27(3):379-383. 2. Lim E, Batchelor T, Dunning J, et al. In hospital clinical efficacy, safety and oncologic outcomes from VIOLET: A UK multi-centre RCT of VATS versus open lobectomy for lung cancer. In: Program and Abstracts of the 2019 World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract PL02.06. 3. Videtic GMM, Donington J, Giuliani M, et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Pract Radiat Oncol. 2017;7(5):295-301. 4. Guckenberger M, Andratschke N, Dieckmann K, et al. ESTRO ACROP consensus guideline on implementation and practice of stereotactic body radiotherapy for peripherally located early stage non-small cell lung cancer. Radiother Oncol. 2017;124(1):11-17. 5. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine

kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8(7):823-859. 6. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323-358. 7. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006. 8. Barlesi F, Mazieres J, Merlio JP, et al; Biomarkers France contributors. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet. 2016;387(10026):1415-1426. 9. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFRmutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. 10. Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):4150. 11. Thatcher N, Hirsch FR, Luft AV, et al; SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763-774. 12. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654-1667. 13. Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-smallcell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):261-270. 14. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab

research remains grossly underfunded. We must explore new paradigms of partnership and collaborative research if we are to drive innovation that truly affects patients with lung cancer. Together, we are committed to nurturing effective collaborations with these oncogenefocused patient groups to deliver meaningful outcomes that improve, extend, and save lives. ✦ About the Authors: Dr. Moore is the director of Science and Research, GO2 Foundation for Lung Cancer. Dr. Basu Roy is vice president of Research, LUNGevity Foundation. References: 1. Pakkala S, Ramalingam SS. Personalized therapy for lung cancer: striking a moving target. JCI Insight. 2018;3(15):e120858. 2. Hennink M, Vandeweyer G, Freeman-Daily J; ROS1ders. The roles of patient groups in fostering cancer research. Nat Rev Clin Oncol. 2020;17(2):65-66. 3. Parikh DA, Walia G, Freeman-Daily J, et al. Characteristics of patients with ROS1+ cancers: results from the first patient-designed, global, pan-cancer ROS1 data repository. J Oncol Pract. Dec 27 2019. [Epub ahead of print]. 4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.

versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. 15. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. 16. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. 17. Fehrenbacher L, Spira A, Ballinger M, et al; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837-1846. 18. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. 19. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. 20. Horn L, Mansfield AS, Szczęsna A, et al; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensivestage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. 21. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. 22. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742. 23. Masters GA, Temin S, Azzoli CG, et al. Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015;33(30):3488-3515.

LUNGCANCERNEWS.ORG / APRIL 2020

Artificial Intelligence in Lung Cancer from page 7

CT scans. The patient demographics and clinical history were given to the radiologists but not to the model. The performance of all six radiologists trended at or below the model’s AUC of 95.9%. In the second part, the radiologists and the model evaluated current and previous year CT scans and interpreted 308 CT volumes from the cohort used in the first part of the comparison. Of note, these 308 scans were not from the initial baseline screening CT; rather, each scan had the previous year CT that was presented as a comparison. The model’s AUC was 92.6%, which was similar to the radiologists’ performance. Interestingly, both the model and the radiologists performed worse in this second part of the comparison compared with the first. Presumably this was because obviously malignant cases were diagnosed at the first screening and were not included in the cohort for the second part of the study, leaving more challenging evaluations for the second part. One of the goals of AI implementation is to reduce the workload for radiologists regarding straightforward evaluations, allowing them to spend increased time on complex cases. The results of the comparison indicate the need for further work to achieve this goal. The study by Ardila et al. also commented on the fundamental questions raised by AI approaches, particularly its perceived “black box” nature, and provided deeper assessment of the modeling results for their validity. They also explored how the model evaluates risk of malignancy and found a few possible clues; however, many unknowns persist about the model’s prediction process, emphasizing that the transparency of deep-learning models is still at an early stage. This is another important message of this article, which honestly declares the unknown aspects of AI models and describes the attempts to open (or at least to peek into) the black box. Many of the AI studies simply describe their models’ performance

out of the black box, without addressing the need for further examinations to decode how the outcomes are reached in the model. As stated by Ardila et al., such attempts are essential for physicians to take advantage of the features used by the model to achieve higher performance. Detection and diagnosis are one of the areas that have been extensively studied for AI approaches in lung cancer.3-5 In addition to improving diagnostic accuracy, AI approaches have been used to improve reproducibility of quantitative feature extraction in radiomics of lung lesions.4 In a study of 104 patients with pulmonary nodules or masses, Choe et al.4 demonstrated that a CNN-based CT image conversion improved the reproducibility of CT radiomic features obtained using different reconstruction kernels. The study demonstrated another meaningful application of AI in quantitative tumor imaging of the lung4,5 because improving reproducibility is a critical step for quantitative imaging techniques, such as radiomics, to prove their practical value in the clinical setting. Imaging features derived from the AI approaches have also shown promise in describing prognostic and molecular phenotypes,6 which can be further investigated in the specific setting of lung cancer. AI approaches have also been applied in the areas beyond radiologic imaging to address important questions for its detection, diagnosis, and prognostication of patients with cancer. For example, Mobadersanya et al.7 developed a survival prediction model using CNN that integrates information from histology images and genomic biomarkers into a unified prediction framework, resulting in superior prognostic accuracy compared to the current WHO paradigm in patients with brain tumors. Similar approaches can be explored in lung cancer, given an increasing trend for automated analyses of microscopic histology features.8 Finally, AI approaches based on deep natural language processing have been applied to the electronic health records in patients with cancer,

allowing for speedy curation of relevant cancer outcomes.9 In conclusion, applying AI approaches to medicine has opened a number of new avenues for optimizing lung cancer detection, diagnosis, and prognostication. Along with the expanding applications of the AI models in various aspects of lung cancer, the attempts to understand the black box nature of the AI models are becoming particularly important so that physicians can also learn from the AI models that have been effectively trained—meaning that they have been created with sufficient volume and breadth of data—and can proceed to develop further sophisticated models to address truly challenging issues in lung cancer practice. ✦ About the Author: Dr. Nishino is Vice Chair of Faculty Development, Department of Imaging, Dana-Farber Cancer Institute, and Associate Professor of Radiology, Harvard Medical School. References: 1. Ardila D, Kiraly AP, Bharadwaj S, et al. End-toend lung cancer screening with three-dimensional deep learning on low-dose chest computed tomography. Nat Med. 2019;25(6):954-961. 2. Lundervold AS, Lundervold A. An overview of deep learning in medical imaging focusing on MRI. Z Med Phys. 2019;29(2):102-127. 3. Ciompi F, Chung K, van Riel SJ, et al. Towards automatic pulmonary nodule management in lung cancer screening with deep learning. Sci Rep. 2017;7:46479. 4. Choe J, Lee SM, Do KH, et al. Deep Learningbased Image Conversion of CT Reconstruction Kernels Improves Radiomics Reproducibility for Pulmonary Nodules or Masses. Radiology. 2019;292(2):365-373. 5. Park CM. Can Artificial Intelligence Fix the Reproducibility Problem of Radiomics? Radiology. 2019;292(2):374-375. 6. Lu H, Arshad M, Thornton A, et al. A mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic- and molecular-phenotypes of epithelial ovarian cancer. Nat Commun. 2019;10(1):764. 7. Mobadersany P, Yousefi S, Amgad M, et al. Predicting cancer outcomes from histology and genomics using convolutional networks. Proc Natl Acad Sci U S A. 2018;115(13):E2970-E2979. 8. Yu KH, Zhang C, Berry GJ, et al. Predicting nonsmall cell lung cancer prognosis by fully automated microscopic pathology image features. Nat Commun. 2016;7: 12474. 9. Kehl KL, Elmarakeby H, Nishino M, et al. Assessment of Deep Natural Language Processing in Ascertaining Oncologic Outcomes From Radiology Reports. JAMA Oncol. 2019 Jul 25. [Epub ahead of print].

INDUSTRY AND REGULATORY NEWS Updated Guidelines for Stage IV, Non-Driver NSCLC Updated recommendations for systemic therapy for patients with stage IV NSCLC and no EGFR or ALK mutations were issued in late January 2020 by the American Society of Clinical

Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel. The updates were based on a systematic review of randomized controlled trials from December 2015 to 2019.

The updated guideline is available on ASCO.org or in the Journal of Clinical Oncology. Recommendations for treatment of patients with EGFR/ALK mutations will be issued in the future. ✦

LUNG CANCER

NEWS

EDITOR Corey J. Langer, MD, FACP ASSOCIATE EDITORS Fabrice Barlesi, MD, PhD Caicun Zhou, MD, PhD EDITORIAL GROUP MEMBERS Edgardo S. Santos Castillero, MD, FACP Marianne Davies, DNP, ACNP, AOCNP Janet Freeman-Daily, MS, Eng Brendon Stiles, MD MANAGING EDITOR AND PUBLISHER Joy Curzio, Curzio Communications COPY EDITORS Alana Williams and Elaine Michl PRODUCTION DIRECTOR Doug Byrnes GRAPHIC DESIGNER Kelli Schmidt, KSchmidt Designs LLC IASLC Lung Cancer News is published bimonthly by the International Association for the Study of Lung Cancer (IASLC). IASLC Headquarters is located at 13100 East Colfax Avenue, Unit 10, Aurora, CO, 80011, US. Purpose and Audience: IASLC Lung Cancer News features news about lung cancer research, patient care, tobacco control, and expert commentary from lung cancer leaders. The target audience for this publication is physicians and other specialists involved in the research and treatment of patients with lung cancer and other thoracic oncologic disorders. Correspondence: Address correspondence to Corey J. Langer, MD, FACP, Editor, c/o curziocommunications@gmail.com. Change of Address: Postmaster send address changes to IASLC Lung Cancer News, c/o IASLC Headquarters, 13100 East Colfax Avenue, Unit 10, Aurora, CO, 80011, US. Subscription: To initiate or cancel a subscription to IASLC Lung Cancer News or to update your mailing address, please email membership@ iaslc.org or call +1-720-325-2956. Advertising: For information on advertising rates or reprints, contact Kevin Dunn, Cunningham Associates, 201-767-4170, kdunn@cunnasso.com. All advertising is subject to acceptance by IASLC. IASLC is not responsible for the content of advertising and does not endorse any advertiser or its products or services. Disclaimer: The ideas and opinions expressed in IASLC Lung Cancer News do not necessarily reflect those of the International Association for the Study of Lung Cancer. The mention of any product, service, or therapy in this publication should not be construed as an endorsement, and the Association accepts no responsibility for any injury or damage to person or persons arising out of or related to any use of material contained in this publication or to any errors or omissions. IASLC MISSION To embrace the study of the etiology, epidemiology, prevention, diagnosis, treatment, and all other aspects of lung cancer and other thoracic malignancies; to provide education and information about lung cancer and other thoracic malignancies to IASLC members, to the medical community at large, and to the public; to use all available means to eliminate lung cancer and other thoracic malignancies as a health threat for the individual patient and throughout the world.

IASLC LUNG CANCER NEWS / APRIL 2020

A DEEPER DIVE

IN REFERENCE TO: Aldrich MC, Mercaldo SF, Sandler KL, Blot WJ, Grogan EL, Blume JD. Evaluation of USPSTF Lung Cancer Screening Guidelines Among African American Adult Smokers. JAMA Oncol. 2019 Jun 27. [Epub ahead of print].

Disparities in Meeting Eligibility Criteria for Lung Cancer Screening By Kim L. Sandler, MD, Melinda C. Aldrich, MPH, PhD, and Jeffrey D. Blume, PhD

smokers who were prospectively enrolled

Lung cancer screening, which includes a

2002 through September 2009. Two-thirds

shared decision-making visit and low-dose

of participants were African American.

computed tomography (CT) scan of the

Among participants diagnosed with lung

chest, is fully covered for those who meet

cancer, a significantly smaller percentage of

eligibility criteria by Affordable Care Act-

African-American smokers diagnosed with

compliant insurers. Eligibility criteria are

lung cancer would have been eligible for

based on the patient population that was

screening compared to Caucasian smokers

selected for the National Lung Screening

diagnosed with lung cancer (32% vs 56%).

Trial (NLST).1 The NLST found a 20% reduc-

This racial disparity in screening eligibility

tion in lung cancer mortality for low dose

can be eliminated by simple modifications

CT imaging compared to chest x-ray after

to current eligibility criteria for African

three annual scans. These results led to a

Americans. By decreasing the pack–year

Class B recommendation from the United

smoking requirement to 20 years and

States Preventive Services Task Force and to

beginning screening at age 50, sensitivity

current screening guidelines.2 These guide-

for lung cancer screening would improve

tional randomized controlled trials that

parities in current eligibility criteria, should

lines, however, exclude a large number of

for African Americans so that it would

have shown even greater mortality benefit

be enough to consider revisions to the cur-

patients who are diagnosed with lung

be almost identical to sensitivity among

with annual screening for lung cancer.

7,8

cancer by limiting screening to smokers

Caucasian smokers.5 Specificity for lung

Follow-up studies from the NLST and

primarily from community health centers across 12 southern states from March

aged 55 to 80, who have a 30 pack–

Novel Screening Approaches

year smoking history and who quit

Many researchers have suggested

no more than 15 years prior to

that screening should be based on

screening.3,4 A recent sub-study anal-

a risk-prediction model rather than

ysis of the NLST data demonstrated

simply age and smoking history.10-12 At

that African Americans receive the

the 2019 World Conference on Lung

most benefit from lung screening,

Cancer in Barcelona, Spain, there were

yet this population fails to meet

70 posters presented on lung cancer

eligibility criteria more often than

screening and early detection. Of

Caucasians.5,6 JAMA Oncology recently published

rent screening guidelines.

these, 12 proposed algorithms based Dr. Kim L. Sandler

Dr. Melinda C. Aldrich

Dr. Jeffrey D. Blume

“Evaluation of USPSTF Lung Cancer

on patient demographics and/or CT imaging findings to refine screening

Screening Guidelines Among African

cancer screening would be similarly aligned

subgroup analyses have also shown that

American Adult Smokers.” This research

eligibility. At the 2018 World Conference on

with Caucasian smokers as well.

the morbidity and mortality benefit from

paper evaluated lung cancer screening

Lung Cancer, several researchers presented

In the 8 years since the publication of

screening is even better than initially

eligibility among more than 48,000 adult

algorithms for screening and emphasized

the NLST, there have been several addi-

reported.9 This, in addition to the racial dis-

how improved mortality benefit and

References: 1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. N Engl J Med. 2011;365(5):395-409. 2. Moyer VA; U.S. Preventive Services Task Force. Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2014;160(5):330-338. 3. Wang Y, Midthun DE, Wampfler JA, et al. Trends in the Proportion of Patients With Lung Cancer Meeting Screening Criteria. JAMA. 2015;313(8):853-855. 4. Yang P, Wang Y, Wampfler JA, et al. Trends in Subpopulations at High Risk for Lung Cancer. J Thorac Oncol. 2016;11(2):194-202. 5. Aldrich MC, Mercaldo SF, Sandler KL, Blot WJ, Grogan EL, Blume JD. Evaluation of USPSTF Lung Cancer Screening Guidelines Among African American Adult Smokers. JAMA Oncol. 2019 Jun 27. [Epub ahead of print]. 6. Li C-C, Matthews AK, Rywant MM, Hallgren E, Shah RC. Racial disparities in eligibility for low-dose computed tomography lung cancer screening among older adults with a history of smoking. Cancer Causes Control. 2019;30(3):235-240. 7. Pastorino U, Silva M, Sestini S, et al. Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy. Ann Oncol. 2019;30(7):1162-1169. 8. Koning HD, Aalst CVD, Haaf KT, Oudkerk M. Effects of volume CT lung cancer screening: mortality results of the NELSON randomised-controlled population based trial (Abstract PL02.05). Presented at: IASLC 19th World Conference on Lung Cancer; September 25, 2018; Toronto, Canada. 9. National Lung Screening Trial Research Team. Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. J Thorac Oncol. 2019;14(10):1732-1742. 10. Tammemägi MC, Katki HA, Hocking WG, et al. Selection Criteria for Lung-Cancer Screening. N Engl J Med. 2013;368(8):728-736. 11. Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of Low-Dose CT Screening According to the Risk of Lung-Cancer Death. N Engl J Med. 2013;369(3):245-254. 12. O’Dowd EL, ten Haaf K. Lung cancer screening: enhancing risk stratification and minimising harms by incorporating information from screening results. Thorax. 2019;74(9):825-827. 13. Ten Haaf K, Bastani M, Cao P, et al. A comparative modeling analysis of risk-based lung cancer screening strategies. J Natl Cancer Inst. 2019 Sep 30. [Epub ahead of print]. 14. Becker N, Motsch E, Trotter A, et al. Lung cancer mortality reduction by LDCT screening-Results from the randomized German LUSI trial. Int J Cancer. 2019 Jun 4. [Epub ahead of print]. 15. Alahmari SS, Cherezov D, Goldgof DB, Hall LO, Gillies RJ, Schabath MB. Delta Radiomics Improves Pulmonary Nodule Malignancy Prediction in Lung Cancer Screening. IEEE Access. 2018;6:77796-77806.

LUNGCANCERNEWS.ORG / APRIL 2020

LUNG CANCER SCREENING

A Cloud-Based Computerized System for the Korean Lung Cancer Screening Project By Jin Mo Goo, MD, PhD, and Yeol Kim, MD, MPH, PhD reduced false-positive rates could be achieved by selecting a screening population based on risk-based eligibility. Importantly, several models, such as the PLCOm2012 model, have shown that risk prediction for lung cancer is improved in part by including race as part of the selection algorithm.10,11 However, a recent paper suggested that screening based on risk estimates may substantially increase overdiagnosis,13 so additional evaluation is necessary. Lung cancer screening works by facilitating the early detection of lung cancer in asymptomatic patients who otherwise may only have been diagnosed with latestage disease after the development of symptoms. Screening for lung cancer with low-dose CT has been proven now to provide an even greater mortality benefit than what was originally published in the NLST.7,8,14 Low-dose CT can find lung cancer with minimal risk to patients. Although the test is not perfect, it is continually being improved, with more advanced CT technology and machine learning being incorporated to better distinguish benign nodules from malig-

In 2015, based on the evidence from the National Lung Screening Trial, the Korean multisociety collaborative committee developed and published a guideline for lung cancer screening using low-dose CT (LDCT). The guideline recommends annual LDCT screening for three groups: high-risk smokers aged 55 to 74 years, with at least a 30 packâ&#x20AC;&#x201C;year smoking history; current smokers; and former smokers who quit smoking within 15 years. Based on this guideline and previous studies of lung cancer screening with LDCT, the Korean Lung Cancer Screening Project (K-LUCAS) was launched to evaluate the feasibility of implementing a population-based lung cancer screening program in South Korea.1 This was a 2-year project to enroll 8,000 participants at 14 institutions. For the nodule management and reporting, the Lung CT Screening Reporting and Data System (Lung-RADS) from the American College of Radiology was adopted.2 Requirements for CT scanners and acquisition parameters include multidetector CT with a minimum of 16 channels, complete scan with one-breath hold, section thickness of 1.25 mm or less, and a volume CT dose index of less than 3.0 mGy for average-sized patients

(170 cm/70 kg; body mass segmented, it can be easily index, 24 kg/m2). A total converted to either diamof 13,692 individueter or volume values. A als underwent LDCT computer-aided detection (CAD) system can for the K-LUCAS, and lung cancer was enhance the detection detected in 79 patients performance of readas of April 2019. Among ers. With the computthem 68.4% of cancers erized support, the results Dr. Jin Mo Goo were stage I or II, which is can be effectively reported much higher than that of the without an erroneous categogeneral population (29.6%), showing a rization of Lung-RADS.3 potential for stage shift of lung cancer In quantitative imaging, there are with lung cancer screening. Based on many sources of variability, and the these results, a national population-based software itself is one cause of variability. lung cancer screening program began in If we use different software, it will genJuly 2019 in South Korea. erate different nodule volume, which will subsequently affect the backbone Necessity for the Cloud-Based of nodule management: the size and Computerized System volume doubling time of a nodule. A To achieve lung cancer mortality reducthin-client approach using a cloud system tion with more benefit than harm, a highis a promising approach to help deal quality lung cancer screening program with this issue. By checking the imaging with LDCT is required. A cloud-based protocol stored in Digital Imaging and computerized system may provide many Communications in Medicine (DICOM) advantages for this purpose. of CT data, which are uploaded in the In the Lung-RADS, the category of a cloud system, quality control of CT data, nodule is determined by the nodule consuch as section thickness and radiation sistency (whether it is a solid nodule, partdose, can be easily applied. In Korea, solid nodule, or ground-glass nodule), many patients visit different hospitals due and the size of the nodule is determined to a variety of reasons, and they usually by averaging its bidimensional measureneed to carry a CD (or DVD) with mediments. By employing an automated nodcal images. Because comparison with previous CT scans is essential in lung cancer ule-segmentation program, reader agreement can be improved. Once a nodule is continued on page 13

nant disease.5,15 Although the research surrounding

Figure. An Overview of the Cloud-Based Computerized System

selection algorithms is promising, we should not deny lung cancer screening to patient groups at increased risk. We can begin by offering screening to patients who we know are routinely excluded, particularly high-risk African Americans who develop lung cancer at younger ages and with less tobacco exposure than their Caucasian counterparts. This is a critical step in reducing the racial disparities that exist in lung cancer survival. â&#x153;Ś

About the Authors: Dr. Sandler is assistant professor in the Department of Radiology at Vanderbilt University Medical Center and co-director of the Vanderbilt Lung Screening Program. Dr. Aldrich is assistant professor in the Department of Medicine at Vanderbilt University Medical Center. Dr. Blume is an associate professor in the Department of Biostatistics and Biomedical Informatics at Vanderbilt University Medical Center. This image was reproduced from a study by Lee J et al.1 with permission.

IASLC LUNG CANCER NEWS / APRIL 2020

REPORTS FROM THE IASLC PATHOLOGY COMMITTEE

DIAGNOSTIC D DI I ONCOLOGY PD-L1 Testing for Lung Cancer in 2019: Perspective From the IASLC Pathology Committee By Sylvie Lantuejoul, MD, PhD, and Mari Mino-Kenudson, MD

Immune checkpoint inhibitors (ICI), which target the PD-1/PD-L1 axis with the aim of restoring anti-tumor immunity, are now available in routine clinical practice for the treatment of patients with advanced or metastatic NSCLC and SCLC. Several biomarkers have been reported to predict clinical response, but to date, only PD-L1 expression assessed by immunohistochemistry (IHC) has been validated as a companion or complementary diagnostic to identify patients who are more likely to benefit from those therapies. Because many articles have been published since release of the IASLC Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer,1 the Immune Biomarker Working Group has proposed to the IASLC Pathology Committee to provide updates on the indications of ICIs for lung cancer in 2019 and a state of science review on PD-L1 IHC assays. The aim was to discuss important considerations on PD-L1 IHC, including issues affecting the quality of the testing at pre-analytical, analytical, and postanalytical steps.

Assays: Availability and Interchangeability The first part of the review, written by thoracic oncologists, summarizes the available immunotherapy-based treatment strategies indicated in first-line and second- or later-line treatment of metastatic or locally advanced NSCLC and SCLC as single-agent immunotherapy or in combination with chemotherapy. Subsequently, four commercial PD-L1 IHC assays—22C3, 28-8, SP142, and SP263—are described, and the predictive role and prognostic value of PD-L1 expression evaluated in clinical trials are discussed. Of note, the four assays were codeveloped and evaluated along with a specific PD-1/PD-L1 agent (pembrolizumab, nivolumab, atezolizumab, and durvalumab, respectively) in clinical trials and have been approved as a companion or complementary diagnostic for the corresponding agent. The review addresses the important practical question about whether the combination of chemotherapy plus immunotherapy is better than immunotherapy alone for patients with the PD-L1 tumor proportion score (TPS) of 50% or greater and

emphasizes the importance of PD-L1 testing in determining first-line treatment strategies between pembrolizumab monotherapy and the combination of immunotherapy and chemotherapy after the implementation of the combination therapy for patients with advanced NSCLC. Given the impracticality of laboratories running multiple PD-L1 assays for the corresponding PD-1/PD-L1 agent, the question of comparability and interchangeability of these assays is also addressed and illustrated by a comparison of the different tests available on different platforms. In a nutshell, there have been at least 14 studies comparing the analytical (staining) performance of the four commercial PD-L1 IHC assays; essentially all studies that included the SP142 assay have reported its lower sensitivity in detecting PD-L1 expression in tumor cells and sometimes in immune cells as compared to all other assays (Fig.). Among studies that compared 22C3, 28-8, and SP263 assays, some noted good concordance between all three assays in detecting PD-L1 staining on tumor cells, while others reported the highest level of concordance between 22C3 and 28-8 assays with greater sensitivity of SP263 than those of 22C3 and 28-8 in detecting tumor cell PD-L1 expression. The possible difference in the sensitivity between SP263 and 22C3 may have clinical implications, if SP263 and 22C3 are used to select patients eligible for pembrolizumab and durvalumab therapy, respectively. In addition, because not all laboratories are equipped with the dedicated IHC platforms, many laboratories have set up in-house or laboratory-developed tests (LDTs), which are more affordable than the generally expensive clinical trial‒ validated commercial assays. The review discusses most studies comparing technical performance between LDTs and the commercial assays with clear evidence that the majority of LDTs are equivalent to the commercial assays from an analytical perspective; nevertheless, an adequate validation with an appropriate standard (a commercial assay) as a reference must be carried out before implementation of an LDT.

General Recommendations The review also provides general considerations on pre-analytical steps of the IHC technique, including cold ischemia

Figure. PD-L1 Expression With Four Commercial PD-L1 IHC Assays

An example of solid and acinar type adenocarcinoma stained with Hematoxylin Eosin Saffron stain (A), the 28.8 assay on DAKO platform (B), the 22C3 assay on DAKO platform (C), the SP142 assay on Ventana platform (D) and the SP263 assay on Ventana platform (E). B, C and E shows membranous staining of PD-L1 on >50% of tumor cells (TPS >50%), while scattered immune cells but no tumor cells are positive for PD-L1 in D (TPS<1%). Original magnification x200 for all.

time, quantity and quality of fixative, fixation time, storage conditions, and age of archived unstained sections/blocks as well as sample types. Although the use of cytologic specimens for PD-L1 testing has not been validated in clinical trials, cytology samples may be the only specimen available for PD-L1 testing in many patients with advanced NSCLC. Consequently, multiple studies have looked at the performance of cell blocks and/or other cytology preparations for PD-L1 testing compared to surgical samples and reported high concordance in PD-L1 expression with a 50% cut-off between the two specimen types irrespective of assays used. Appropriate IHC protocols for cytology materials, however, should be first validated and submitted to quality-control measures. If the cytology laboratory offers more than one format (e.g., cyto-spins and cell blocks), the protocols must be developed accordingly with any pretreatment, including antigen-retrieval conditions for multiple fixatives and optimization of dilutions. Further, intratumoral and intertumoral heterogeneity of PD-L1 expression in association with the representativity of small samples such as cytology specimen and biopsies is discussed, and recent data from the literature on the effects of chemoradiotherapy on PD-L1 expression are introduced. The review briefly touches on possible inter- and intraobserver variabilities on PD-L1 assessments, given the semiquantitative nature of assay scoring. It assures the good agreement on PD-L1 tumor cell scoring using

various assays and cut-offs but reveals the poor agreement on immune cell scoring in NSCLC specimens. Last but not least, the review emphasizes the importance of the pathology laboratory’s participation in quality assurance program(s), as well as the importance of the pathologist attending at least one of multiple online or formal hands-on training sessions to improve the quality and reproducibility of PD-L1 testing. Although PD-L1 IHC may not be a perfect biomarker for immunotherapy, it has been implemented in the vast majority of pathology laboratories, and it is widely used by clinicians to identify patients eligible for immunotherapy. Thus, it is important to meet the standard of pre-analytical, analytical, and post-analytical requirements discussed in the review to make PD-L1 IHC as reliable as possible. Appropriate clinical care depends on this. ✦ About the Authors: Dr. Mino-Kenudson is a director of the Pulmonary Pathology Service, Department of Pathology at Massachusetts General Hospital and a professor of pathology at Harvard Medical School. Dr Lantuejoul is a consultant in the Department of Biopathology at the Centre Léon Bérard, Lyon and a professor of biopathology at the Grenoble Alpes University, France. Reference: 1. Tsao MS, Kerr KM, Dacic S, et al. IASLC Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer. iaslc.org/Portals/0/ iaslc_pd-l1_atlas_mar2018_lo-res. pdf?ver=2019-06-06-153849-143. Published 2017. Accessed February 15, 2020.

LUNGCANCERNEWS.ORG / APRIL 2020

Cloud-Based Computerized System from page 11

screening, a cloud system is an effective tool to enhance workflow and reduce cost and inconvenience. Data collected in the system will provide answers to research questions and help to establish future policies in lung cancer screening.

in positive Lung-RADS rates among institutions. Further analyses are being conducted to compare the institutional reading with the retrospective central review.

Challenges and Future Directions

Protecting personal information is a big hurdle in implementing a cloudbased system in Korea. Establishment of Therefore, although this the System system is now parInitially, the K-LUCAS tially integrated into started with a conventhe Korean National tional reading system Cancer Screening (visual assessment Program after the and manual measureK-LUCAS, all data ment at PACS). The are anonymized, and cloud-based computerthe access to the cloud is Dr. Yeol Kim ized system was fully establimited to the correspondlished in November 2018 (Fig.). ing hospital where the participant Because it was the first medical usage of underwent LDCT. Therefore, further a cloud system in a public sector, it took analysis or use of these data for follow up a long time to receive approval from mul- is not possible at the moment. Hopefully tiple departments of the government. this issue will be resolved when this CT data were uploaded to a cloud center system is installed in the National Health through a virtual private network from Insurance Service in a few years. 14 participating hospitals. As soon as With recent advances in artificial intelthe data were uploaded, a CAD program (Visia, MeVis) automatically generated CAD results. Radiologists used a viewer program (AVIEW, Coreline Soft) with a thin-client approach, which provided nodule segmentation, categorization, and reports. Readers could see the CAD results after initial review of CT images and were On February 26, 2020, the Oncologic allowed to modify the segmentation Drugs Advisory Committee, a U.S. results if they were not satisfactory. Final Food and Drug Administration (FDA) decisions were made by radiologists at advisory committee, voted to recomeach hospital, and these results were stored mend approval of combination ramuin the cloud system. In the second year, if cirumab injection and erlotinib for firstsection thickness or radiation dose of CT line therapy for patients with NSCLC scans did not meet the protocol guidelines, and EGFR exon 19 deletions or exon the system posted a red flag in the worklist 21 substitution mutations and NSCLC of the program. based on data from the phase III RELAY trial. The narrow vote of 6-5 reflected Preliminary Results concern regarding lack of proven OS When a survey was conducted among improvement while acknowledging the significant PFS benefit. Also, some participating radiologists, most favored the cloud-based system over a convenconcern was expressed regarding toxtional reading system. After installing icity and the every-2-week infusion the computerized system, an increase in schedule. positive rates of lung cancer screening was In the RELAY trial, 449 patients with noticed. The increased positive rate was metastatic NSCLC and EGFR exon 19 mainly caused by a larger average diameter deletions or exon 21 L858R mutations on a three-dimensional plane in a comwho had not received prior treatment puterized system than an average diamwere randomly assigned to 150 mg of eter on transverse planes in manual meadaily erlotinib plus either 10 mg/kg of surements. Therefore, the measurement ramucirumab or placebo every 2 weeks. plane was modified to orthogonal planes The primary endpoint of investigatorin a computerized system according to the assessed PFS proved superior for the full Fleischner Society recommendations. combination-therapy group (median In the K-LUCAS, a conventional read19.4 months) than the erlotinib/plaing was performed initially, which was cebo group (12.4 months; HR=0.59; replaced by a computerized system. When 95% CI, 0.46-0.76). Median PFS benefit the two systems were compared, the comwas very similar regardless of mutation: puterized system resulted in detection of 19.6 months for patients with exon 19 more nodules while reducing variability

ligence techniques, we expect that the performance of nodule detection and segmentation programs to improve. In addition, smoking-related diseases such as chronic obstructive pulmonary disease and coronary artery disease can also be assessed by emphysema quantification and analysis of coronary artery calcification. By combining data extracted from LDCT, predicting the risk and prognosis of lung cancer will be feasible. â&#x153;Ś About the Authors: Dr. Goo is a professor in the Department of Radiology, Seoul National University Hospital; president of the Korean Society of Imaging Informatics in Medicine; and director of the Institute of Radiation Medicine, Seoul National University Medical Research Center. Dr.

Kim is a board-certified family physician at the Center for Cancer Prevention and Detection and the Smoking Cessation Clinic, Hospital, NCC. Dr. Kim is the principal investigator of K-LUCAS. References: 1. Lee J, Lim J, Kim Y, et al. Development of Protocol for Korean Lung Cancer Screening Project (K-LUCAS) to Evaluate Effectiveness and Feasibility to Implement National Cancer Screening Program. Cancer Res Treat. 2019;51(4):1285-1294. 2. Lee JW, Kim HY, Goo JM, et al. Radiological Report of Pilot Study for the Korean Lung Cancer Screening (K-LUCAS) Project: Feasibility of Implementing Lung Imaging Reporting and Data System. Korean J Radiol. 2018;19(4):803-808. 3. Han DH, Goo JM, Chong S, Ahn MI. Are Lung Imaging Reporting and Data System Categories Clear to Radiologists? A Survey of the Korean Society of Thoracic Radiology Members on Ten Difficult-to-Classify Scenarios. Korean J Radiol. 2017;18(2):402-407.

IASLC Lung Cancer News is online!

LungCancerNews.org

INDUSTRY AND REGULATORY NEWS Approval Expected for Ramucirumab/Erlotinib Combination for NSCLC

deletions and 19.4 months for exon 21 L858R mutations. There were 79 deaths at the time of data cutoff in January 2019, at which time the hazard ratio (HR) for OS was 0.83 (95% CI, 0.53-1.3). After reviewing updated survival data (as of December 31, 2019) in response to a request from the FDA, researchers reported 125 deaths and an HR for OS of 0.92 (95% CI, 0.65-1.32).

Grade-3 or higher adverse events were experienced more often by patients who received the combination therapy (72%) compared with those who received erlotinib/placebo (54%). The most commonly reported adverse event in the combinationtherapy group was hypertension. One treatment-emergent adverse event, also in the combination-therapy group, resulted in death. â&#x153;Ś

IASLC LUNG CANCER NEWS / APRIL 2020

E V O LV I N G S TA N D A R D S O F C A R E

Liquid Biopsy’s Role in Marker Identification: An Interview With Dr. Martin Filipits As we know, molecular marker identification allows for more rational use of existing therapies. When markers can be identified more effectively and quickly, patient care advances. In the following interview, Martin Filipits, PhD, discusses liquid biopsy’s role in marker identification and the downstream effects of its use. Dr. Filipits is a group leader at the Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.

to detection of relapse by radiographic imaging.

be a surrogate marker for drug resistance in the adjuvant setting after complete resection of tumors.

Q: Will this strategy have

a role in detecting new primaries? Or is the Q: Do you envision a time when we shed rate of circulatmight be able to lengthen the period ing tumor-free DNA between routine scans, using abnorin disease confined to Q: In your opinion, mal results on liquid biopsy as a the thorax likely to be is there a future for prompt to order new imaging? too low? PD-L1 expression in A: Imaging intervals may be extended blood as a prognostic or A: Currently, there is no Dr. Martin Filipits based on the results of liquid biopsy. role for liquid biopsy in predictive biomarker? Or detecting new primaries, Patients without detectable ctDNA and do you think that tumor absence of clinical signs of tumor probut this may change in the future. One mutational burden (TMB) and microgression may be selected for longer imaglimitation of this strategy may be the low satellite instability (MSI) in blood will ing intervals. However, this strategy must be the major players as biomarkers for rate of shedding in early-stage NSCLC. Q: To what extent might liquid biopsy be proven and validated within clinical Nevertheless, clinical studies on the role immunotherapy? complement or supplant radiographic trials before it can be recommended for A: PD-L1 expression in tissue assessed of liquid biopsy for early detection of imaging in the detection of early recurimplementation in clinical routine. by immunohistochemistry is simple, new primaries are warranted. rence of definitively treated NSCLC? fast, inexpensive, and it is already used in A: At present, liquid biopsy can only Q: Are there any roles of liquid biopsy everyday clinical practice in many coun- Q: Are there differences in the complement but not replace radio- in the prediction of chemotherapy tries based on the approval of immuno- various platforms and panels curgraphic imaging in the detection of efficacy or toxicity? therapies. Currently, tissue-based PD-L1 rently available? early recurrence in operable expression is studied at the RNA level by A: There may be differences in the NSCLC. However, the assess- LIQUID BIOPSY EXPERT VOICES polymerase chain reaction testing, but it is platforms and panels. For example, ment of minimal residual unclear whether PD-L1 at the RNA level the most commonly used sequencing disease by the detection of circulating A: The presence of ctDNA after surgery is more accurate or a better biomarker platforms are currently provided by tumor DNA (ctDNA) is very promis- is a powerful prognostic factor in several than immunohistochemistry. I don’t see a Ion Torrent and Illumina. Ion Torrent ing. In a publication by Chaudhuri et solid tumors, including NSCLC. Whether future for PD-L1 expression in blood, but uses pH measurements to read nucleoal., post-surgical detection of ctDNA liquid biopsy is also a predictive marker there will be other blood-based biomark- tide sequences, whereas Illumina uses a ers. Blood-based TMB is feasible and was fluorescence-based strategy for reading correlated with relapse and preceded the for chemotherapy or immunotherapy effiradiologic detection by a median of 5.2 cacy has to be determined in appropriate recently shown by Gandara et al. to pre- the bases in a nucleotide sequence. In months in 72% of patients.1 It remains to clinical trials. Circulating tumor DNA dict atezolizumab benefit.2 These findings addition to the difference in sequencbe seen, however, whether early detec- may be an important marker for resisare interesting but require further studies ing technology, there are differences in tion of relapse by liquid biopsy will tant disease. Determination of residual before blood-based TMB or MSI can be type of data generation, the error rates, and the reproducibility. Therefore, both prolong survival of patients compared disease after adjuvant chemotherapy may recommended for clinical routine use. internal as well as external validation is of critical importance before implementation in everyday clinical practice. In particular, the analytical validity, the clinical validity, and the clinical utility of each method must be assessed in suitable studies. Professor Jean-Charles Soria has Fabrice Barlesi as medical Research Directorate. Prof. Barlesi director of the institute. been appointed general direccoordinated the French Thoracic Q: What is the optimal frequency of An associate editor for tor of Gustave Roussy for a Intergroup (IFCT) Biomarkers liquid biopsy in its monitoring of term of 5 years. A medithe IASLC Lung Cancer France study, which, with more than targeted therapy? News, Prof. Barlesi is cal oncologist and profes18,000 patients, is still one of the A: Several trials in patients with advanced professor of medicine sor of medicine at Parislargest molecular profiling study on EGFR-mutated NSCLC have shown that at the University of AixSaclay University, Prof. patients with lung cancer. He is also treatment monitoring using liquid biopsy Soria was the director of Marseille and was the head coordinating the PIONeeR project, is feasible and clinically meaningful. I Jean-Charles the Gustave-Roussy SIRIC ProfessorSoria of the Multidisciplinary a €25 million-project dedicated to would suggest liquid biopsy before the Socrate (Integrated Cancer Oncology and the understanding and bypass start of treatment, 6 to 12 weeks after Research Site) between 2012 and 2017. Innovative Therapies departof resistances to PD-(L)1 treatment initiation, and thereafter every Since September 2017, Prof. Soria was ment and the Marseille inhibitors in patients with 3 months until clinical progression. This responsible for novel research and prod- Centre for Early Trials in lung cancer. strategy, however, requires confirmation within clinical trials. ✦ uct development in immuno-oncology, Oncology at the Assistance Profs. Soria and cell therapy, and conjugated antibod- Publique Hôpitaux de Barlesi worked together References: ies for AstraZeneca as vice president, Marseille. In addition, he at the French Thoracic 1. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early Detection of Molecular Residual Disease Research & Development in Oncology. is the co-founder of the Intergroup (IFCT), where in Localized Lung Cancer by Circulating Tumor Prof. Soria also studied health manage- Marseille Immunopole, a Professor Fabrice Barlesi they developed and conDNA Profiling. Cancer Discov. 2017;7(12):1394ment at the Harvard Business School in French Immunology netducted several trials 1403. 2. Gandara DR1, Paul SM2, Kowanetz M, et al. 2017-2018. work, and he previously served as the together, with the last one—the preciBlood-based tumor mutational burden as a preOne of Prof. Soria’s first actions in vice-chair of the Provence, Alps and sion medicine SAFIR02 lung trial—to dictor of clinical benefit in non-small-cell lung his new role was to appoint Professor Côte d’Azur (PACA) Region Cancer be presented this year. ✦ cancer patients treated with atezolizumab. Nat

Names and News

Gustave Roussy’s New Leadership

Med. 2018;24(9):1441-1448.

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Time to End the Debate on Genomic Testing in NSCLC broad genomic testing have these assays routinely done, which is infrequent.12 It’s an exciting time to be a thoracic oncol- Outside of the United States, testing rates ogist. We live in an era of unprecedented are highly variable but likely either similar discovery in medicine—and in oncol- to the United States, in the best cases, or ogy in particular—with basic scientific considerably lower in others.13 breakthroughs such as targetable In part, this has to do with how testing is done and driver oncogenes translathow it is reimbursed. ing into highly effective Initial testing for treatments for patients genetic markers in in record time. In my relatively short career, NSCLC was done I have seen treatments with single-gene tests change the lives of (SGT) such as PCR or FISH, and those tests patients whose tumors harbor EGFR mutations,1 have been reimbursed Dr. Nathan Pennell followed later by ALK gene by insurance for some time. fusions2 and then in short However, each test uses up order ROS1 gene fusions3 and BRAF valuable tissue and takes time, especially V600E mutations.4 Although a decade or if done sequentially (waiting for results so ago, median survival for patients with before the next test is ordered), and each advanced NSCLC was less than 1 year,5 for test has a cost. One study found that the first time in my career, I can now tell while one SGT was successful in 88% of some patients that their expected median biopsies, any subsequent test had a signifsurvival with targeted drugs may be num- icantly lower rate of success due to tissue bered in multiples of years.6 And these exhaustion. By the fourth recommended were just the first wave of driver onco- test (the minimum recommended today), genes, with effective therapies emerging only 53% could be successfully tested.14 in trials for patients whose tumors harbor How well can this strategy work when we NTRK fusions, RET fusions, MET exon 14 have six, nine, or more tests to perform? mutations, HER2 mutations, and perhaps A much more elegant solution is a muleven KRAS G12C mutations.7,8 tiplexed assay that can examine all the What do all of these examples have in targets of interest at once—both current common? They all rely on biomarker test- as well as emerging targets—most coming of tumor biopsies to identify the salient monly using next-generation sequencgenetic alteration before the patient can ing (NGS). This is, in fact, the recomreceive treatment. This type of universal mended strategy already in the College testing has been automatic and widely of American Pathologists/IASLC/ accepted in other diseases like breast Association for Molecular Pathology cancer and hematologic malignancies for a Guidelines.10 Clearly, NGS testing is long time, but for some reason, there is still the most efficient use of tissue, but how debate about the value of testing for lung does it compare to SGTs on cost? In other cancer. It is time to put this debate to rest. words, would it cost more to do multiple tests, each individually less expensive Finding Elegant Solutions than NGS, than to do a single test for The era of biomarker testing for NSCLC all required markers but that costs more began with EGFR mutation testing, rec- than the SGT? And how does this affect ommended by the American Society of turnaround time and success rates? Clinical Oncology in 2011.9 Guidelines We looked at this by constructing a now recommend routine testing at model from a payers’ perspective comdiagnosis of all patients with nonsqua- paring the cost and turnaround time mous NSCLC for EGFR, ALK, ROS1, (TAT) of NGS to multiple simultaneous and BRAF, at a minimum.10 There have and sequential SGT strategies. The model been some successes, as the limited data indicated that for the four current recomon testing rates suggest that by 2018, the mended markers, NGS testing was both majority (87%) of eligible patients in the less costly and faster than any strategy United States were being tested for EGFR. that used single-gene tests, and perhaps However, when we get beyond EGFR, test- most importantly, it identified the highing rates are much less impressive, with est percentage of patients with targetable even ALK testing coming in at only 69%.11 findings.15 A separate recent analysis Approved treatments for ROS1- and comparing multiplexed testing to SGTs in BRAF-positive NSCLC have been avail- NSCLC was able to show improved costable since 2016 and 2017, respectively, but effectiveness with this strategy as well.16 the data suggest that only patients getting This imbalance will only become more By Nathan Pennell, MD, PhD

marked as we move to use an increasing number of markers, and these results are starting to be reflected into better payer coverage for NGS testing, although this is still far from settled.13 It is past time to stop debating the utility and value of broad genomic testing for patients with NSCLC and to move to improving routine implementation. Although there are meaningful debates to be had about the utility of extending broad NGS testing for all patients with cancer,17 this simply doesn’t apply to lung cancer. Although each of the current and emerging targets in NSCLC is rare individually (1% to 15% of cases), when combined, an “actionable” target should be present in up to 45% to 50% of patients. There is still much work to do in making testing widely available, accurate, and timely as well as convincing payers that it is necessary. Let’s roll up our sleeves and get to work. ✦ About the Author: Dr. Pennell is director of the Lung Cancer Medical Oncology Program at the Cleveland Clinic Taussig Cancer Institute and an assistant professor of Medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. References: 1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmall-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-2139. 2. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALKpositive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011-1019. 3. Shaw AT, Solomon BJ. Crizotinib in ROS1rearranged non-small-cell lung cancer. N Engl J Med. 2015;372(7):683-684. 4. Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984-993. 5. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-98. 6. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2019 Nov 21. [Epub ahead of print]. 7. Valentino F, Borra G, Allione P, et al. Emerging targets in advanced non-small-cell lung cancer. Future Oncol. 2018;14(13s):61-72. 8. Molina-Arcas M, Moore C, Rana S, et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019;11(510):pii: eaaw7999. 9. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients With Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 29(15):2121-2127 10. Lindeman NI, Cagle PT, Aisner DL, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of

Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323-358. 11. in the Molecular Diagnosis of Lung Cancer: Results from an Online Market Research Survey. Friends of Cancer Research. focr.org/publications/trends-molecular-diagnosis-lung-cancerresults-online-market-research-survey. Accessed December 7, 2019. 12. Presley CJ, Tang D, Soulos PR, et al. Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non– Small Cell Lung Cancer in the Community Oncology SettingBroad-Based Genomic Sequencing and Survival in Advanced Non– Small Cell Lung CancerBroad-Based Genomic Sequencing and Survival in Advanced Non–Small Cell Lung Cancer. JAMA. 2018;320(5):469-477. 13. Pennell NA, Arcila ME, Gandara DR, et al. Biomarker Testing for Patients With Advanced Non-Small Cell Lung Cancer: Real-World Issues and Tough Choices. Am Soc Clin Oncol Educ Book. 2019;39:531-542. 14. Yu TM, Morrison C, Gold EJ, et al. Multiple Biomarker Testing Tissue Consumption and Completion Rates With Single-gene Tests and Investigational Use of Oncomine Dx Target Test for Advanced Non-Small-cell Lung Cancer: A Single-center Analysis. Clin Lung Cancer. 2019;20(1):20-29. 15. Pennell NA, Mutebi A, Zhou ZY, et al. Economic impact of next generation sequencing vs sequential single-gene testing modalities to detect genomic alterations in metastatic non-small cell lung cancer using a decision analytic model. J Clin Oncol. 2018;36(Suppl. 15):9031-9031. 16. Steuten L, Goulart B, Meropol NJ, et al. Cost Effectiveness of Multigene Panel Sequencing for Patients With Advanced Non–Small-Cell Lung Cancer. JCO Clin Cancer Inform. 2019;1-10. 17. Marquart J, Chen EY, Prasad V. Estimation of the Percentage of US Patients With Cancer Who Benefit From Genome-Driven Oncology. JAMA Oncol. 2018;4(8):1093-1098.

INDUSTRY AND REGULATORY NEWS FDA Issues Two Priority Reviews On February 17, 2020, the US Food and Drug Administration (FDA) granted a priority review designation for lurbinectedin’s new drug application (NDA). The NDA is for treatment of patients with SCLC and progression after a platinum-based therapy and was based on data presented at the 2019 American Society of Clinical Oncology Annual Meeting. A Prescription Drug User Free Act (PDUFA) target action date has been set as August 16, 2020. Earlier in the year, the FDA granted priority review to the supplemental biologics license application for nivolumab and ipilimumab for firstline treatment of metastatic or recurrent NSCLC for patients with wildtype EGFR or ALK. The application was partially based on data from CheckMate-227. The PDUFA target action date is May 15, 2020. ✦

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