IASLC Lung Cancer News: V5, N1

U.S. EDITION

LUNG CANCER

V5 / N1 / FEBRUARY 2020

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

INSIDE 3

Smoking Ban in Austria Passed After Years of Political Wrangling

5

Increasing the Role of Local Consolidation in Oncogenic-Driven Advanced NSCLC

6

TRK Inhibition in TRK Fusion–Positive Lung Cancers

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Multidisciplinary Teams at AUSL Romagna

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Palliative Care in China

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Dr. Chandra P. Belani Named New CSO for the IASLC

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Educating Non-Oncology Providers About the Management of Immunotherapy AEs

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CheckMate 568: Efficacy and Biomarker Analysis for Nivolumab and Ipilimumab in NSCLC

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TMB: Evolution of a Controversial Biomarker From the Pathologist’s Perspective

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Treating Patients with MET Alterations: A Q&A with Dr. Ravi Salgia

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Lung Cancer Surveillance After Definitive Curative-Intent Therapy: A Q&A With Dr. Edgardo S. Santos Castillero

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 S M O K I N G C E S S AT I O N & T O B A C C O C O N T R O L

Déjà Vu, With a Twist: The Vaping Industry’s Approach to Youth-Oriented Advertising Via Social Media As of early December 2019, the Centers for Disease Control and Prevention (CDC) have received reports from all 50 states, Puerto Rico, the U.S. Virgin Islands, and the District of Columbia comprising 2,291 individuals who were hospitalized for acute lung injury caused by vaping.1 Of these patients, many of whom are teenagers or young adults, 48 have died.

Lisa Fucito, PhD, associate professor of Psychiatry and director of the Tobacco Treatment Service Smilow Cancer Hospital at Yale-New Haven, spoke with the IASLC Lung Cancer News about the recent advent of e-cigarette/vapingassociated lung injury (EVALI), as well as about how e-cigarette/vaping companies have learned much more quickly than healthcare providers how to influence substance habits of youth. Dr. Fucito’s current research includes a randomized clinical trial (RCT) of tobacco cessation tools for individuals undergoing lung

cancer screening, implementation of a statewide tobacco treatment program for patients treated through the Yale Cancer Center care network, and an RCT of a novel mobile alcohol prevention program for young adults.

She discusses sensitive approaches to communication between healthcare professionals and patients with lung cancer regarding e-cigarette use.

Q: Is e-cigarette/vaping use an epidemic among youth?

A: Well, it’s important to think about how we define an epidemic. Typically when we’ve thought about an epidemic, we think about a very rapid spread of an infectious disease to a large number

of people. I think the rapid increase in e-cigarette use follows a pattern similar to an epidemic when solely looking at time. continued on page 3

IMMUNOTHERAPY

Ongoing Immunotherapy Challenges Part II: Defining Benefit for Elderly Patients With NSCLC

By Valérie Gounant, MD, and Elisabeth Quoix, MD, PhD

The advent of targeted therapies and immune checkpoint inhibitors (ICIs) was a major turning point in the management of advanced NSCLC. As mentioned in Part I of this series, the U.S. Food and Drug Administration (FDA) approvals of atezolizumab, nivolumab, and pembrolizumab were major breakthroughs in patient care for most, but use of these therapies in special populations remains challenging. The approvals for all three agents were based on the results of phase III clinical trials, in which very old patients were seldom included despite there being no upper age limit for eligibility.

Elderly patients are frequently included in special populations, although patients 70 years of age and older constitute 50% of all the patients with metastatic NSCLC, and those aged 75 years and older represent 30%.

Some theoretical arguments exist against the use of ICIs in elderly patients, especially the concept of immunosenescence.1 Immunosenescence may be one of the main explanations for the increased incidence of cancer with age and may affect the efficacy and toxicity of anticancer treatments. There is a highly dynamic remodeling of all of the immune functions as we age, with a decrease in the size of the thymus, and in the capacity of the bone marrow, lymph nodes, and spleen. Chronic antigenic stimulation

This article is the second in a two-part series on ongoing challenges using immunotherapy in special populations. The first part, which focused on patients with poor performance status, ran in the December issue and is available online at lungcancernews.org. during life is responsible for the transformation of naive T lymphocytes into memory cells; thus, there is a reduction of the antigenic diversity of immune cells with age, and the immune system of elderly people is less able to neutralize new antigens. Proliferation, but not the function, of T cells also decreases with

age. Costimulatory molecules (CD28 and CD27) on T-lymphocytes are also reduced. B-lymphocytes are also modified with age, resulting in less production of antibodies with high affinity and specificity for antigens. On the other hand, secretion of auto-antibodies and pro-inflammatory cytokines is increased, leading to a state of low-grade chronic inflammation called “inflammaging.”

Besides these modifications of adaptive immunity, immunosenescence also has an effect on innate immune response.

Antigen-presenting cells have reduced ability to process antigens and have less expression of Toll-like receptors.

Each of the second-line phase III trials comparing the ICIs (nivolumab,2,3 pemcontinued on page 4

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Youth-Oriented Advertising from page 1

Between 2011 and 2015, e-cigarette use

by U.S. middle and high school students increased by 900%. That’s an astronomical figure. Currently, the acute lung injuries, or EVALI, that are being seen across the country feel very much akin to an epidemic. Although reports of EVALI are slowing, there was an extremely rapid increase over the span of just a few months starting in June 2019, some of which resulted in the deaths of otherwise healthy adults, young adults, and teens.

Q: How do you explain such a large uptake of e-cigarette/vaping use by youth seen in such a short period of time?

A: There are a number of contributing factors, such as the ability to use very youth-friendly flavors (candy or fruit) with these devices. Most youth who begin using e-cigarettes report that they start with a flavored product and that the flavor itself was a key reason they tried the product.1 I mentioned previously that there was a steep rise in e-cigarette use between 2011 and 2015, but then there was actually a dip between 2015 and 2017. In 2017, however, a new nicotine-based derivative product (i.e., Juul) came onto the market.

These products use a salt-solution–based form of nicotine that allows the user to reach peak nicotine levels that are similar to those achieved by combustible

cigarettes. These newer popular with young people: products are pretty Instagram, YouTube, and discreet to use; they Twitter versus Facebook. are very small, look Young adult influencers like a computer flash were also paid thoudrive, and don’t prosands of dollars a month duce as much vapor to vape and review or smell. Teens have devices on YouTube, a site anecdotally reported frequented more by youth Dr. Lisa Fucito that a lot of teachers did than adults. Thus, youth may not even realize that these experience greater exposure to e-cigarette/vaping marketing and devices were being used in schools because they were that discreet. So in content.

2017, again, there was another sharp Youth may also be more vulnerable to increase in usage, with e-cigarette/ misleading marketing/information than vaping increasing by 78% among U.S. adults. Many vaping-related websites and high school students. social media sites, where young people Throughout this entire time period, tend to get their product-related informathese products were promoted on social tion, do not report complete information media platforms, like Instagram and about vaping such as the recent vapingTwitter, to influence youth behavior. related injuries.

E-cigarette manufacturers used attractive, young models to pitch their products Q: If tobacco-related information is on social media and hosted live events regulated in advertising and marketing, where free samples were made available why are there no regulations around to youth. So it was the combination of e-cigarette/vaping-related information? easy access, youth-friendly marketing A: Tobacco companies are no longer practices, and flavors that really drove permitted to use the advertising tricks their uptake by so many. that they previously used, such as youth-friendly characters like Joe Camel, Q: Does social-media marketing/ because they encourage young people to initiate smoking. content influence adults and youth in the same ways?

Some e-cigarette/vaping product A: Young people tend to use different manufacturers are in fact owned by the forms of social media than adults/older tobacco companies, and there has been adults. E-cigarette/vaping advertissome backlash regarding manufacturer advertising tactics. For example, Juul got ing occurred more frequently on sites

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into a lot of trouble for pitching products directly to youth on social media.

However, even if Juul is no longer permitted to advertise directly on social media, the problem is not solved. Socialmedia influencers—individuals with thousands or millions of followers—can adopt a product and market that product through positive reviews or even just usage. Companies no longer have to invest in advertising campaigns for products. Currently, there is no way to regulate that kind of third-party marketing. Due to social media, I think we have entered a totally different landscape now in terms of advertising and how to regulate it.

Q: What is the current status regarding investigations of EVALI cases?

A: Following these cases, the CDC conducted extensive investigations in collaboration with the U.S. Food and Drug Administration (FDA) and state and local health officials. On December 20, 2019, the CDC concluded that vitamin E acetate, an additive in some THC-containing e-cigarettes, was closely associated with EVALI. Although vitamin E acetate appears to be associated with EVALI, the CDC cautioned that they are investigating other substances and product sources.

All of the individuals with EVALI have reported a history of using e-cigarettes or vaping products. THC, an active ingredient in marijuana, was present in the product samples that the CDC tested, and continued on page 5

INDUSTRY AND REGULATORY NEWS Smoking Ban in Austria Passed After Years of Political Wrangling November 1, 2019—After years of political volleying and public outcry, Austria implemented a full indoor smoking ban in bars, cafes, and restaurants. With its capitol, Vienna, consistently being voted “the most livable city in the world” according to an index compiled by the Economist Intelligence Unit,1 the decrease in Austria’s smoking rates still lagged far behind the rest of Europe. As of 2014, rates for adults (aged 15 or older) who smoked daily were comparable with rates in 1997 (24%) and increased slightly since 2006 (23%). These rates can be contrasted with the marked decline seen in 93% of Organization for Economic Cooperation and Development countries during the same time period; on average, smoking rates decreased from 26% in 2000 to 19% in 2014.2 As the IASLC Lung Cancer News reported in August 2018, the new ruling coalition in Austria, the far-right People’s Party and the Freedom Party, reversed this same ban in May 2018, arguing that it was an example of excess interference from the government and that it restricted the people’s freedom of choice. During the election campaign, party leader Heinz-Christian Strache, an avid smoker, promised a reversal of the ban.3 After the election, Strache made this a non-negotiable condition for entering a coalition government with the conservative People’s Party. People’s Party leader Chancellor Kurz, a nonsmoker who supported tobacco control prior to the election, accepted this demand to form a functioning government.

In retaliation to this political move, more than 900,000 signatures (out of 8.8 million residents in Austria) were captured on a petition. To strengthen the petition, lawsuits were filed in Austria’s institutional court in June 2018 by inn-keepers, waiters, and the government of Vienna against the cancellation of the smoke-free

hospitality industry policy. The Ministry of Health then drafted an ordinance to limit exposure in smoking sections for underage trainees to no more than 1 hour per day. Guidance for enforcement of this ordinance was not provided, however.

The coalition government fell apart in May 2019 shortly after a scandal, and the interim government passed the long-awaited ban. ✦ References: 1. The Economist. Global Livability Index. http://www.eiu.com/topic/liveability?zid=liveability2019&utm_ source=economist-daily-chart&utm_medium=link&utm_name=liveability2019. Accessed December 21, 2019.

2. Karasz P. Austria’s Far Right Wants the Freedom to Smoke. The New York Times. March 18, 2018. nytimes.com/2018/03/18/world/europe/austria-smoking-ban.html. Accessed May 5, 2018.

3. Organisation for Economic Co-operation and Development. OECD Health Policy Overview: Healthy Policy in Austria. https://www.oecd.org/els/health-systems/Health-Policy-in-Austria-March-2017.pdf.

Published March 2017. Accessed December 21, 2019.

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IASLC LUNG CANCER NEWS / FEBRUARY 2020

Tumor-Agnostic Targeted Therapies the very oldest enrollees on these studies were not numerous and probably highly brolizumab,4 atezolizumab,5 and ave- selected, as they were obviously underlumab)6 to docetaxel had no upper limit represented based on demographic data. of age for inclusion, but were restricted to Regarding first-line therapy with PS 0 or 1 patients. In these trials, which ICIs, either given as a monotherapy in all favored immunotherapy over che- patients with a PD-L1 tumor propormotherapy with respect to OS (with the tion score of > 50%,9 or in association exception of the JAVELIN trial testing with chemotherapy,10 or chemotherapy avelumab), there was no dilution of the and bevacizumab,11 the definitive phase survival benefit when the cutoff was set at II and III trials featured no upper age age 65 years. However, with age 75 as the limit with respect to enrollment. In cutoff, there was no significant OS ben- KEYNOTE 024, which compared pemefit with immunotherapy in any of these brolizumab to standard chemotherapy, trials (Table 1). Of note, the percent- and in KEYNOTE 189, which compared age of patients 75 and older was pembrolizumab in combination with chemotherapy only 7%-10% of all patients enrolled; thus, definite to chemotherapy alone, conclusions cannot be each of which showed drawn regarding very a survival benefit old patients given overall, age had little their under-represenbearing on outcome. tation on these trials A significant survival and wide confidence benefit was observed intervals. The FDA crein both trials in favor Dr. Valérie Gounant ated a pooled analysis of the pembrolizumab of the survival of the 2,824 arm. With a cutoff of age 65, patients included in four there was no difference in trials comparing ICIs the treatment effect for to docetaxel. 7 These the pembrolizumab trials included three arm compared to of the trials already chemotherapy or for discussed2,4,5 as well as the pembrolizumab plus chemotherapy the POPLAR phase II arm compared to randomized trial comparing atezolizumab to chemotherapy alone.

Prof. Elisabeth Quoix Regarding the trial comdocetaxel.8 They found that paring carboplatin plus the treatment effects were similar across most age groups using paclitaxel plus bevacizumab to the same both unadjusted and adjusted HRs. In combination plus atezolizumab, a signifparticular, the upper bound of the 95% icant PFS and OS benefit was observed confidence intervals fell below 1 for regardless of PD-L1 expression. Of the patients aged 65 and older as well as for total patients included in this trial, those aged 70 and older, but this was not 9.75% were aged 75 and older, but there the case for patients aged 75 and older was no analysis of the results according (Table 1). Median survival time ranged to age. A meta-analysis of all randombetween 14.1 months and 14.7 months ized trials comparing chemotherapy to for those receiving PD-1‒ and PD-L1‒ immunotherapy or chemotherapy plus blocking antibodies versus 8.8 months immunotherapy to chemotherapy alone and 9.5 months in the docetaxel “con- was recently published12; it confirmed a trol” groups across the various age cat- PFS and survival gain in favor of immuegories. Regarding adverse events in the notherapy. Using an age cutoff of 65 anti‒PD-1/‒PD-L1 arms, the incidence years, there was no significant difference of grade 3 to 4 adverse events appeared in the magnitude of benefit between the lower in patients aged 75 and older at two age categories, as expected.

23%, compared to 49% of those aged 65 A French Cooperative Thoracic and older, and 47% of those younger than Intergroup clinical trial for patients with 65 years. Grade 5 toxicities were observed metastatic NSCLC between the ages of 70 in 5%, 7%, and 4% of the patients, respec- and 90 is currently recruiting. The trial tively. Similarly, there was no significant compares chemotherapy with monthly difference regarding adverse events of carboplatin and weekly paclitaxel to the special interest (colitis, hepatitis, pneu- combination of this chemotherapy with monia, and hypothyroidism/elevated atezolizumab (NCT03977194), and it will TSH) across each age groups. Thus, hopefully provide a definitive, prospecno signal of heightened toxicity was tive answer regarding the feasibility and observed in patients aged 75 and older, utility of combined immunotherapy and although one must take into account that chemotherapy in elderly patients. ✦

from page 1

Table 1. Overall Survival in Second-Line Phase III Trials Comparing Immunotherapy to Docetaxel Study

Age subgroup

Number of patients

HR (95% CI) ICI vs doc

Nivo vs. doc non-squamous cell2

All patients < 65 ≥ 65 to < 75 ≥ 75

582 339 200 43

0.73 (0.59-0.89) 0.81 (0.62-1.04) 0.63 (0.45-0.89) 0.90 (0.43-1.87)

Nivo vs. doc squamous cell3

All patients <65 ≥ 65 to 75 ≥ 75

272 152 91 29

0.59 (0.44-0.79) 0.52 (0.35-0.75) 0.56 (0.34-0.91) 1.85 (0.76-4.51)

Pembro vs. doc4

All patients < 65 ≥ 65

1,033 604 429

0.67 (0.56-0.8) 0.63 (0.5-0.79) 0.76 (0.57-1.02)

Atezo vs. doc5

All patients < 65 ≥ 65

850 453 397

0.73 (0.62-0.87) 0.80 (0.64-1.00) 0.66 (0.52-0.83)

FDA analyses7

All patients < 65 ≥ 65 ≥ 70 ≥ 75

2,824 1,620 1,204 540 360

0.68 (0.63-0.76) 0.71 (0.63-0.80) 0.66 (0.57-0.76) 0.67 (0.55-0.82) 0.81 (0.58-1.13)

Abbreviations: HR, hazard ratio; ICI, immune checkpoint inhibitor; doc, docetaxel; nivo, nivolumab; pembro, pembrolizumab; atezo, atezolizumab; FDA, U.S. Food and Drug Administration.

About the Authors: Dr. Gounant is with the Thoracic Oncology Department, Hôpital Bichat, APHP, France. Prof. Quoix is with the Department of Pneumology, University Hospital of Strasbourg, France.

References: 1. Ferrara R, Mezquita L, Auclin E, Chaput N, Besse B. Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter? Cancer Treat Rev. 2017;60:60-68.

2. 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.

3. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-135.

4. Herbst RS, Baas P, Kim D-W, et al.

Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550.

5. Rittmeyer A, Barlesi F, Waterkamp D, et al.

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet.

2017;389(10066):255-265.

6. Barlesi F, Vansteenkiste J, Spigel D, et al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol. 2018;19(11):1468-1479.

7. Marur S, Singh H, Mishra-Kalyani P, et al. FDA analyses of survival in older adults with metastatic non-small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies. Semin Oncol. 2018;45(4):220-225.

8. Fehrenbacher L, Spira A, Ballinger M, et al.

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.

9. Reck M, Rodriguez-Abreu D, Robinson AG, et al.

Pembrolizumab versus Chemotherapy for PD-L1Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-1833.

10. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al.

Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-2092.

11. Socinski MA, Jotte RM, Cappuzzo F, et al.

Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301.

12. Liu T, Ding S, Dang J, Wang H, Chen J Li G. First-line immune checkpoint inhibitors for advanced non-small cell lung cancer with wildtype epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK): a systematic review and network meta-analysis. J Thorac Dis. 2019;11(7):2899-2912.

INDUSTRY AND REGULATORY NEWS New First-Line Treatment ent for Metastatic Nonsquamous NSCLC December 4, 2019—Indications for atezolizumab have been expanded to include its use in combination with chemotherapy for the first-line treatment of adults with EGFR/ALK wildtype metastatic nonsquamous NSCLC. This approval was based on data from the phase III IMpower130 study in the intention-to-treat wild-type population, which demonstrated an improved median OS for atezolizumab plus chemotherapy vs chemotherapy alone (18.6 vs 13.9 months, respectively; HR = 0.80; 95% CI = 0.64–0.99; p = 0.04). Progression-free survival and risk of death were also improved (median PFS = 7.2 vs 6.5 months; HR = 0.75; 95% CI = 0.63–0.91; p = 0.002).

No new safety signals for the agent were identified in the trial, with 73.2% of patients who received the agent experiencing grade 3/4 adverse events compared with 60.0% of patients who received chemotherapy alone.

Atezolizumab is already approved as first-line therapy for metastatic nonsquamous NSCLC in combination with bevacizumab, paclitaxel, and carboplatin. It is also approved as a first-line therapy for patients with extensive-stage SCLC when combined with chemotherapy. ✦

LUNGCANCERNEWS.ORG / FEBRUARY 2020

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

Increasing the Role of Local Consolidation in Oncogenic-Driven Advanced NSCLC

By Youquan Li, MD, FRCR, and Andrea Bezjak, MDCM, MSc, FRCPC

Targeted agents including TKIs of EGFR, ALK, and ROS1 have significantly improved the outcomes of advanced oncogene-driven NSCLC. 1,2 Despite initial high response rates, durable and complete responses are rare, and most patients eventually experience treatment failure.3 Residual disease is defined as a population of tumor cells within a mostly therapy-sensitive tumor that survives the first wave of targeted therapy and regrows, eventually leading to treatment failure and tumor progression.4 Intra-tumor heterogeneity, tumor cell evolution during treatment, and pharmacokinetic failure are the main mechanisms of residual disease.4,5 Approximately 60% of patients develop first clinical failure at the initial sites of disease.6,7 Liquid biopsy results suggest that treatment failure develops before radiologic progression is seen.8

Targeting Residual Disease Different strategies can be used to enhance the clinical response of targeted therapy. Upfront next-generation TKIs and polytherapy combining TKIs with anti-VEGF or cytotoxic chemotherapy have shown superior results in recent phase III studies.9,10 However, these approaches are limited by cost, accessi-

Youth-Oriented Advertising from page 3

most of the sickened patients reported a history of vaping THC-containing products.

The other established element about these products, particularly those that contained THC, is that they were obtained off the street or from informal sources—illicit dealers and family or friends. In addition, products that people were able to modify are also suspected as contributory. Some vaping devices are closed systems that use complementary nicotine-containing pods. Other devices, however, have a more open system that allows for modifications.

The CDC website for EVALI has information for healthcare providers as to how to establish, document, and report toxic cases of EVALI to local/state health departments and the CDC.2 Statistics and information are updated every week.

Q: Knowing what we do about e-cigarettes, should they be used for cessation,

bility of novel drugs, and toxicities related to combined treatment.

Local consolidation with cytoreductive surgery or radiation is another strategy to target residual tumors and improve patient outcomes. Recent randomized trials have increasingly provided evidence that this strategy works for oligometastatic lung cancer and for several other cancers such as oligometastatic renal cell carcinoma11 and prostate cancer.12 In oligometastatic NSCLC, two “proof of concept” phase II studies haves shown that local consolidative therapy tripled progression-free survival (PFS) compared with observation in the preimmunotherapy era.13,14 Gomez et al. updated survival data recently, and showed that local consolidation could lead to a significant OS benefit (median OS 41.2 months in the consolidation arm versus 17.0 months in the observation arm).15 However, both studies had either no or few patients with EGFRpositive NSCLC, which has distinct biologic behavior and treatment options.

Another recent phase II study targeting metabolic residual disease after TKIs with stereotactic ablative body radiation (SABR) has shown that adding local therapy achieves an encouraging 1-year PFS of 62.5%.16 Such a strategy of early consolidation, targeting residual disease in oligometastatic NSCLC with radiation (or

surgery) after initial response on TKIs, targets in different organs is expanding could potentially overcome the quickly, there is a paucity of proabove-described biologic spective evidence regarding resistance mechanisms. the safety of concurrent Early consolidation TKIs and SABR versus requires increased the potential risk of collaboration among progression when medical oncologists, withholding TKIs. radiation oncologists, For locally advanced and thoracic surgeons.

NSCLC, the safety It also creates unique data of concurrent Dr. Youquan Li opportunities to underTKIs with conventional stand the biology of residual fractionated thoracic radiation are mixed, with grade disease and to generate 3 to 5 toxicities as high more patient-derived as 37.5% in some small models to investigate the mechanisms of cohorts, 18 whereas other studies suggest acquired resistance.

Liquid biopsy includno increase in risk. ing circulating tumor The optimal concells or ctDNA and solidative option, genomic analysis could especially for intrathoDr. Andrea Bezjak become potential biomarkracic disease, mandates ers to select patients with multidisciplinary collabooligometastatic disease who are likely ration among medical and radiation to benefit from aggressive local therapy. oncologists and thoracic surgeons to However, many important questions individualize treatment decisions. From remain to be addressed in prospective the radiation oncologists’ perspectives, studies before proceeding further. Safety target volume for consolidative thoracic of treatment has to be prioritized in the radiation will focus on residual disease setting of local consolidation. Of note, instead of attempting to include prethere was a small treatment-related therapy volume. “Ablative” SABR, modmortality (4.5%) in the recent SABR erate hypofractionation, or conventional COMET trial.17 Although the practice of fractionation radiotherapy are considSABR or high-dose radiation to multiple continued on page 10

or are they creating more addiction?

A: In our tobacco cessation program, we recommend that patients first use FDAapproved tools and counseling strategies.

Even if they have tried these products in the past, we encourage them to try them again with the added benefit of additional, regular support from our program.

We remind them that sometimes it takes several attempts before an individual can achieve long-term abstinence. However, if individuals have tried these other strategies with limited success and want to pursue the use of e-cigarettes, we try to support people and at least meet them where they are on their cessation journey.

A trial by Hajek et al.3 performed in the United Kingdom showed that e-cigarettes were more effective at helping smokers quit combustible cigarettes than nicotine replacement therapy (NRT) of patients’ choice, including use of combination NRT. All smokers were provided at least four weekly counseling sessions and randomly assigned to e-cigarettes or NRT for 3 months in this trial of 886 smokers attending smoking cessation

services. Although cessation of combustible cigarettes was significantly better in the e-cigarette group, a less positive note was that for the smokers who achieved abstinence in the e-cigarette group, most (80%) continued using e-cigarettes at 1 year. Furthermore, approximately 40% of smokers assigned to e-cigarettes had dual use of combustible and e-cigarettes at 1 year. And so, although e-cigarettes may facilitate cessation of combustible cigarettes, they may be habit forming in and of themselves. We don’t know the potential long-term risks of using these products.

The CDC website has helpful recommendations for clinicians and provides key information about these products.

Many individuals do not understand that these products contain nicotine. Many are using these products more often than they were using cigarettes, for example in their homes, because there are fewer restrictions on their use and the vapors emitted are less noticeable than cigarette smoke. We have had patients come through our service who were using a

vaping device so often that their nicotine levels exceeded 2 or 3 packs a day. Paying attention to how compulsive a behavior can become for someone is important.

Healthcare providers can engage these individuals in an open-ended conversation about how, when, and where they are using these products and how they feel when they cannot use it. The nicotine withdrawal that people experience when they cannot use these products can be pretty profound, so I think being able to empathically point that out can be very reassuring to patients. It is a helpful dialogue. ✦ References: 1. Landry RL, Groom AL, Vu TT, et al. The role of flavors in vaping initiation and satisfaction among U.S. adults. Addict Behav. 2019;99:106077.

2. Centers for Disease Control and Prevention.

Smoking and Tobacco Use: Outbreak of Lung Injury Associated with the Use of E-Cigarette, or Vaping, Products. Available at: https://www. cdc.gov/tobacco/basic_information/e-cigarettes/ severe-lung-disease.html#what-is-new. Accessed December 10, 2019.

3. Hajek P, Phillips-Waller A, Przulj D, et al.

A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy. N Engl J Med. 2019;380(7):629-637.

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IASLC LUNG CANCER NEWS / FEBRUARY 2020

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

TRK Inhibition in TRK Fusion–Positive Lung Cancers

By Alexander Drilon, MD

The receptor tyrosine kinases TRKA/B/C are encoded by the genes NTRK1/2/3.

TRK fusions are oncogenic drivers of various adult and pediatric cancers. These fusions are found at high frequencies (> 90% in select series) in rare cancers such as secretory carcinoma and at lower frequencies in more common cancers.1 In NSCLCs, the estimated frequency of TRK fusions is 0.23%.2 TRK fusions are typically mutually exclusive with other drivers. These are found at a younger median age (48 years, range 25 to 86 years), seen in patients with minimal to no prior smoking history (median packyear history 0, range 0 to 58), and identified largely in adenocarcinomas. Similar to other drivers, however, all patients with NSCLC should be screened for TRK fusions regardless of these features given that not all patients fit this profile.

DNA-based next-generation sequencing (NGS) is an ideal first test to use; it is important to select an assay that reliably detects these alterations. It should be recognized that, due to technical reasons, DNA-based NGS can miss some TRK fusions. RNA-based sequencing is a complementary test that can detect these false-negative cases.3 In environments in which NGS is not available, immunohistochemistry (with a pan-TRK antibody) can be used to screen for TRK fusions, as many of these tumors will overexpress the oncoprotein.4 Other assays such as FISH, RT-PCR, and plasma ctDNA testing can also detect TRK fusions, but these assays have their own limitations.

The first-generation TRK inhibitors (larotrectinib and entrectinib) are approved by several regulatory agencies for the treatment of TRK fusion–positive cancers in adult and pediatric patients.

Larotrectinib is a selective TRK inhibitor, whereas entrectinib inhibits ROS1 and ALK in addition to TRK. The objective response rates (ORR) in all TRK fusion–positive cancers were 81%5 and 58%,6 respectively (Table). The median

Fig. 1. Distribution and Frequency of NTRK Fusions in Adult and Pediatric Tumors

Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731–747.

progression-free survival (PFS) was not reached for larotrectinib and was 11.2 months for entrectinib. Response rates in TRK fusion–positive NSCLCs were comparable (larotrectinib: ORR 71% [n = 5/7],7 entrectinib: ORR 70% [n = 7/10]8). Both drugs achieved intracranial responses in patients with central nervous system metastases (entrectinib: intracranial ORR 67% [n = 4/6] in NSCLC).8,9 Larotrectinib and entrectinib have favorable safety profiles. Most adverse events were grade 1 or 2. Rates of dose reduction (larotrectinib: 9%, entrectinib: 27%) and treatment discontinuation (larotrectinib: 1%, entrectinib: 4%) were low compared to other targeted therapies.5,6 On-target adverse events mediated

by TRK inhibition occasionally occur.

These include weight gain, paresthesias, and dizziness/ataxia. In addition, pain flares can be observed in patients who temporarily or permanently discontinue TRK inhibitor therapy. These side-effects are predicted by the role that the TRK pathway plays in nervous system development and maintenance.1 Resistance to TRK inhibition can eventually occur. A proportion of cancers will

Table. First-Generation TRK Inhibitors

Drug targets

Larotrectinib

Entrectinib

TRKA/B/C

TRKA/B/C, ROS1, ALK

ORR (all TRK fusion–positive cancers)

81%

58%

ORR (TRK fusion–positive lung cancers)

71%

70%

Not reached

11.2 months

9%

27%

1%

4%

United States, Canada, Europe, Brazil

United States, Japan

Median PFS (all TRK fusion–positive cancers) Dose reduction rate Treatment discontinuation rate Regulatory approval

Abbreviations: ORR, overall response rate; PFS, progression-free survival.

Fig. 2. Consequences of Loss, Decreased Activity, or Inhibition of TRK

Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731–747.

acquire on-target resistance in the form of NTRK kinase domain mutations.

These result in substitutions involving the solvent front, gatekeeper, and xDFG residues.1 Next-generation TRK inhibitors such as selitrectinib10 and repotrectinib11 have been developed to address several of these mutations. Both drugs are being evaluated in ongoing clinical trials (NCT03215511, NCT03093116), and clinical proof-of-concept cases (TRK fusion–positive cancers responding after progression on a prior TRK inhibitor) have been reported for both agents. This highlights the utility of a sequential paradigm of TRK inhibitor use in the appropriate context. Off-target resistance has also been described and can be mediated by activation of MET or the RAS-RAFMEK pathway.12

In summary, TRK fusions are clinically actionable drivers that are found in NSCLCs. Screening for TRK fusions should be performed in the clinic. Two first-generation drugs (larotrectinib and entrectinib) are currently approved for the treatment of TRK fusion–positive cancers in adult and pediatric patients.

These drugs are well tolerated, although occasional and unique on-target side effects are observed. Next-generation TRK inhibitors that address on-target resistance are already in clinical trials. ✦ About the Author: Dr. Drilon is a medical oncologist, research director of Early Drug Development Service, and an associate attending physician of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center. continued on page 7

LUNGCANCERNEWS.ORG / FEBRUARY 2020

7

SUPPORTIVE CARE

Multidisciplinary Teams at AUSL Romagna

By Federico Cappuzzo, MD

Lung cancer treatment is becoming extremely complex. It requires specific competencies to identify the correct diagnosis, tumor biology, staging, and best therapeutic strategy. Our institution first illustrated this concept 20 years ago when it established its first multidisciplinary team, which at the time only included a medical oncologist, radiation oncologist, and thoracic surgeon. During the subsequent years, the increased complexity of lung cancer management has led to active partici-

TRK Inhibition from page 6

References: 1. E Cocco, M Scaltriti, Drilon A. NTRK fusionpositive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-747.

2. Farago AF, Taylor MS, Doebele RC, et al. Clinicopathologic Features of Non-Small-Cell Lung Cancer Harboring an NTRK Gene Fusion. JCO Precis Oncol. 2018 Jul 23. [Epub ahead of print].

3. Benayed R, Offin M, Mullaney K, et al. High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden. Clin Cancer Res. 2019;25(15):4712-4722.

4. Hechtman JF, Benayed R, Hyman DM, et al.

Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions. Am J Surg Pathol. 2017;41(11):1547-1551.

5. Tan DSW, Lassen UN, Albert CM, et al.

Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach.

Ann Oncol. 2018;29:viii133-viii148.

6. Demetri GD, Paz-Ares L, Farago AF, et al.

Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumours: Pooled analysis of STARTRK-2, STARTRK-1, and ALKA-372001. Ann Oncol. 2018;29:ix173-ix178.

7. Drilon A, Kummar S, Moreno V, et al. Activity of larotrectinib in TRK fusion lung cancer Ann Oncol. 2019;30(suppl_2).

8. Paz-Ares L, Doebele R, Farago AF, et al.

Entrectinib in NTRK Fusion-Positive Non-Small Cell Lung Cancer (NSCLC): Integrated Analysis of Patients Enrolled in STARTRK-2, STARTRK-1 and ALKA-372-001. Ann Oncol. 2019;30 (suppl_2):ii38-ii68.

9. Drilon AE, DuBois SG, Farago, AF, et al.

Activity of Larotrectinib in TRK Fusion Cancer Patients with Brain Metastases or Primary Central Nervous System Tumors. J Clin Oncol.

2019;37(15_suppl):2006.

10. Drilon A, Nagasubramanian R, Blake JF, et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov.

2017;7(9):963-972.

11. Drilon A, Ou SI, Cho BC, et al. Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ ALK Inhibitor That Potently Inhibits ROS1/TRK/ ALK Solvent- Front Mutations. Cancer Discov.

2018;8(10):1227-1236.

12. Cocco E, Schram AM, Kulick A, et al. Resistance to TRK inhibition mediated by convergent MAP kinase pathway activation. Nat Med. 2019 Aug 12.

[Epub ahead of print].

pation of other specialists including pathologists, radiologists, pneumologists, biostatisticians, and molecular biologists.

Since 2018, a single multidisciplinary team composed of at least eight different specialists meet regularly (every Wednesday), to discuss all cases of thoracic malignancies diagnosed in Romagna, a region with an overall population of 1,100,000 people.

In Romagna, five different hospitals (Ravenna, Lugo, Faenza, Rimini, and Cattolica) formally represent a single institution called AUSL Romagna, which in turn collaborates with an institution dedicated to cancer research (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori [IRST]).

IRST has the facilities to allow accurate tumor biology assessment of all patients with thoracic malignancies.

In our multidisciplinary meeting, we focus particular attention on research that aims to offer the most innovative therapy to our patients. Clinical and

Dr. Federico Cappuzzo told the IASLC Lung Cancer News that the most important thing for the success of multidisciplinary teams at AUSL Romagna is the enthusiasm in collaborating.

biologic data are systematically and accurately collected for correlative studies. More than 50 clinical trials are currently ongoing, in all disease stages and in all drug development phases (from phase I to phase IV), with two innovative phase I units (one in Ravenna and one at IRST). Irrespective of inclusion

in a clinical trial, our organization allows all patients evaluated to receive appropriate and tailored treatment near home. ✦ About the Author: Dr. Cappuzzo is director of the Oncology and Hematology Department at AUSL Romagna-Ravenna, Italy.

SUPPORTIVE CARE

Palliative Care in China SPOTLIGHT ON PALLIATIVE CARE

By Lixia Ju, PhD

The main purpose of palliative care for advanced cancer in China is to alleviate symptoms, reduce complications, improve quality of life, and prolong survival. The palliative care a patient receives can be ranked into three levels according to the patient’s condition. First, for patients with cancer receiving radical treatment, the integration of anticancer treatment and palliative care can alleviate the symptoms of cancer, as well as the adverse reactions of anticancer treatment. Second, for patients with advanced cancer for whom the aim of treatment is not to cure disease but rather to prolong survival and quality of life, palliative care is the main way to make these patients comfortable. The last level of palliative care is hospice care, which means that life ends with dignity.

Although patients and their families may have different opinions about the treatment of terminal cancer, approximately two-thirds of patients with advanced cancer in China are inclined to

spend more money on aggressive treatlow costs—much like palliative care in ment, even though it may result in little other cultures. The therapeutic prinimprovement in patients’ outcomes ciples of TCM can be divided into and only prolong the painful four aspects: strengthening process of death. At the the healthy qi (or ch’i)— final stage of life, such essentially the life force treatment is not beneof all living things— ficial to patients’ wellinhibiting tumors, being and satisfaction, alleviating sympand it may hinder the toms, and protecting effective use of limited organ functions. Not medical resources. limited to the general There are two main concept of “medical Dr. Lixia Ju reasons for the dispute treatment,” TCM is comregarding end-stage cancer posed of a unique thinking treatment. First, in China, whether to and a comprehensive healing system. accept palliative care or hospice care is an Holistic concepts and treatment based ethical challenge because of traditional on pattern identification are the core societal values about death. Second, the theories of TCM. The healing measures necessity of palliative care and hospice include herbs, acupuncture, massage, care has not been promoted well to the and a series of psychological, emotional, public, and the lack of financial investspiritual, and social-related therapies ment and resources in the form of trained to meet the needs of patients and their professionals limits the development of families. Among them, acupuncture and palliative care and hospice care. related therapies are particularly effecTraditional Chinese medicine (TCM) tive in reducing pain, relieving fatigue, is widely used in the clinical treatment and improving quality of life. ✦ of cancer in China because it is good at alleviating symptoms, regulating visAbout the Author: Dr. Ju is with the Department ceral functions, and improving immuof Integrative Medicine, Shanghai Pulmonary nity with little adverse reactions and Hospital, Tongji University, Shanghai, China.

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IASLC LUNG CANCER NEWS / FEBRUARY 2020

INDUSTRY AND REGULATORY NEWS Dr. Chandra P. Belani Named New Chief Science Officer for the IASLC December 2, 2019—The International Association for the Study of Lung Cancer named Chandra P. Belani, MD, as its new chief science officer (CSO). As CSO, Dr. Belani will direct, guide, and support the IASLC scientific strategy, including, but not limited to, scientific research projects, publications, educational content for conferences, and educational offerings for members. In this role, Dr. Belani will also serve as a spokesperson for the IASLC at conferences, with the media, and in meetings with industry partners and donors.

Dr. Belani is currently professor of Medicine in the Division of Hematology/ Oncology in the Department of Medicine at the Penn State Hershey Medical Center—a post he will maintain while serving as the IASLC CSO. Dr. Belani has also worked in several

positions at the Penn State College of Medicine as deputy director of the Penn State Cancer Institute, associate director of Clinical Research, and director of the Lung Cancer Program. Prior to that Dr. Belani served in multiple leadership positions at University of Pittsburgh Cancer Institute in Pittsburgh, PA including director of Community Oncology, codirector of the Lung Cancer Program, and co-director of the Experimental Therapeutics Program. His research accomplishments in the areas of lung cancer and new drug development have led to changes in treatment paradigms.

Interacting with experts across the world, he has developed and identified novel therapeutic strategies that have been approved and adopted as standards of care for the management of lung cancer.

“At the IASLC, the chief science officer

position provides me with his residency in internal a unique opportunity medicine, he was a to give, contribute, and fellow in Hematology grow the organization. and Oncology at I am embarking on this the University of challenge with the spirit Mar yland from of dedication, inspiration, 1985 to 1988. He and motivation to improve joined the faculty at the Dr. Chandra P. Belani the quality of the educational, University of Maryland research, and scientific proCancer Center thereafgrams in collaboration with the IASLC ter and served as assistant professor of members worldwide,” Dr. Belani said. “In Medicine and Oncology and director, my role as CSO, I hope to develop a cohe- Thoracic Oncology at the University of sive communications plan and ensure Maryland Medical School in Baltimore. that the information released is consis- He is board certified by the American tent with the strategy at large, and work Board of Internal Medicine and the towards the ultimate goal of improving American Board of Internal Medicine lung cancer outcomes.” in Oncology and holds memberships Dr. Belani is a graduate of Sawai Man in the IASLC, the American Society of Singh Medical College, University of Clinical Oncology, and the American Rajasthan, Jaipur, India. After completing Association of Cancer Research. ✦

N U R S E S A N D A L L I E D H E A LT H P R O F E S S I O N A L S

Doctor of Nursing Practice Project Aims to Educate Non-Oncology Providers About the Management of Immunotherapy AEs

By Enza Esposito Nguyen, DNP, RN, ANP-BC

Although we continue to see many immunotherapy clinical trials mature and deliver marvelous improvements in PFS and OS in lung cancer and many other malignancies, managing some of the adverse events (AEs) of immunotherapy has become a unique challenge. This is most evident when patients receiving immunotherapy present outside of the cancer center, for example to an emergency department (ED). This has led to the identification of a clinical chasm among non-oncology providers in community cancer centers. This clinical gap is now well documented in the emergency and critical care medicine literature.1,2,4 The purpose of the Doctor of Nursing Practice (DNP) project was to educate and facilitate the adoption of evidence-based guidelines (National Comprehensive Cancer Network V 1.2018) in the management of checkpoint inhibitor-related AEs by nononcology providers at Providence St. Joseph in Orange, California, a community hospital. As a result, the study questions included: What is the baseline knowledge about checkpoint inhibitors, their AEs, and their management by non-oncology providers? What would be the most effective way to impart this information to non-oncology providers?

Can we examine the effects of this new knowledge on the clinical outcomes of patients receiving immunotherapy who are seen in the ED and admitted to the hospital for suspected AEs?

Methods During this project, educational in-services were provided to non-oncology providers on the newly published guidelines. A knowledge pretest and posttest assessed changes from baseline understanding, and chart audits were completed to evaluate success of knowledge dissemination on patient treatment.

Lastly, de-identified data from quality improvement audits through the electronic medical records were reviewed to assess patient outcomes.

Targeted 7- to 10-minute microteaching sessions were provided for nurses in various non-oncology areas including the ED, medical-telemetry, and the intensive care units. Similar concise micro-teaching education was also provided for physicians in the ED; physician education focused on the pharmacokinetics of immunotherapy, commonly seen AEs, and newly released management guidelines. These micro-teaching sessions consisted of one to seven providers at a time and included the use of a laptop or a ringed booklet with PowerPoint slides as audiovisual aides. A knowledge pretest/

posttest was administered to the nurses and physicians.

All data from the pre/posttest knowledge questionnaire were analyzed using SPSS (version 24) statistics software. Data were checked for accuracy. Descriptive statistics were used to illustrate the demographic characteristics of providers who completed the knowledge tests at each time point. Total scores were calculated, and phi coefficients were calculated to assess the relationship between baseline and post-education knowledge for each item. Nursing data from all units and specialties were reported under “all RNs” in the result section, and physician data were reported separately.

Results Between October and December 2018, 73 (66%) nurses and 16 (72%) physicians from the ED received the in-service. This met the goal to educate most of this critical frontline staff. Additionally, 18 nurses from intensive care, 13 nurses from oncology, nine nurses from medical-telemetry, and 12 from general surgery participated in the microteaching in-services for inpatient nursing staff.

Nurses The results (Table 1) reflect increased knowledge for all nurses between pre- and posttest (125 nurses). For each of the five continued on page 9

Table 1. Responses to Pretest and Posttest Questionnaire by All Nurses Pre 129 nurses

Post 125 nurses

Yes

No

Yes

No

Are you familiar with immunotherapy as a treatment for cancer?

51.9% (67)

48.1% (62)

96.8% (121)

3.2% (4)

< 0.0001

Are you familiar with national guidelines for the management of immunotherapy adverse events?

8.5% (11)

91.5% (118)

90.4% (113)

8.0% (10)

< 0.0001

Are you familiar with the intervention(s) needed to start reversing most immunotherapy adverse events?

14% (18)

86% (111)

96% (120)

3.2% (4)

< 0.0001

Pre 129 nurses

Post 125 nurses

P value

P value

True

False

True

False

Immunotherapy and chemotherapy may be administered in combination.

52.7% (68)

45% (58)

89.6 % (112)

9.6% (12)

< 0.0001

Neutropenic patients who are receiving chemotherapy and immunotherapy may be treated with steroids.

49.6 % (64)

48.1% (62)

95.2% (119)

4.0% (5)

< 0.0001

LUNGCANCERNEWS.ORG / FEBRUARY 2020

DNP Project from page 8

questions, the percentage of nurses who correctly responded to the item significantly increased at posttest (p < 0.001).

Baseline nurse knowledge of interventions to reverse checkpoint inhibitor AEs was low prior to the microteaching; 14% correctly responded compared to 96% after education.

Physicians Table 2 reports the results for the ED physicians (16 physicians). At baseline, physician knowledge scores were higher than baseline knowledge for all nurses.

For example, at baseline, for the question “Are you familiar with the intervention needed to start reversing most immunotherapy adverse events,” 21.4% of ED physicians answered “yes” compared to 14% for all nurses. On only two questions did physicians increase their knowledge significantly post-teaching. One was the question mentioned previously, which featured a significant increase in knowledge following the micro-teaching in-service (p

< 0.0001). The other item with a significantly increased proportion of correct responses was being familiar with national guidelines for the reversal and management of AEs due to checkpoint inhibitors (p = 0.004).

in the emergency department literature regarding checkpoint inhibitors, AEs, and their assessment and management, as appraised in our literature review. Second, some of these physicians may have previously Dr. Enza Esposito Nguyen attended the introductory Discussion/ educational in-service with Implications the institution of immunotherapy idenNurses more than physicians demontification cards as part of phase 1, which strated limited baseline understanding was provided in Summer 2017. of the signs and symptoms of immunoAlthough the project was conducted therapy AEs. Interestingly, many nurses over a short period of time, which did and physicians when asked to “name not allow for training of all nursing staff some immunotherapy adverse events” members and all specialists regarding IO wrote down AEs associated with cheAE management,4 the project was sucmotherapy. This is consistent with other cessful in that it increased the knowledge publications that suggest similar deficits base of the emergency frontline staff about among providers.1,4 immunotherapy, its complicated AEs, and Knowledge among physicians was how to reach out to the oncology team and higher during baseline assessment, with manage these AEs more confidently in a pretest results demonstrating means community tertiary center. The project between 14% and 85%. This could be also revealed additional gaps in care that attributed to a couple of factors. First, were readily addressed. ✦ there has been more recent publications

Table 2. Responses to Pretest and Posttest Questionnaires by Emergency Department Physicians Pre 13 physicians

Post 12 physicians

Yes

No

Yes

No

Are you familiar with immunotherapy as a treatment for cancer?

92.3% (12)

7.7% (1)

91.7% (11)

8.3 % (1)

0.953

Are you familiar with national guidelines for the management of immunotherapy adverse events?

23.1% (3)

69.2 % (9)

75% (9)

16.7% (2)

0.006

Are you familiar with the intervention(s) needed to start reversing most immunotherapy adverse events?

46.2% (6)

46.2% (6)

83.3% (10)

16.7% (2)

0.083

Pre 13 physicians

Post 12 physicians

P value

P value

True

False

True

False

Immunotherapy and chemotherapy may be administered simultaneously.

69.2 % (9)

23.1% (3)

91.7 % (11)

8.3% (12)

0.273

Neutropenic patients who are receiving chemotherapy and immunotherapy may be treated with steroids.

69.2 % (9)

23.1% (3)

91.7% (11)

8.3.% (1)

0.273

About the Author: Dr. Nguyen was a Thoracic Oncology Nurse Practitioner at Providence St Joseph Hospital in Orange at the time this doctoral project was conducted.

References: 1. Hryniewicki AT, Wang C, Shatsky RA, Coyne CJ. Management of immune checkpoint inhibitor toxicities: A review and clinical guideline for emergency physicians. J Emerg Med. 2018;55(4):489-502.

2. Kroschinsky F, Stölzel F, von Bonin S, et al.

New drugs, new toxicities: Severe side effects of modern targeted and immunotherapy of cancer and their management. Crit Care. 2017;21(1):89.

3. National Comprehensive Cancer Network.

Management of immunotherapy-related toxicities (Version 5.0 2018). nccn.org/professionals/ physician_gls/pdf/immunotherapy.pdf. Published 2018. Accessed August 15, 2019.

4. Wang DY, Salem YE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: A systematic review and meta-analysis.

JAMA Oncol. 2018;4(12):1721-1728.

INDUSTRY AND REGULATORY NEWS New FDA Commissioner Confirmed December 12, 2019—Stephen M. Hahn, MD, FASTRO, was confirmed as commissioner of the U.S. Food and Drug Administration by a Senate vote of 72 to 18. Dr. Hahn will vacate his current position as chief executive officer of The University of Texas MD Anderson Cancer Center, which he has held since 2017. He is also the Gilbert H. Fletcher Memorial Distinguished Chair and professor of radiation oncology there.

Previously, he worked at the National Cancer Institute in the 1990s and

ing challenges for the joined the University agency, such as the of Pennsylvania in increase of vaping 1996, where he was the chair of radiation use in teens and the development of oncology from 20052014. He moved to acute lung injuries MD Anderson in 2015 that have resulted in a to become division number of deaths. (See Dr. Stephen M. Hahn the article on page 1 of this head of radiation oncolissue for more about the ogy. Dr. Hahn specializes in lung cancer and sarcoma. vaping crisis.) In addition, prescription Dr. Hahn will be faced with several pricing and regulation of CBD or canlooming issues that have been ongonabidiol will be other top priorities. ✦

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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 MANAGING EDITOR AND PUBLISHER Joy Curzio, Curzio Communications COPY EDITOR Alana Williams 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.

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IASLC LUNG CANCER NEWS / FEBRUARY 2020

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

CheckMate 568: Efficacy and Biomarker Analysis for Nivolumab and Ipilimumab in NSCLC with 288 patients with untreated recurrent or metastatic NSCLC. Patients were Programmed death receptor (PD-1) unselected for histology or programmed checkpoint monoclonal antibody death receptor ligand-1 (PD-L1) therapy has proven a major status, and the study excluded advancement in the manknown EGFR or ALK agement of advanced sensitizing alterations.

NSCLC, with prolonged Therapy consisted of duration of response and nivolumab (3 mg/kg significant 5-year surevery 2 weeks) and vival rates not seen with ipilimumab (1 mg/kg combination platinumevery 6 weeks) for up to based chemotherapy.1-6 2 years. The primary endCheckMate 012, CheckMate point was overall response Dr. Neal Ready 568, and CheckMate 227 are rate (ORR) by blinded indea series of phase I, phase II, and phase pendent central review (BICR) per III trials aimed at broadening the options RECIST v1.1 with required confirmation for immunotherapy in NSCLC, includ- at 4 weeks or later, assessed in patients ing studying the immunotherapy combi- with > 1% or greater or < 1% tumor nation of the PD-1 inhibitor nivolumab PD-L1 expression. Secondary endpoints plus the CTLA-4 inhibitor ipilimumab.7-9 included PFS, OS, toxicity, and efficacy by The studies investigated toxicity, efficacy, PD-L1 expression and total mutational biomarkers, and the optimal phase II/III burden (TMB). regimen.

CheckMate 012 was a multi-insti- TMB and PD-L1 tutional phase I trial including treat- Correlation, or Lack Thereof ment arms combining nivolumab plus The ORR of 30% by BICR for all ipilimumab every 3 weeks, 6 weeks, or treated patients confirmed the apparent 12 weeks. Nivolumab (3 mg/kg every 2 increased efficacy reported in CheckMate weeks) plus ipilimumab (1 mg/kg every 012 for nivolumab plus ipilimumab com6 weeks) was chosen for phase II/III pared to nivolumab alone.7 The grade 3 or clinical trial development based on tol- higher toxicity rate of 30% was also conerability, promising efficacy, and evidence sistent with published data for nivolumab from other tumor types in which greater plus ipilimumab every 6 or 12 weeks.7 ipilimumab exposure was associated with Biomarker testing was prioritized for improved activity.

PD-L1 first and TMB second. Out of 288 CheckMate 568 was a phase II study treated patients, 252 (87.5%) were sucBy Neal Ready, MD, PhD

Role of Local Consolidation from page 5

erations, depending on the volume and location of the disease.

While awaiting the evidence of local consolidation in EGFR-positive advanced NSCLC (NCT03410043), we should proceed with caution so as not to cause severe toxicities and compromise the quality of life in patients already on effective and well-tolerated treatment.

Integrating translational research and interdisciplinary collaboration in the thoracic oncology community is the key to providing better clinical outcomes for oligometastatic NSCLC harboring EGFR mutations and other oncogenic drivers. ✦ About the Authors: Dr. Li is an associate consultant in the Department of Radiation Oncology at the National Cancer Centre Singapore. Dr. Bezjak is a professor in the Department of Radiation Oncology at the University of Toronto.

References: 1. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.

2. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):21672177.

3. Zhong WZ, Chen KN, Chen C, et al.

Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. J Clin Oncol. 2019 Jun 13. [Epub ahead of print].

4. Bivona TG, Doebele RC. A framework for understanding and targeting residual disease in oncogene-driven solid cancers. Nat Med. 2016;22(5):472-478.

5. Nahar R, Zhai W, Zhang T, et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat Commun. 2018;9(1):216.

6. Al-Halabi H, Sayegh K, Digamurthy SR, et al.

Pattern of Failure Analysis in Metastatic EGFRMutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy. J Thorac Oncol. 2015;10(11):1601-1607.

7. Sorensen BS, Wu L, Wei W, et al. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-

Fig. 1. Primary Endpoint: ORR by Tumor PD-L1 Expressiona,b

a

Irrespective of TMB status; bORR was 33% in patients with non-quantifiable tumor PD-L1 expression (n = 36); CR = 3%; dCR = 3%

c

cessfully tested for PD-L1. The ORR for the 138 tumors with PD-L1 expression > 1% was 41% in CheckMate 568 (Fig. 1), comparing favorably to the ORR rate of 28% for the 32 tumors with PD-L1 expression > 1% receiving nivolumab in CheckMate 012 and 27% for the 637 tumors with PD-L1 expression of 1% or greater receiving pembrolizumab in KEYNOTE-042.8, 10, 11 TMB was tested only after tumors were tested for PD-L1. TMB testing required 10 unstained slides and was conducted using the U.S. Food and Drug Administration–approved companion diagnostic next generation sequencing– based FoundationOne CDx assay. At least 10 slides were available for 121 cases, and 98 of those (82%) were successfully tested for TMB. Nonparametric receiver

operating characteristic curve estimates were used to evaluate the performance of TMB as a classifier of ORR per BICR. A regression analysis demonstrated no association between TMB and PD-L1 expression, consistent with results from the CheckMate 026 and 227 studies.12, 9 In the TMB-evaluable population, ORR increased in subgroups of patients with higher TMB, plateauing at > 10 mut/Mb or greater. ORR was 44% versus 12% in patients with TMB >10 mut/Mb versus TMB < 10 mut/Mb. No additional ORR benefit was observed in patients with TMB > 15 mut/Mb (Fig. 2, page 13). PFS was superior for tumors with TMB > 10 mut/Mb compared to tumors with < 10 mut/Mb. Therefore, TMB > 10 mut/Mb was chosen as the cutoff for TMB bio-

small cell lung cancer during treatment with erlotinib. Cancer. 2014;120(24):3896-3901.

8. Oxnard GR, Paweletz CP, Kuang Y, et al.

Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res. 2014;20(6):16981705.

9. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced nonsquamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol.

2019;20(5):625-635.

10. Vanita N, Amit J, Vijay MP, et al. Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C) [abstract]. J Clin Oncol. 2019; 37(15): Suppl 9001.

11. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655-1659.

12. Parker CC, James ND, Brawley CD, et al.

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet.2018;392(10162):2353-2366.

13. Gomez DR, Blumenschein GR Jr, Lee JJ, et al.

Local consolidative therapy versus maintenance

therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17(12):1672-1682.

14. Iyengar P, Wardak Z, Gerber DE, et al.

Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018;4(1): e173501.

15. Gomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients with Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol.

2019;37(18):1558-1565.

16. Chan OSh, Lam KC, LI J, et al. ATOM: A Phase II Study to Assess Efficacy of Preemptive Local Ablative Therapy to Residual Oligometastases After EGFR TKI[abstract]. J Thorac Oncol.

2018;13(10S):Suppl S336.

17. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet.

2019;393(10185):2051-2058.

18. Zhuang H, Yuan Z, Chang JY, et al. Radiation pneumonitis in patients with non-small-cell lung cancer treated with erlotinib concurrent with thoracic radiotherapy. J Thorac Oncol.

2014;9(6):882-885.

continued on page 13

IASLC 2020 Meetings Schedule FDA-AACR-IASLC Workshop to Address the Criticality of Tobacco Use Assessment in Oncology Therapeutic Trials February 28, 2020 | Silver Springs, MD #FDAWorkshop20

European Lung Cancer Congress 2020 April 15-18, 2020 | Geneva, Switzerland #ELCC20

Lung Cancer Hot Topic: Liquid Biopsy May 7-9, 2020 | Baltimore, MD

#LiquidBiopsy20

IASLC 2020 World Conference on Lung Cancer August 9-12, 2020 | Singapore #WCLC20

IASLC 2020 North America Conference on Lung Cancer October 15-17, 2020 | Chicago, IL #NACLC20

Lung Cancer Hot Topic: Immunotherapy November 2020

12

IASLC LUNG CANCER NEWS / FEBRUARY 2020

REPORTS FROM THE IASLC PATHOLOGY COMMITTEE

DIAGNOSTIC D DI I ONCOLOGY Tumor Mutation Burden: Evolution of a Controversial Biomarker From the Pathologist’s Perspective

By Lynette M. Sholl, MD, and John W. Longshore, PhD, FACMG

The profound impact of immunotherapy in patients with lung cancer has been described extensively by many experts within the IASLC.1,2 There are, however, broad disparities in outcomes for patients with lung cancer treated with various anti‒PD-1/‒PD-L1 therapies, reflecting the tremendous heterogeneity of the disease itself. The PD-1/PD-L1 axis is the target of many approved immunotherapeutics, and consequently, the predictive power of PD-L1 expression on tumor cells has served as a major focus of clinical trials. Across these clinical trial and cohort studies, PD-L1 expression on tumor cells enriches for response to these therapies; however, its predictive ability is modest at best and is relevant only for certain inhibitors in specific contexts.

This quagmire has led to the search for alternative or complementary biomarkers of response to immunotherapies.

Many lung cancers harbor large numbers of mutations resulting from extrinsic DNA damage from exposures like tobacco smoke or intrinsic DNA damage processes such as apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-induced cytidine deamination.3,4 Correlative studies have consistently shown a relationship between high mutational load (or tumor mutation burden [TMB]) and response to immunotherapies. Mechanistically, this relationship is thought to be driven by the greater likelihood of generating immunogenic novel proteins (neoantigens) in highly mutated tumor cells.

Whole-exome sequencing delivers an absolute quantitation of TMB (in number of mutations per exome); however, large-panel sequencing is more readily available in clinical practice. In general, the TMB can be extrapolated via bioinformatic methods from the focused data generated by the panel and reported as the number of mutations per megabase of genome sequenced.

Finding Answers for a Long List of Questions Although there is little doubt that TMB constitutes a unique characteristic of individual lung cancers, many questions remain about its tractability as a biomarker of response to immunotherapy.

Given the wide range of possible TMB

scores, a robust cutpoint optimized Figure. Frequency of TMB-High NSCLC at Different Cutpoints for sensitive and specific prediction of therapeutic response must be derived from clinical outcomes data. Proposed cutpoints have ranged from 10 to 15 mutations/Mb in tissue and six to 20 mutations/Mb in plasma-derived cell free (cf) DNA.5-9 Adding further complexity, “eligible” mutations have not been fully established—these may or may not include missense (nonsynonymous), synonymous, insertion-deletion mutations, and splice site mutations.

Subclonal mutations—those present only in a subpopulation of tumor cells— may be included in some calculations Permission granted by Dr. Marina Garassino but not others. Some panels require parallel sequencing of a paired normal specimen to exclude germline variants nize TMB results across specific panels. sufficient for use as a surrogate for TMB from analysis; others remove germline Larger multi-institutional efforts led by analysis? What type and size of targeted variants from tumor-only sequencing the Friends of Cancer Research and the panel is required to generate a reliable results using population database fil- Qualitätssicherungs-Initiative Pathologie TMB? How should TMB be considered ters. The targeted content of panel have undertaken a multipronged in the context of other established or next-generation sequencing approach examining bio- putative biomarkers including PD-L1 informatic and wet-lab expression, immune environment, and itself may be a confoundvariables influencing genomic context?17,18 All of these issues ing factor, as certain genes are more or less TMB calculation, with are under intense scrutiny in the lung prone to mutation the ultimate goal of cancer research community. The IASLC and, thus, may bias generating a global Pathology Committee is working to sumthe TMB estimation standard to permit marize the existing issues and provide of a given panel. To cross-laboratory har- clarity on the potential role for TMB in address the disparities monization.13 the management of patients with lung inherent to different panel Efforts to develop TMB cancer. ✦ Dr. Lynette M. Sholl designs and bioinformatic as a robust biomarker are rules for variant calling, motivated by data sug- About the Authors: Dr. Sholl is an associate promultiple investigators gesting that TMB can fessor of Pathology at Harvard Medical School have undertaken syspredict improvements and an Associate Pathologist in the departtematic evaluation of in response and pro- ment of Pathology at Brigham And Women’s TMB across different gression-free survival Hospital. Dr. Longshore is director of Molecular sequencing panels. following immu- Pathology at Carolinas Pathology Group, Atrium Garrido-Martin and notherapy. The data Health, Carolinas HealthCare System. Drs. Sholl from trials are contra- and Longshore co-chair the IASLC Pathology colleagues10 describe similar rates of “TMBdictory, however, with Committee Molecular Pathology Working Group.

Dr. John W. Longshore high” calling at different little evidence to date that Members of the working group are preparing a cutpoints between three higher TMB predicts better multidisciplinary review and perspective piece on commercially available sequencing overall survival.14 In patients receiving the clinical utility of TMB and technical complexpanels. However, Budczies and col- combined PD-1 inhibition and chemo- ity of this biomarker. leagues11 uncovered a substantial rate therapy, TMB does not appear to predict of TMB misclassification around 10 outcomes.15 In contrast, TMB may be a References: 1. Garon EB, Hellmann MD, Rizvi NA, et al. mutations/Mb using panels covering robust biomarker of response with PD-1 Five-Year Overall Survival for Patients With Advanced NonSmall-Cell Lung Cancer Treated up to 1.4Mb of genomic content. They inhibitor monotherapy in the first and With Pembrolizumab: Results From the emphasized the need for a larger panel second lines in patients with PD-L1‒posPhase I KEYNOTE-001 Study. J Clin Oncol.

16 to more accurately assess TMB levels itive tumors. Ultimately, several ques2019;37(28):2518-2527. and proposed a three-tiered reporting tions must be addressed before TMB can 2. Antonia SJ, Borghaei H, Ramalingam SS, et al.

Four-year survival with nivolumab in patients approach to reduce misclassification. be fully incorporated into clinical pracwith previously treated advanced non-small-cell Applying whole-exome sequencing as tice. In what clinical context will TMB lung cancer: a pooled analysis. Lancet Oncol.

2019;20(10):1395-1408. a gold standard, Vokes and colleagues12 best inform choice of therapy? What 3. McGranahan N, Furness AJ, Rosenthal R, et al.

TMB cutpoint provides optimal sencompared tumor-only and paired tumorClonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blocknormal sequencing approaches and pro- sitivity and specificity for response? Is ade. Science. 2016;351(6280):1463-1469. posed a transformation step to harmotissue-based TMB required, or is cfDNA

LUNGCANCERNEWS.ORG / FEBRUARY 2020

CheckMate 568

13

Fig. 2. ORR by TMBa,b

from page 10

marker analysis. The association of efficacy with TMB did not depend on tumor PD-L1 expression (Fig. 3).

4. Wang S, Jia M, He Z, Liu XS. APOBEC3B and APOBEC mutational signature as potential predictive markers for immunotherapy response in non-small cell lung cancer.

Oncogene. 2018;37(29):3924-3936.

5. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018;378(22):20932104.

6. Garassino MC. KEYNOTE 189: Tumor Mutational Burden Not Significantly Associated with Efficacy of Pembrolizumab (abstract). J Thorac Oncol. 2019.

7. Peters S. Abstract CT074: Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab ± tremelimumab vs chemotherapy. Cancer Res. 2019;79(13).

8. Wang Z, Duan J, Cai S, et al. Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non-Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel. JAMA Oncol. 2019;5(5):696-702.

9. Gandara DR, Paul SM, Kowanetz M, et al.

Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab.

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

10. Garrido-Martin EM, RamosParadas J, Hernandez Prieto S, et al.

LBA17Harmonization study of tumour mutational burden determination in nonsmall cell lung cancer (NSCLC). Ann Oncol.

2019;30(Suppl_5).

11. Budczies J, Allgauer M, Litchfield K, et al.

Optimizing panel-based tumor mutational burden (TMB) measurement. Ann Oncol.

2019;30(9):1496-1506.

12. Vokes NI, Liu D, Ricciuti B, et al.

Harmonization of Tumor Mutational Burden Quantification and Association With Response to Immune Checkpoint Blockade in Non– Small-Cell Lung Cancer. JCO Precis Oncol.

2019;1-12.

13. Stenzinger A, Allen JD, Maas J, et al. Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions.

Genes Chromosomes Cancer. 2019;58(8):578588.

14. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(5):863-870.

15. Paz-Ares L, Langer CJ, Novello S, et al.

LBA80Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: Tissue TMB (tTMB) and outcomes in KEYNOTE-021, 189, and 407.

Ann Oncol. 2019;30.

16. Herbst RS, Lopes G, Kowalski DM, et al.

LBA79Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials. Ann Oncol.

2019;30.

17. Lu S, Stein JE, Rimm DL, et al. Comparison of Biomarker Modalities for Predicting Response to PD-1/PD-L1 Checkpoint Blockade: A Systematic Review and Meta-analysis. JAMA Oncol. 2019 Jul 18. [Epub ahead of print].

18. Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov.

2018;8(7):822-835.

Implications for Future Study Approximately 40% of tested tumors had TMB > 10 mut/Mb, and the ORR was 44% for TMB-high tumors. The ORR was 47% in TMB > 10 mu/Mb tumors with PD-L1 expression < 1%. Thus, CheckMate 568 data suggested impressive activity for nivolumab plus ipilimumab in PD-L1– negative NSCLC with TMB > 10 mu/Mb. Approximately 40% of advanced NSCLC is PD-L1 negative, and approximately 40% of those tumors would be expected to have TMB > 10 mut/Mb, resulting in 10% to 20% of NSCLCs being both PD-L1 negative and TMB high by the Foundation Medicine assay. Patients with tumors that had PD-L1 expression < 1% and TMB < 10 mut/Mb had ORR of only 5%, suggesting that using the combination PD-L1 and TMB testing could identify a group of patients with a low likelihood of benefiting from combination PD-1 and CTLA-4 checkpoint blockade.

The TMB 10 mut/Mb cutoff identified in CheckMate 568 informed the statistical plan for the co-primary endpoint of PFS in patients with TMB > 10 mut/Mb in CheckMate 227. Patients with TMB > 10 mut/Mb had significantly prolonged PFS with first-line nivolumab plus ipilimumab versus chemotherapy; this validated the TMB cutoff identified in CheckMate 568.9 No significant difference in PFS between the two treatments was observed in patients with TMB < 10 mut/Mb. CheckMate 568 demonstrates that the combination of nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks was tolerable with superior efficacy compared to historical outcomes for nivolumab monotherapy in untreated advanced stage NSCLC. TMB > 10 mut/ Mb was a cutpoint for ORR, and there was no evidence of increased efficacy for tumors with TMB > 15 mut/Mb. PD-L1 and TMB were independent predictive biomarkers. TMB > 10 mut/Mb was validated as a predictive biomarker when prospectively applied to CheckMate 227, and it showed improved PFS for nivolumab plus ipilimumab compared to standard chemotherapy. Nivolumab plus low dose ipilimumab produced durable responses by BICR in more than 40% of PD-L1–positive or TMB > 10 mut/Mb tumors. However, TMB has not consistently been predictive of improved overall survival with combination therapy. The part 1 results of Checkmate 227 presented at the 2019 European Society for Medical Oncology Annual Meeting in Barcelona,

a

Irrespective of PD-L1 expression; b12% ORR for < 10 mut/Mb and 50% ORR for ≥ 10 to < 15 mut/Mb; CR = 0; dCR = 4%; eCR = 8%; fCR = 7%

c

Fig. 3. Responses Observed in TMB > 10 mut/Mb Irrespective of Tumor PD-L1 Expressiona

a ORR for all treated patients: 41% in PD-L1 ≥ 1% subgroup (n = 138) and 15% in PD-L1 < 1% subgroup (n = 114); bCR = 0; cCR = 16%; dCR = 4%; eCR = 4%

Spain showed an overall survival benefit for the nivolumab and low dose ipilimumab immunotherapy combination compared to chemotherapy.13 Consistent with the results for CheckMate 568, the ORR with nivolumab plus ipilimumab in CheckMate 227 was higher for PD-L1 > 1% tumors compared to PD-L1 < 1% tumors. However, the relationship between the PD-L1 biomarker and efficacy with the nivolumab and low dose ipilimumab combination is complex, since in CheckMate 227 there was a similar survival advantage for nivolumab and low dose ipilimumab compared to standard chemotherapy in PD-L1 positive and PD-L1 negative tumors. ✦ About the Author: Dr. Ready is a professor of medicine at Duke University School of Medicine.

References: 1. 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.

2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-135.

3. 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.

4. Rittmeyer A, Barlesi F, Waterkamp D, et al.

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomized controlled trial. Lancet.

2017;389(10066):255-265.

5. Reck M, Rodriguez-Abreu D, Robinson AG, et al.

Pembrolizumab versus Chemotherapy for PD-L1Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-1833.

6. Gettinger S, Horn L, Jackman D, et al. FiveYear Follow-Up of Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: Results From the CA209-003 Study. J Clin Oncol.

2018;36(17):1675-1684.

7. Hellmann MD, Rizvi NA, Goldman JW, et al.

Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol.

2017;18(1):31-41 8. Ready N, Hellmann MD, Awad MM, et al. FirstLine Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers. J Clin Oncol. 2019;37(12):992-1000.

9. Hellmann MD, Ciuleanu T-E, Pluzanski A, et al.

Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018;378(22):2093-2104.

10. Gettinger S, Rizvi NA, Chow LQ, et al. Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34(25):2980-2987.

11. Mok TSK, Wu YL, Kudaba I, et al.

Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet.

2019;393(10183):1819-1830.

12. Carbone DP, Reck M, Paz-Ares L, et al.

CheckMate 026 Investigators. First-Line Nivolumab in Stage IV or Recurrent NonSmall-Cell Lung Cancer. N Engl J Med. 2017;376(25):2415-2426.

13. Peters S, Ramalingam S, Paz-Ares L, et al.

Nivolumab + Low-Dose Ipilimumab Versus Platinum-Doublet Chemotherapy as First-Line Treatment for Advanced Non-Small Cell Lung Cancer: CheckMate 227 Part 1 Final Analysis.

European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain (Presentation #LBA4).

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IASLC LUNG CANCER NEWS / FEBRUARY 2020

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

Treating Patients with MET Alterations: A Q&A with Dr. Ravi Salgia Ravi Salgia, MD, PhD, is the Arthur & Rosalie Kaplan Endowed Chair in Medical Oncology and the associate director for clinical sciences at City of Hope’s Comprehensive Cancer Center.

His many decades of research in MET and other oncogenic drivers has helped further lung cancer research and patient care. In the following interview, Dr. Salgia discusses current and future directions in the treatment of patients with lung cancer with MET alterations.

Q: Is MET a true oncogenic driver?

A: I’ve been working on MET research for a little more than 20 years now. The MET receptor tyrosine kinase was initially described in hereditary papillary renal cell carcinoma as having mutations, which were first seen in the tyrosine kinase domain. Laura Schmidt, PhD, who was at the National Cancer

Institute at the time, conducted this research. The mutations that were observed were gain-of-function mutations, and they represented the MET oncogenic driver.

Then, through the work of various brilliant investigators, the hepatocyte growth factor was identified as the ligand for MET. Over time—specifically for the past 20 years—we have been able to study how in lung cancer, MET can be overexpressed, amplified, or mutated.

In addition, MET may not be degraded properly, so it is constantly signaling at the cell surface. All of these factors help MET become oncogenic in a normal cell.

This took us considerable time to determine. Today, it’s really exciting that MET is a known oncogene.

Q: How viable is MET as a therapeutic target?

A: Very viable. My colleagues and I were among the first research groups

to identify the amplificaQ: We’re seeing data about tion and overexpression exon 14 skipping mutaof MET in lung cancer, tions more frequently. and we were actually Is this the next phase the first ones to disfor research? cover that MET could A: We first described be mutated in lung it in 2003 in SCLC cancer. We did that in and then in 2005 in NSCLC, but it took us all SCLC first; that was our seminal discovery in 2003. this time to realize that it is Dr. Ravi Salgia We also identified the exon a targetable receptor tyro14 skipping mutation at that point, and sine kinase. Now we must determine my lab also identified it in NSCLC in how MET is important as a resistance 2005. It took us approximately 10 to 12 mechanism to other therapeutics. How years to determine that some of these can it be targeted? And are there other mutations as well as MET amplification mutations? We clearly have identified a could be a potential therapeutic target. large number of mutations of MET in Drug companies developed MET inhibi- lung cancer, but we do not know if they tors, and clinical trials were performed. I represent anything for us to target. This commend so many researchers who are is a whole branch of MET research, as is currently investigating the MET recep- further exploration of MET fusions that tor tyrosine kinase as a therapeutic have recently been identified. target; it constitutes a very viable target, as mentioned, in lung cancer. continued on page 15

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

Lung Cancer Surveillance After Definitive Curative-Intent Therapy: A Q&A With Dr. Edgardo S. Santos Castillero Edgardo S. Santos Castillero, MD, FACP, is an IASLC Lung Cancer News Editorial Group Member and served as a co-chair on the expert panel that developed the American Society of Clinical Oncology (ASCO) Lung Cancer Surveillance After Definitive Curative-Intent Therapy guideline.1 In the following interview, Dr. Santos Castillero discusses key takeaways from the guideline as well as remaining questions on the topic.

lyzed recently published literature and identified 1,296 studies that met certain eligibility criteria. From these, 14 were included and form the evidentiary basis for the guideline recommendations.

The efforts described in the guideline apply to curatively treated stage I to III NSCLC and SCLC. We recognize that the recurrence rate goes up as a patient is diagnosed with more advanced disease, and these recurrences are more frequent in SCLC than NSCLC. Early detection of recurrence after curative-intent therapy will allow us to offer a more aggressive Q: What motivated the creation of the approach (e.g., stereotactic body radioguideline? therapy) rather than a complete palA: As we continue to improve liative and systemic approach early detection due to lung when recurrence is diagcancer screening pronosed too late. However, grams, we have also only recently has early affected lung cancer detection via surveilclinical outcomes due lance shown clinical to novel treatments benefit in patients with and new biotechnoloNSCLC. This guideline was gies. Consequently, we have found ourselves prepared with active parDr. Edgardo S. Santos ticipation from all mediwith more patients with Castillero cal specialties associated lung cancer being placed with lung cancer management as well on surveillance after a curative-intent approach, which has created a chal- as patient advocacy groups and public lenge for our clinicians. To respond to opinion. The guideline will help clinithis need, ASCO reviewed and ana- cians determine the best course of action

based on the actual scientific data available today.

Q: What are the most salient takeaways for patient care?

A: In the past, we have been very aggressive about surveillance for patients with lung cancer. The guideline now recommends a CT scan every 6 months for the first 2 years, followed by yearly CT scans at year 3 cutoff until completion of 5 years post-curative intent. After 2 years of curative-intent therapy, patients with lung cancer are at a higher risk of developing a second primary and may benefit from a screening approach like that offered to those who meet the National Lung Screening Trial screening eligibility.

Two recent randomized prospective trials have established low-dose CT screening as an important tool for the detection of potentially curable, early-stage NSCLC in patients at high risk of developing lung cancer.

The guideline also clarifies the role of PET CT scan as well as circulating biomarkers; these novel technologies are not considered standard of care and should not be encouraged to be used.

Finally, the guideline clarifies the role of magnetic resonance imaging (MRI) of the brain; this imaging modality should not

be part of NSCLC surveillance but may play a role in the surveillance of SCLC during the first 2 years post curativeintent approach. No distinction on brain surveillance with MRI was made between those patients who did or did not receive prophylactic cranial irradiation.

Q: Are there any questions on the topic that the guideline doesn’t fully address?

A: Many questions remain unanswered.

For example, as biotechnology continues to improve and becomes more sensitive and predictive, how can we incorporate circulating biomarkers into the surveillance equation? What is the role of gene expression profiles, circulating tumor cells, and other proteomic profiles in the early detection of lung cancer recurrence over imaging tests?

Better prospective trials are needed to assess risk of recurrence by pathologic stage and histologic types. Most of the efforts performed to date include a large variety of clinical stages, which will cause problems and noise at the time of data analysis and interpretation. ✦ Reference: 1. Schneider BJ, Ismaila N, Aerts J, et al. Lung Cancer Surveillance After Definitive CurativeIntent Therapy: ASCO Guideline. J Clin Oncol.

2019 Dec 12. [Epub ahead of print].

LUNGCANCERNEWS.ORG / FEBRUARY 2020

Treating Patients with MET Alterations from page 14

Q: What is the best way to identify MET alterations?

A: MET exon 14 skipping mutations as well as MET mutations and amplifications can be identified through next-generation sequencing, for which there are multiple platforms. MET overexpression can be identified through immunohistochemistry. As we design the next set of trials for identification of future biomarkers, we must keep in mind that, not only can you identify the amplifications, mutations, or the overexpression, but you can also identify the CBL molecule, which is the reason for MET’s inability to be degraded, as a mutation or loss of heterozygosity.

the molecular and therapeutic responses to agents that target these drivers, so that you can drive research. If a patient does not qualify for clinical trials, then TKIs should be considered. We are seeing MET amplification more frequently because of the drugs that target EGFR, which is leading us to conclude that MET amplification is not an uncommon mechanism of resistance. We also know that certain chemotherapies, for example cisplatin, can also cause MET amplification and/ or overexpression. So as we think about lung cancer and its responsiveness to therapeutics, when a patient’s disease progresses from standard therapy or TKIs, MET has to be part of the equation in evaluating mechanisms of resistance.

MET should be looked at as a de novo molecule in terms of actionable genetic alterations

Q: In terms of the agents that might be active against MET, what is your perspective on the roles of crizotinib, capmatinib, and tepotinib?

A: I helped write the initial clinical trial for crizotinib for MET. When I was at Dana Farber Cancer Institute and then at the University of Chicago, we identified crizotinib as a very active drug against MET and MET mutations. Crizotinib has U.S. Food and Drug Administration (FDA) approval but only for exon 14 skipping mutations; we must determine crizotinib’s importance for other genetic or genomic alterations. Capmatinib has yielded durable responses and a manageable safety profile in patients with NSCLC and a MET exon 14 skipping mutation in the GEOMETRY mono-1 phase II trial. I think therapeutic selection should be determined by efficacy but also by duration of response and expected toxicities associated with each agent.

Q: Assuming that capmatinib and tepotinib do get FDA approval like crizotinib, do you think toxicities are going to prove a challenge with those?

A: As you know, immunotherapy is incredibly well tolerated but when toxicities develop, they can be quite challenging. Of course, that holds true for any of the drugs that we use regularly in our clinics. So is that going to be hard to manage? I don’t think so, but I believe we have to understand the potential toxicities and how we can help all of our colleagues in our multidisciplinary teams to best manage them.

Q: How is MET managed when it appears as a resistance mutation?

A: Ideally for any MET alteration that one identifies, we would love to have that patient on a clinical trial. That’s how you make breakthroughs—by understanding

Q: Combatting therapeutic resistance will start with enrolling patients in clinical trials; then where do we go from there?

A: Heterogeneity becomes an issue. We worry about temporal heterogeneity, that is, the kind of molecular or cellular evolution that can occur over time. But we also worry about spatial heterogeneity— what happens to different metastases. Is the primary lung tumor the same as its metastasis to the brain or its metastasis to the liver? Is the metastasis to the liver the same as metastasis to the brain? Studying resistance in the context of spatial and temporal heterogeneity, especially for lung cancer, is crucial.

Q: What are the effects of brain metastasis on patients with MET alterations?

A: Patients with MET alterations can have brain metastasis. One must determine if stereotactic radiosurgery can be given to solitary metastasis or a number of metastases, or if one should consider oral therapeutics, and whether these oral therapeutics can cross the blood–brain barrier. I do not think enough is known at this moment to recommend a single course of action. There are incidental reports in the literature where one drug might cross the blood–brain barrier as compared to another one, but we need more data and greater understanding about the mechanism of action. Not only do brain metastases become an issue, but every once in a while we see leptomeningeal disease, which also is a serious complication. So how do we treat all of this? It’s an open-ended question for us for now.

reotactic radiosurgery, I tend to do that first. If the metastases are too numerous to count, then you have to think potentially about whole-brain radiation therapy (WBRT); however, we tend to reserve WBRT for extreme cases. If there is a very significant metastatic burden in the brain with a lot of edema and potential for herniation, you have to think about neurosurgery. Consequently, I still think a lot about the traditional therapeutic approaches for brain metastasis, but I also determine whether to give an oral TKI. For example, in the literature, there’s a case report about cabozantinib having efficacy against brain metastasis in a patient with a MET alteration. All of these things must be taken into consideration but, ultimately, the way we decide to treat brain metastases is in a multidisciplinary fashion with all of our colleagues weighing in, while at the same time also staying focused on the needs and considerations of the individual patient.

Q: What novel agents, if any, might make a difference regarding CNS efficacy in patients with MET alterations?

Are there any ongoing trials for this?

A: Again, it’s an open-ended question for us for now because I don’t think enough is known about how these drugs penetrate the brain and how sustainable they are in the brain and in the spinal fluid. We need to conduct more studies, including prospective clinical trials, to be able to understand this issue. In vivo modeling and other modeling exist to help us determine which drugs can cross the blood–brain barrier, but I think the human blood–brain barrier is complex, and the capacity of cytotoxic agents and TKIs to penetrate into the brain is completely different, so we must study this.

In terms of ongoing trials, I don’t think there is anything specific to this topic.

The ongoing trials are much broader.

For example, capmatinib and tepotinib are being assessed in ongoing trials that often allow brain metastases. I think those trials should be further refined to include a cohort reserved for patients with brain metastases, once the initial data are reported. The other question is whether agents can be used in combination (such as with bevacizumab) if one has brain metastasis. Those are each important questions to ask in further research. ✦

Donations to the ILCF support the next generation of lung cancer physicians and scientists.

Donate today at IASLC.org/ILCF The ILCF Young Investigator Award has been a terrific vote of confidence, not only for an early-career clinician researcher, but more importantly for the entire multidisciplinary team I am part of. Recognition of our efforts with a grant from a prestigious international organization such as ILCF is validation that we are on track to do more for patients with lung cancer.”

Dr. Ashanya Malalaserkera ILCF Young Investigator Award Recipient 2019-2020

Q: What is your current strategy for managing brain metastasis?

A: If it’s a solitary lesion or multiple lesions that can be encompassed by ste-

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