LUNG CANCER
NEWS
V2/ N4 / AUGUST 2017
FOR THORACIC SPECIALISTS www.iaslc.org
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 GLOBAL RESEARCH REPORT
INSIDE 2
IASLC Workshop in Lung Cancer Clinical Research
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Comments on the 8th Edition of the TNM Classification of Lung Cancer
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Names and News
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FDA Corner: In Speech to Agency, New FDA Commissioner Highlights Anti-Smoking Effort
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Shanghai Cancer Recovery Club
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NCI Corner: Interview with Jeff Abrams, MD Breaking News Briefs Ellen V. Sigal, PhD: Leading the Cancer Research Advocacy Community
Changing Treatment Paradigm for ALK-Positive Lung Cancer By Cynthia L. Kryder, MS, CCC-Sp
Rearrangements in the anaplastic lymphoma kinase (ALK) gene occur in approximately 2% to 7% of patients with advanced non-small cell lung cancer (NSCLC).1 For patients with advanced ALK-positive NSCLC, the current firstline standard of care is crizotinib, a MET tyrosine kinase inhibitor (TKI) with activity in ALK-rearranged NSCLC. It has been shown to yield very high response rates (exceeding 60%) and to improve progression-free survival (PFS) compared with standard chemotherapy when used in patients with advanced ALK-positive NSCLC whose disease has progressed on previous chemotherapy, including those with brain metastases.2-4 Nevertheless, most patients with ALK-positive NSCLC treated with firstline crizotinib will eventually relapse, either due to the development of ALK resistance mutations or inadequate CNS drug penetration.3,5
Ceritinib, alectinib, and brigatinib are next-generation ALK TKIs that have emerged as standard therapy for patients with advanced ALK-positive NSCLC who experience disease progression while on crizotinib. These agents have been shown to be more potent with more brain penetrance than crizotinib. Additionally, ceritinib and alectinib both demonstrate activity against common crizotinib-resistance mutations, such as the gatekeeper ALK L1196M mutation.6,7 Emerging data suggest that these agents also may have a role in the first-line setting. The global, randomized phase III ASCEND-4 trial compared ceritinib with platinum/pemetrexed chemotherapy in newly diagnosed patients with advanced ALK-positive NSCLC. Ceritinib reduced the risk of disease progression or death by 45% compared with standard chemotherapy. Patients who received ceritinib had significantly longer median PFS, 16.6
S M O K I N G C E S S AT I O N A N D T O B A C C O C O N T R O L
months versus 8.1 months in the chemotherapy arm (HR = 0.55, P<0.00001).8 Based on these positive results, ceritinib (Zykadia) was approved by the FDA on May 26, 2017, for first-line treatment of patients with ALK-positive, advanced NSCLC. Following closely behind is alectinib, which in the phase III global ALEX trial showed superior efficacy compared with crizotinib as first-line therapy for treatment-naive patients with advanced ALK-positive NSCLC. Compared with crizotinib, alectinib prolonged PFS, as well as the time to CNS progression, in treatment-naive patients with ALKpositive NSCLC. Results of the ALEX trial were presented in June at the 2017 annual meeting of the American Society of Clinical Oncology during the thoracic oncology plenary session.9 continued on page 4
IN MEMORIAM
World No-Tobacco Day 2017: Women Against Lung Cancer in Europe’s European Union Event on Primary Prevention By Gian Piero Bandelli, MD, Federica Ferraresi, WALCE Advocate, and Silvia Novello, MD, PhD
On the occasion of World No Tobacco Day 2017, Women Against Lung Cancer in Europe (WALCE), in partnership with European Network for Smoking and Tobacco Prevention (ENSP), European Lung Foundation (ELF), European Respiratory Society (ERS), Fondazione Insieme Contro il Cancro, and Associazione Italiana Pneumologi Ospedalieri (AIPO), promoted a double event in Brussels focused on primary prevention and smoking cessation. The initiative was a great success, both in broad appeal and in terms of the number of visitors. On May 30-31, a 2-day exhibition entitled “Go out of the tunnel. Don’t burn away your future” was held in Place de la Monnaie (Figure 1A) in a structure shaped like a giant cigarette. Committed pulmonologists and oncologists performed counseling during the exhibition,
and educational materials on smoking cessation were displayed. Attendees were offered a basic spirometry test; a total of 450 spirometries were performed. Over 600 people of all ages, mainly smokers,
reviewed the exhibit and requested information on smoking-related diseases and smoking cessation programs (Figures 1B and 1C). There is a lack of knowledge in the general population about pulmonary function tests and about the wide array of diseases related to smoking history. For example, most of the people entering the exhibit did not know that 3.1 million people continued on page 7
Figure 1. A) External view of campaign exhibit for “Go out of the tunnel. Don’t burn away your future,” Place de la Monnaie, Brussels. B) Internal view of campaign exhibit: attendees waiting for spirometry, C) attendees asking for information.
Robert L. Comis, MD Clinical Trial Leader and Patient Champion Passes Away at 71 Robert L. Comis, MD, passed away suddenly in his home on May 10, 2017. He was 71. A leader in international oncology research since 1977, Dr. Comis was a champion of patient access to clinical studies in cancer, spearheading initiatives to raise awareness about the pivotal role of cancer clinical trials in cancer prevention, detection, and treatment. Dr. Comis’ leadership in the field of oncology was key to the development of continued on page 6
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IASLC LUNG CANCER NEWS / AUGUST 2017
MEETING NEWS
IASLC Workshop in Lung Cancer Clinical Research
LUNG CANCER
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
By Luis E. Raez, MD
The IASLC-Latin American Group (LATAM) successfully organized another “Workshop in Lung Cancer Clinical Research,” as it has done before in other countries like Chile and Peru. Dr. Christian Rolfo and Dr. Luis Corrales chaired the workshop. They were joined by another 10 IASLC faculty from LATAM, including Drs. Luis E. Raez (US), Christian Caglevic (Chile), Nise Yamaguchi (Brazil), Marileila Garcia (US), David Hong (US), Oscar Arrieta (Mexico), and Norma Pilnik (Argentina). A number of these faculty are shown in Figure 1. This event took place May 18-20 in San Jose, Costa Rica. Dr. Fred R. Hirsch, IASLC CEO, came in person to open the workshop and to give several lectures regarding lung cancer targeted therapy and personalized medicine. These workshops, created by the IASLC-LATAM group, have the goals of not only teaching oncology fellows and young Latin American oncologists from different specialties the latest in lung cancer diagnosis and therapy, but also giving them the tools to be able to move forward with clinical research. The next workshop will be in 2018 in Punta del Figure 1. Workshop faculty (partial): Drs. Corrales, Pilnik, Raez, Hirsch, Yamaguchi, and Garcia. Este, Uruguay. ✦
EDITOR Corey J. Langer, MD, FACP ASSOCIATE EDITORS Fabrice Barlesi, MD and Caicun Zhou, MD IASLC CEO Fred R. Hirsch, MD, PhD MANAGING EDITOR AND PUBLISHER Deb Whippen, Editorial Rx, Inc. PRODUCTION DIRECTOR Doug Byrnes GRAPHIC DESIGNER Amy Boches, biographics 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 editor@iaslclungcancer.net. 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.
Official Journal of the International Association for the Study of Lung Cancer Editor-in-Chief: Alex A. Adjei, MD, PhD, FACP, Mayo Clinic, Rochester, MN, USA The Journal of Thoracic Oncology ( JTO), the official journal of the International Association for the Study of Lung Cancer, is the primary educational and informational publication for topics relevant to detection, prevention, diagnosis, and treatment of thoracic malignancies. JTO emphasizes a multidisciplinary approach, and includes original research (clinical trials and translational or basic research), reviews, and opinion pieces. The audience consists of epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonary specialists, radiologists, pathologists, and research scientists with a special interest in thoracic oncology.
ISSN: 1556-0864 A subscription to JTO is a benefit of membership in the IASLC. To join, visit www.IASLC.org.
To subscribe visit jto.org Not yet a member of the IASLC? Take our non-member survey by September 15 for your chance to win a prize! Find more information at: www.iaslc.org/survey
Disclaimer: The ideas and opinions expressed in IASLC Lung Cancer News do not necessarily reflect those of the International Association for the Study of Lung Cancer. The mention of any product, service, or therapy in this publication should not be construed as an endorsement, and the Association accepts no responsibility for any injury or damage to person or persons arising out of or related to any use of material contained in this publication or to any errors or omissions. IASLC MISSION To embrace the study of the etiology, epidemiology, prevention, diagnosis, treatment, and all other aspects of lung cancer and other thoracic malignancies; to provide education and information about lung cancer and other thoracic malignancies to IASLC members, to the medical community at large, and to the public; to use all available means to eliminate lung cancer and other thoracic malignancies as a health threat for the individual patient and throughout the world.
IASLC LUNG CANCER NEWS / AUGUST 2017
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L U N G C A N C E R S TA G I N G
Comments on the 8th Edition of the TNM Classification of Lung Cancer By Fabrice Barlesi, MD, PhD, and Eric Vallières, MD, FRCSC
An article by Cynthia Kryder and Ramón Rami-Porta in the IASLC Lung Cancer News recently highlighted the innovations of the 8th Edition of the TNM Classification of Lung Cancer. This new classification is more detailed than the 7th edition, as it now contains 11 T descriptors, 6 N descriptors, and 4 M descriptors. These added “details” allow for a more precise prognostic assessment of the tumors, at the cost, however, of more complexity. This raises a crucial question. What are the potential practical consequences of this new classification? In early stages, the prognostic value added by the centimetric division of the T components should have little impact on the local options for therapy whether one is dealing with surgery or radiosurgery per established treatment guidelines. The awaited results of randomized trials in Japan and North America addressing the role of lesser resections in tumors less than 2 cm in size could however
potentially set new standards of surgical treatments for T1AN0 and T1BN0 tumors (stages 1A1 and 1A2). The 8th TNM classification also adds the categories of Tis and T1mi to differentiate the early adenocarcinomas with a lepidic component of AIS (adenocarcinoma in situ) and MIA (minimally invasive adenocarcinoma) from the more invasive adenocarcinomas of 3 cm or less in size: Tis tumors are now considered stage 0 and T1mi stage IA1. Finally, the new centimetric division at 4 cm (T2b) might be useful in more precisely determining the surgical population that may benefit from adjuvant chemotherapy after surgery (stages IIa and above as per the 8th edition) and therefore be helpful in designing and defining inclusion criteria for future adjuvant trials. In locally advanced stages, and especially for patients with stage III NSCLC, introducing the concept of quantifying and describing the N status by the
number of involved N1 and N2 stations (single versus multiple, N1 with N2, N2 without N1), although adding complexity, is a significant step in addressing the vastly different groups of node positive patients we treat. This delineation will help better define therapeutic strategies on or off trial for this very heterogeneous group of patients, where combined modality treatments are the norm. Indeed, the value of surgery, induction chemotherapy, and potentially adjuvant radiotherapy may be better characterized in the future on the basis of these new stage distinctions. In advanced stages, the subclassification of the M component now separates patients with isolated extrathoracic metastasis (M1b) from those with multiple extrathoracic sites of disease (M1c), a differentiation that will be useful in an era where local consolidative therapy in selected cases of oligometastatic involvement has yielded strong PFS benefit in
INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER
Conquering Thoracic Cancers Worldwide
8th Edition of the TNM Classification for Lung Cancer
T – Primary Tumour TX
T0 Tis T1 T1mi T1a T1b T1c T2
T2a T2b T3 T4
Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy No evidence of primary tumour Carcinoma in situ Tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)1 Minimally invasive adenocarcinoma2 Tumour 1 cm or less in greatest dimension1 Tumour more than 1 cm but not more than 2 cm in greatest dimension1 Tumour more than 2 cm but not more than 3 cm in greatest dimension1 Tumour more than 3 cm but not more than 5 cm; or tumour with any of the following features3 • Involves main bronchus regardless of distance to the carina, but without involving the carina • Invades visceral pleura • Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, either involving part of the lung or the entire lung Tumour more than 3 cm but not more than 4 cm in greatest dimension Tumour more than 4 cm but not more than 5 cm in greatest dimension Tumour more than 5 cm but not more than 7 cm in greatest dimension or one that directly invades any of the following: chest wall (including superior sulcus tumours), phrenic nerve, parietal pericardium; or associated separate tumour nodule(s) in the same lobe as the primary Tumours more than 7 cm or one that invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; separate tumour nodule(s) in a different ipsilateral lobe to that of the primary Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s)
N2 N3
M- Distant Metastasis M0 M1 M1a M1b M1c
No distant metastasis Distant metastasis Separate tumour nodule(s) in a contralateral lobe; tumour with pleural or pericardial nodules or malignant pleural or pericardial effusion 4 Single extrathoracic metastasis in a single organ 5 Multiple extrathoracic metastases in one or several organs
The uncommon superficial spreading tumour of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1a. 2 Solitary adenocarcinoma (</= 3 cm), with a predominantly lepidic pattern and </= 5 mm invasion in greatest dimension in any one focus. 3 T2 tumours with these features are classified T2a if 4 cm or less, or if size cannot be determined and T2b if greater than 4 cm but not larger than 5 cm. 4 Most pleural (pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumour, and the fluid is non-bloody and is not an exudate. Where these elements and clinical judgement dictate that the effusion is not related to the tumour, the effusion should be excluded as a staging descriptor. 5 This includes involvement of a single distant (nonregional) node.
References
1. 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;17:1672-1682.
INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER
Conquering Thoracic Cancers Worldwide
STAGE Occult carcinoma 0 IA1 IA2 IA3 IB IIA IIB
IIIA
N – Regional Lymph Nodes NX N0 N1
some clinical trials. It is anticipated that such strategies will be used more frequently in the future, especially in the case of oncogenic-addicted tumors. As stated above, the 8th TNM classification, although more complex than previous iterations, has both practical and clinical research implications and consequences. Lung cancer clinicians will need to become familiar with this new TNM classification and to learn how to use it to its full potential. Hopefully, as in the past, the IASLC will be able to provide ample tutorial and educational material to its members and to the international lung cancer community to help with the transition. ✦
1
IIIB
IIIC IVA IVB
Stage Grouping for the 8th Edition of the TNM Classification for Lung Cancer T
N
M
References
TX
N0
M0
N0 N0 N0 N0 N0 N0 N0 N1 N1 N1 N1 N1 N0 N2 N2 N2 N2 N2 N1 N0 N1 N3 N3 N3 N3 N3 N2 N2 N3 N3 Any N Any N Any N
M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1a M1b M1c
1. Rami-Porta R, Bolejack V, Giroux DJ et al. The IASLC Lung Cancer Staging Project: the new database to inform the 8th edition of the TNM classification of lung cancer. J Thorac Oncol 2014; 9: 1618-1624. 2. Rami-Porta R, Bolejack V, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol 2015; 10: 990- 1003. 3. Asamura H, Chansky K, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol 2015; 10: 1675-1684. 4. Eberhardt WEE, Mitchell A, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the M descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol 2015; 10: 1515-1522. 5. Goldstraw P, Chansky K, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the stage grouping in the forthcoming (8th) edition of the TNM classification of lung cancer. J Thorac Oncol 2015; 11: 39-51. 6. Nicholson AG, Chansky K, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the clinical and pathologic staging of small cell lung cancer in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol 2016; 11: 300-311. 7. Travis WD, Asamura H, Bankier A et al. The IASLC Lung Cancer Staging Project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2016; 11: 1204-1223.
Tis T1mi T1a T1b T1c T2a T2b T1a T1b T1c T2a T2b T3 T1a T1b T1c T2a T2b T3 T4 T4 T1a T1b T1c T2a T2b T3 T4 T3 T4 Any T Any T Any T
Table. Courtesy of International Association for the Study of Lung Cancer. Permission must be requested and granted before photocopying or reproducing this material for distribution. This reference card is provided as an educational service of Eli Lilly and Company with the permission of IASLC. ATONC00274 11/2016
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IASLC LUNG CANCER NEWS / AUGUST 2017
Changing Treatment from page 1
The ALEX Trial
The open-label, randomized phase III ALEX trial compared first-line alectinib 600 mg BID with crizotinib 250 mg BID in patients with stage IIIB/IV ALK-positive NSCLC, as determined by immunohistochemistry. The trial enrolled 303 systemic-treatment-naive patients from 29 countries. About 40% of patients in each treatment arm had CNS metastases, all of whom had undergone CNS-metastasis treatment, including whole-brain radiotherapy, radiosurgery, brain surgery, or a combination of these modalities. The primary endpoint was investigator-assessed PFS, with systematic CNS imaging in all patients. Secondary endpoints included independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression (TTP), objective response rate (ORR), overall survival (OS), and safety. Patients who received alectinib experienced significantly longer PFS than those who received crizotinib (HR 0.47, 95% CI 0.34–0.65, P <0.0001). Median PFS was 11.1 months (95% CI 9.1–13.1) for crizotinib, but was not reached in the alectinib arm (95% CI 17.7–not estimated [NE]). Overall survival data were not yet mature. Time to CNS progression was a key secondary endpoint of this trial. Alectinib showed neuroprotective capacity and significantly delayed CNS progression. CNS progression was detected in 12% of patients in the alectinib arm, compared with 45% in the crizotinib arm (HR 0.16, P <0.0001). The cumulative incidence rates of 12-month CNS progression were 9.4% (95% CI 5.4–14.7) in the alectinib arm and 41.4% (95% CI 33.2–49.4) in the crizotinib arm. Other key secondary endpoints showed superiority for alectinib compared with crizotinib. IRC-assessed median PFS was 25.7 months (95% CI 19.9–NE) for alectinib versus 10.4 months (95% CI 7.7–14.6) for crizotinib. The IRC-assessed cause-specific hazard ratio of CNS progression was 0.16 (95% CI 0.10–0.28, P<0.0001). The ORR was 83% (95% CI 76–89) for alectinib versus 76% (95% CI 68–82, P=0.09) for crizotinib. With regard to adverse events (AEs), patients treated with alectinib had fewer grade 3 and 4 AEs, 41% versus 50% with crizotinib. The rate of AEs leading to discontinuation, dose reduction, and interruption of treatment was lower in the alectinib arm. The results of the ALEX trial replicate earlier findings of J-ALEX, a phase III trial that compared alectinib (300 mg BID) and crizotinib head to head in
207 Japanese patients with ALK-positive NSCLC.10 At the second interim analysis, median PFS had not yet been reached with alectinib (95% CI 20.3-NE) and was 10.2 months (95% CI 8.2-12.0) with crizotinib.
Where Do We Go Next?
The results of the ASCEND-4 and the ALEX trials signal a shifting treatment paradigm that moves away from cytotoxic chemotherapy and crizotinib toward next-generation ALK inhibitors as first-line therapy for patients with
advanced ALK-positive NSCLC. Still, several questions remain. For example, given the neuroprotective activity of alectinib, what is the role of radiotherapy in patients who present with CNS metastases at the time of diagnosis? And how should physicians treat patients who develop resistance to first-line ceritinib and alectinib? Can we develop a single algorithm based on resistance mutations that occur on treatment to determine which TKI to administer next? Or do we default to standard chemotherapy once second-line agents migrate into the first-
line setting? Ultimately, a better understanding of the resistance mechanisms will be necessary to develop future effective second-line therapies. Still unknown is the effect that nextgeneration ALK inhibitors will have on overall survival. Whether the prolonged PFS seen with alectinib and ceritinib translates into a survival advantage has not yet been determined. Nevertheless, the results of the ALEX trial point to a new standard of care for previously untreated patients with ALK-positive NSCLC. ✦ References continued on page 8
THOUGHT LEADER PERSPECTIVE
with Benjamin Solomon, MBBS, PhD, FRACP Please give us a global perspective on the results of global ALEX. Will alectinib definitively displace crizotinib or ceritinib as the first-line treatment for ALK-rearranged non-small cell lung cancer (NSCLC)? The rapid pace of development of ALKtargeted therapies in NSCLC in the last decade has transformed outcomes for patients with ALK-rearranged NSCLC. Crizotinib, the first in class ALK inhibitor, was approved for ALK -rearranged NSCLC on the basis of phase I and II data in 2011 and established as optimal first-line therapy for newly diagnosed ALK-rearranged NSCLC compared with chemotherapy in 2014 by the PROFILE 1014 study. Ceritinib was also shown to be another option for treatment for ALK-rearranged NSCLC given its superiority to chemotherapy demonstrated in the ASCEND-4 study. The global ALEX phase III study represents a major practicing-changing advance setting a new international standard for the first-line treatment of ALK-rearranged NSCLC. ALEX is a well-designed and conducted study that unequivocally demonstrated the superiority of alectinib over crizotinib, the previous standard first-line therapy. Efficacy was superior with alectinib not just in terms of progression-free survival (PFS) but also in terms of CNS activity. PFS was superior for alectinib over crizotinib with a hazard ratio of 0.47–a hazard ratio similar in magnitude to the PFS benefit of crizotinib over chemotherapy. In addition, alectinib was highly active in the CNS, both treating established metastases and by preventing CNS
progression. Notably this efficacy is associated with a favorable toxicity profile. Of note, ALEX was not the first study to examine the efficacy of firstline alectinib. The remarkable efficacy of first-line alectinib was reported in the Japanese phase 1/II study (AF-001JP) and confirmed in the J-ALEX study, but the applicability of these results outside the Japanese population was not established until global ALEX was reported. The ALEX study unequivocally establishes alectinib as a superior option for the initial treatment of patients with newly diagnosed ALK-rearranged NSCLC worldwide and indicates that if alectinib is available it should be used as first-line treatment instead of crizotinib. While there is no direct comparison with ceritinib, the efficacy and safety profile of alectinib over ceritinib again suggest that alectinib is to be preferred Unfortunately, as is the case for other tyrosine kinase inhibitors (TKIs), resistance to alectinib will remain an issue. We will continue to need to develop drugs such as lorlatinib that can target mechanisms of resistance to alectinib and to identify alternative strategies to delay or prevent emergence of resistance to ALK TKIs to further improve outcomes for ALK-rearranged NSCLC. What are the cost considerations when it comes to these highly specialized TKIs? Timely and equitable access to highly effective therapies for lung cancer and other diseases remains a major issue worldwide. Delays in drug approval and reimbursement lead to global disparities and indeed inequities in access to
Benjamin Solomon
effective treatment. Cost considerations are significant–TKIs such as crizotinib, ceritinib, and alectinib can cost patients between $5,000 and $15,000 per month. In many parts of the world delays in approval can mean that these costs need to be born by patients and their families–meaning that patients may have to resort to crowd funding, risk financial difficulties or perhaps not have access to drug. Do you think we can get by on 300 mg BID as employed in the J-ALEX trial? Or should we stick with 600 mg BID? In the J-ALEX study a dose of 300 mg BID, the approved dose in Japan, was used in contrast to the dose of 600 mg BID used in the global ALEX study. This reflects peculiarities of dosing for Japanese patients where dose escalation in the Japanese phase I study (AF -001 JP) was limited to 300 mg BID due to maximal concentrations of sodium lauryl sulfate indicated by Japanese regulatory authorities. Data indicate that plasma levels of alectinib in Japanese patients treated on 300 mg BID are similar to those seen with 600 mg in Western patients. There are concerns that there may be variability in drug levels achieved with doses less than 600 mg in Western patients. On this basis, outside Japan (or perhaps outside a Japanese population) the standard dose should remain 600 mg BID.
IASLC LUNG CANCER NEWS / AUGUST 2017
THOUGHT LEADER PERSPECTIVE
with Alice Shaw, MD, PhD Based on global ALEX, has crizotinib been relegated to the therapeutic scrapheap when it comes to patients with ALK rearrangements? Or does it retain some role? The global ALEX study, presented at ASCO 2017 and published simultaneously in the NEJM, compared alectinib head-to-head with crizotinib in previously untreated, advanced ALK-positive NSCLC. The study met its primary endpoint and showed that alectinib led to significant prolongation in progression-free survival (PFS) compared with crizotinib (HR= 0.47). In addition, alectinib demonstrated greater CNS activity than crizotinib, and significantly delayed time to CNS progression. Given the positive results, particularly regarding CNS disease, alectinib has become the new standard of care for newly diagnosed patients with advanced ALK-positive NSCLC. While crizotinib may soon be replaced as the preferred first-line agent for ALK-positive NSCLC, crizotinib could still have a role in later lines of therapy. For example, patients who fail on alectinib due to MET amplification may be responsive to crizotinib, which is a multitargeted ALK/ROS1/ MET inhibitor. A second example may be the use of crizotinib in patients who have relapsed due to a specific ALK resistance mutation—ALK L1198F— which we previously showed can resensitize resistant patients to crizotinib. As we continue to study resistance to ALK-targeted therapies, additional roles for crizotinib could be identified.
is also superior to crizotinib. While ceritinib and alectinib have not been directly compared in a randomized trial, crosstrial comparisons suggest that alectinib is likely superior to ceritinib. In ASCEND4, the median PFS with first-line ceritinib was 16.6 months, while in global ALEX, the median PFS with first-line alectinib (based on independent review) was 25.7 months. In addition, alectinib is CNS penetrable and highly CNS active. This has been demonstrated not only in the treatment-naïve setting, but also in the post-crizotinib and post-ceritinib settings. Finally, in terms of safety, alectinib has been associated with only mild side effects, while ceritinib can cause significant gastrointestinal toxicity including transaminitis. Thus, both the efficacy and safety data now available support the use of alectinib over ceritinib as firstline therapy. As with crizotinib, there may still be a role for ceritinib in later lines of therapy. As an example, one of the most common alectinib-resistance mutations–ALK I1171X–is sensitive to ceritinib in preclinical studies and clinical case reports.
Given the results observed in global ALEX, is there a viable role for ceritinib?
How often should patients with ALK translocations be screened for CNS metastases?
Ceritinib is another second-generation ALK inhibitor that has been extensively studied in the crizotinib-resistant setting, and has also now been studied in the treatment-naïve setting. In ASCEND-4 published by Soria and colleagues in Lancet earlier this year, ceritinib was shown to be superior to platinum/pemetrexed chemotherapy as first-line therapy for advanced ALK-positive NSCLC. Of note, the comparator was chemotherapy rather than crizotinib; however, based on the positive results, it is likely that ceritinib
For patients with ALK-positive tumors with no known brain metastases who are receiving treatment with crizotinib, I typically recommend surveillance brain MRIs every 3 to 6 months (sooner if new symptoms occur). Crizotinib is known to be poorly CNS penetrable, and a significant proportion of ALK-positive patients treated with crizotinib will develop CNS metastases. In the global ALEX study, we showed that in crizotinib-treated patients, the cumulative incidence rate of CNS progression was 41% at 12 months, highlighting the need for frequent CNS
Alice Shaw
surveillance. For patients without brain metastases treated with ceritinib, I would recommend a similar frequency of brain imaging. Alectinib is highly CNS penetrant and has been shown in multiple studies to be very effective in treating and preventing CNS metastases. Nevertheless, patients treated with alectinib can still develop progressive CNS disease. Thus, I also recommend surveillance brain MRIs in patients receiving alectinib, on the order of every 6 to 12 months. The optimal frequency of surveillance brain scans in patients without known CNS disease remains to be determined. However, in the global ALEX study, the cumulative incidence rate of CNS progression at 12 months was 9% in the alectinib arm. How do you manage myalgias and muscle cramps that occur with alectinib? Muscle symptoms—pain, tenderness, weakness—are commonly seen with initiation of alectinib. These symptoms tend to peak during the first 1 to 2 months, and then usually subside. Often, but not always, these symptoms are associated with elevation in creatinine phosphokinase (CPK). Many patients describe feeling as if they had an intense workout. For mild muscle symptoms, patients may take an occasional over-the- counter pain reliever such as acetaminophen or ibuprofen. For moderate to severe muscle symptoms, patients may require a dose interruption and possibly dose reduction. Most patients will notice that these muscle symptoms resolve rapidly with dose hold, and they often can tolerate a lower dose of alectinib well. Over the years, I have had a handful of patients with severe muscle symptoms, ultimately requiring permanent discontinuation, but these cases are rare. What do we do therapeutically once patients develop resistance to alectinib? Patients who develop resistance to alectinib have a number of therapeutic options. I strongly recommend rebiopsy of a resistant site, as we have recently shown that in about one-half of alectinibresistant cases, the cancer has become resistant due to a secondary mutation within the ALK kinase domain. The presence of an ALK mutation suggests that the cancer may still be ALK dependent and hence responsive to further ALK inhibition. In preclinical and early clinical studies, we have shown that resistant cancers harboring an ALK kinase mutation are responsive to the pan-inhibitory, third-generation ALK inhibitor
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lorlatinib. Depending on the exact ALK resistance mutation, the cancer may also respond to other ALK inhibitors, including ceritinib and brigatinib. In addition to ALK-targeted therapies, patients whose disease progresses on alectinib are also candidates for standard therapy (such as pemetrexedbased chemotherapy) and clinical trials (with experimental ALK inhibitors or emerging combination therapies). Are we at a point where we can match “resistance mutations” with appropriate TKI? Or is this still a “pipedream?” Unlike EGFR mutant NSCLC, in ALKpositive NSCLC, a multitude of different ALK resistance mutations have been discovered in patients relapsing on first- and next-generation ALK inhibitors. Preclinical studies with cell line models harboring different ALK resistance mutations suggest that different ALK inhibitors have differential activity depending on the exact resistance mutation. This has led to the idea of personalizing or matching ALK inhibitors based on the underlying ALK resistance mutation. This idea has become increasingly important with the widespread use of second-generation ALK inhibitors post crizotinib. As an example of the potential clinical relevance of matching drugs with mutations, in patients who have failed sequential crizotinib followed by a second generation ALK inhibitor, rebiopsies have shown that about a quarter of cases have acquired an ALK G1202R resistance mutation. This mutation confers resistance to both first- and second-generation ALK inhibitors, so just switching the patient to a different second-generation ALK inhibitor is unlikely to be effective. However, lorlatinib does have clinical activity against this particular mutation, so ideally patients harboring ALK G1202R should be directed to this drug (currently available through an expanded access program in the US). To prospectively examine the utility and feasibility of personalizing ALK therapies, the National Cancer Institute, in collaboration with the NRG cooperative group, will be launching the ALK Master Protocol in early 2018. This protocol will focus on ALK-positive NSCLC patients whose disease has progressed on a next-generation ALK inhibitor, and will use ALK mutation status (as determined by tumor and liquid biopsies) to match patients to the appropriate ALK inhibitor(s).
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IASLC LUNG CANCER NEWS / AUGUST 2017
Names and News Gideon M. Blumenthal, MD was named Acting Deputy Director, Office of Hematology & Oncology Products, US Food and Drug Administration, Silver Spring, US. Prior to this appointment, Dr. Blumenthal was Clinical Team Leader for Thoracic Oncology and Head and Neck Cancer and Scientific Liaison for Lung Cancer in the Division of Oncology Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, US. David R. Gandara, MD, was honored as the lung cancer “Giant of Cancer Care” in the 2017 Giants of Cancer Care® recognition program by OncLive. Awardees are selected by their peers for advancing the field of oncology by contributions in research and clinical practice. Dr. Gandara is Professor and Director of Thoracic Oncology at UC Davis Comprehensive Cancer Center, Sacramento, US. He is former President of IASLC, past World Conference President 2009, and current IASLC Treasurer. Solange Peters, MD, PhD, was elected President for 20202021 of the European Society for Medical Oncology (ESMO). Professor Peters is Head of the Medical Oncology Service, Chair of Thoracic Oncology, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Roman V. Petrov, MD, PhD, has been appointed Assistant Professor, Department of Surgical Oncology, Fox Chase Cancer Center; and Assistant Professor, Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, US. Prior to his appointment, Dr. Petrov served as an Attending Physician and Chief of the Department of Thoracic Surgery at Memorial Health System in Marietta, OH, US. Naiyer A. Rizvi, MD, was named to the ARMO BioSciences, Inc., Board of Directors, Redwood City, US. Dr. Rizvi is Director of Thoracic Oncology and Co-Director of Cancer Immunotherapy, Division of Hematology and Oncology, Columbia University Medical Center, NY, US, and holds the Price Chair in Clinical Translational Research. Ravi Salgia, MD, PhD, was awarded the IACA Award for Outstanding Contributions to Oncology by the Indo-American Cancer Association (IACA). This award is given to medical oncologists and researchers who have helped define modern cancer medicine. Dr. Salgia is the Arthur & Rosalie Kaplan Chair in Medical Oncology and Therapeutics Research at City of Hope, and the Associate Director for Clinical Sciences in City of Hope’s Comprehensive Cancer Center, Duarte, US.
Comis In Memoriam from page 1
several therapeutic agents used in stateof-the-art treatment regimens administered to generations of patients with cancer, with a core focus in thoracic neoplasms. His accomplishments and collaborative work, in collaboration with Phil Bonomi, MD, and Alan Sandler, MD, included phase III ECOG studies that led to FDA approval of both paclitaxel and bevacizumab for non-small cell lung cancer. Dr. Comis is also credited with leading the design and implementation of the NCI-MATCH (EAY131) trial, a precision medicine trial across multiple cancers, which completed the enrollment of 6,000 patients in 15 months. Most recently, Dr. Comis was Group Co-Chair of the ECOG-ACRIN Cancer Research Group (1995–2017), a multidisciplinary NCI-sponsored scientific organization that designs and conducts biomarker-driven cancer research. There
he was responsible for its entire scientific program, overseeing the design and conduct of cancer research in the adjuvant and advanced disease setting. He was also Professor of Medicine and Director of the Drexel University Clinical Trials Research Center, Philadelphia, US. A career practicing medical oncologist and clinical researcher, Dr. Comis served on the boards of the American Society of Clinical Oncology, American Radium Society, C-Change, and the National Coalition for Cancer Research, and on the editorial boards of the Journal of Clinical Oncology, Cancer Research, and Clinical Cancer Research. He authored more than 150 scientific articles, and contributed to more than 20 scientific and medical textbooks on cancer. Dr. Comis also served in various clinical practice and research leadership
Left to right: Phil Bonomi, Bob Comis, Frances Shepherd, Paul Bunn, and Corey Langer. Santa Monica, CA, February 2017.
“Bob Comis was a pioneer in thoracic oncology. At a time when the outlook for lung cancer patients was bleak, Bob’s enthusiasm and innovative ideas inspired us. Many of us also had the good fortune to gather around the piano and enjoy his musical talent while sharing his zest for life. —Phil Bonomi, MD
positions at Thomas Jefferson University Hospital, Temple University School of Medicine, Fox Chase Cancer Center and Allegheny Cancer Center. His leadership in clinical research continued through his membership on the National Cancer Institute’s National Clinical Trials Leadership Management Committee and frequent appearances as an expert to the US Congress, Institute of Medicine, President’s Cancer Panel, National Cancer Advisory Board, and many others. Finally, Dr. Comis played a fundamental role in the history of the International Association for the Study of Lung Cancer (IASLC), having mentored or collaborated with many IASLC members throughout the course of his career. Noting his contributions to cancer clinical trials, Paul A. Bunn, Jr, MD, stated, “Bob Comis had a huge impact on lung cancer...and on cancer clinical trials. After his training, Dr. Comis worked at the NCI CTEP. This group of distinguished investigators transformed the way that early-stage cancer clinical trials are conducted.”
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A NY native and graduate of Fordham University, Dr. Comis received his medical degree from the State University of New York Health Science Center School of Medicine in Syracuse, NY, where he also completed his medical internship and residency. He served as a Staff Associate at the National Cancer Institute and completed a medical oncology fellowship at the Sidney Farber (now DanaFarber) Cancer Center in Boston. “I owe Bob a lifelong debt of gratitude. Without him, I’d never have had the career I’ve had or the opportunities I’ve been offered," said Corey J. Langer, MD, Editor of IASLC Lung Cancer News, in response to Dr. Comis' passing.” At each step of my professional journey, he was tirelessly supportive every time I tried to 'stretch the envelope' and a reality check when I went a bit too far. I am deeply saddened. The world is an emptier place without Bob." “Dr. Comis was a compassionate colleague, a dedicated husband, father, and grandfather with loving friends and family who will miss him dearly but remember him fondly,” said Dr. Bunn in reflection. ✦
IASLC LUNG CANCER NEWS / AUGUST 2017
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No-Tobacco Day 2017 from page 1
In Speech to Agency, New FDA Commissioner Highlights Anti-Smoking Efforts By Erik T. MacLaren, PhD
On May 11, 2017, Scott Gottlieb, MD, was sworn in as the 23rd Commissioner of Food and Drugs of the US Food and Drug Administration (FDA). Dr. Gottlieb previously served as Deputy Commissioner for Medical and Scientific Affairs at the FDA, and his background includes experience in medicine, medical policy, and public health advocacy. As the new FDA Commissioner, Dr. Gottlieb delivered his first speech to FDA staff on May 15, emphasizing patient and consumer protection as the core mission of the agency.1 In an address that also discussed the need for the agency to achieve operational efficiencies and the challenge of addressing the increase in opioid abuse, Dr. Gottlieb highlighted tobacco cessation, harm reduction, and youth smoking prevention as an area of great consequence for public health. He said that “among these and many other opportunities, there’s probably no single intervention or product we’re likely to create in the near future that can have as profound an impact on reducing illness and death from disease as our ability to increase the rate of decline in smoking.” In remarks touching on the future of drug development, the Commissioner noted, “Congress gave us a clear mandate to be forward-leaning when it comes to how we’ll evaluate safety and efficacy in view of emerging scientific insight and better analytical tools,” and he identified the implementation of the 21st Century Cures Act as a priority. Both Dr. Gottlieb and
(Figure 2): Prof. Silvia Novello (WALCE President and Full Professor of Medical Oncology at the University of Turin), Prof. Galina Sakharova (WHO, from Russia), Dr. Carlos Jimenez-Ruiz (ERS Tobacco Control Committee Chair, from Spain), Prof. Francisco Rodriguez Lozano (ENSP President from Spain), Gilles Pargneaux (Member of European Parliament), Dr. Paraskevi Katsaounou (Athens Medical School), Prof. Martin Raw (University of Nottingham– UK), and Donal Buggy (Irish Cancer Society). ✦
Scott Gottlieb
Robert M. Califf, MD, the previous FDA Commissioner, have pointed to this legislation as a vehicle for greater regulatory clarity in the development of digital health technologies and for increased efficiency in clinical trials through changes in study design such as common control arms for trials of different drugs for the same indication.2,3 On the issue of high consumer prices for medications, the Commissioner suggested the FDA could take actions to indirectly reduce prices and to ensure that the generic drug process is not gamed at the expense of consumers. “We still need to be taking meaningful steps to get more low-cost alternatives to the market, to increase competition, and to give consumers more options,” he said. Dr. Gottlieb also indicated the need for action is even more urgent with the emergence of more complex drugs and biosimilars. The Commissioner’s emphasis on efforts to prevent youth smoking, to help more smokers quit, and to produce scientific data to inform potential harm reduction strategies
CORNER
die every day due to chronic obstructive pulmonary disease, with cigarette smoking the major cause. The campaign also caught the attention of local television broadcasters and journalists. In Italy, the program “Go out of the tunnel” has been organized as a roadshow. During 2015 and 2016 (from World No Tobacco Day in May until November, which is Lung Cancer Awareness Month) the tunnel toured 7 major Italian cities (Turin, Bari, Milan, Padua, Lecce, Messina, and Rome). Over 10,000 individuals have visited the tunnel, including young people, adults, and seniors, and more than 2,000 spirometries have been performed. In addition, the Italian Minister of Health, the Hon. Beatrice Lorenzin, attended the event in 2015 in Rome. In autumn 2017, a third edition of this campaign will take place, in 3 additional cities in Italy (Palermo, Turin and Ravenna). Along with the tunnel exhibit in Brussels, on May 31 at the EU Parliament, a high-level event entitled “FCTC Article 14–Time to prioritise tobacco cessation and dependence treatment” (Fig. 2) was organized and hosted by an Italian Member of European Parliament, Alberto Cirio, and by a French Member of European Parliament, Gilles Pargneaux. The aim of this session, which featured the participation of the EU Commissioner for Health and Food Safety, Dr. Vytenis Andriukaitis, was to facilitate the implementation of World Health Organization Framework Convention on Tobacco Control article 14 at a national level. “Tobacco is a real threat to development,” Dr. Andriukaitis declared during the workshop. “It cuts lives short, weakens human capital and workforce, increases health and social costs – all this in countries struggling to cope with serious economic and social problems. And this is why tobacco control must be part and parcel of our efforts to reach the sustainable development goals–right here in Europe and worldwide. To ‘ensure healthy lives for all’—our key goal for 2030—we need stronger efforts to reduce smoking.” Article 14, in fact, states that “each Party shall develop and disseminate appropriate, comprehensive and integrated guidelines based on scientific evidence and best practices, taking into account national circumstances and priorities, and shall take effective measures to promote cessation of tobacco use and adequate treatment for tobacco dependence.” Delegates with valuable information and practices in place to advocate and guide this issue included
for those unwilling or unable to quit is of particular interest to the thoracic oncology community, and Dr. Gottlieb has continued to promote smoking prevention. In June 2017, he highlighted agency efforts in this area in a statement on the results of the 2016 National Youth Tobacco Survey.4 Dr. Gottlieb pointed to FDAfunded, science-based educational campaigns such as “The Real Cost” as effective tools to keep young people from smoking; 4,000 warning letters have been issued by the FDA to retailers since August 2016 for selling newly regulated tobacco products such as e-cigarettes, cigars, and hookah tobacco to minors. As an organization promoting not only the study of thoracic cancers but also patient education and cancer prevention efforts, the IASLC is uniquely suited to assist in the FDA’s drive to reduce the harms of smoking as an important step toward eliminating thoracic cancer. ✦ References
1. Gottlieb, S. Dr. Gottlieb’s first remarks to FDA staff. 2017 May 15. Available at: https://www. fda.gov/NewsEvents/Speeches/ucm558566.htm. 2. Gottlieb, S. Fostering medical innovation: A plan for digital health devices. FDA Voice. 2017 June 15. Available at: https://blogs.fda.gov/ fdavoice/index.php/2017/06/fostering-medicalinnovation-a-plan-for-digital-health-devices/. 3. Califf, M. 21st Century Cures Act: Making progress on shared goals for patients. FDA Voice. 2016 December 13. Available at: https:// blogs.fda.gov/fdavoice/index.php/2016/12/21stcentury-cures-act-making-progress-onshared-goals-for-patients/. 4. Gottlieb, S. Statement from FDA Commissioner Scott Gottlieb, MD, on the 2016 National Youth Tobacco Survey results. 2017 June 15. Available at: https://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm563338. htm.
Figure 2. Delegates participating at the event “FCTC Article 14 – Time to prioritise tobacco cessation and dependence treatment” at the European Parliament, Brussels.
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IASLC LUNG CANCER NEWS / AUGUST 2017
ADVOCACY AND SURVIVORSHIP
Profile of Advocacy: Shanghai Cancer Recovery Club IASLC Lung Cancer News is pleased to present the following Q&A with the staff of Shanghai Cancer Recovery Club, an organization in Shanghai, China, whose mission is ‘’spreading the idea that cancer does not equal death, carrying forward the work of cancer fighting groups, and ‘transcending life’.’’ Please describe the purpose of the Shanghai Cancer Club. Shanghai Cancer Club is a self-help support group and non-governmental organization (NGO) voluntarily united by different cancer patients. “We fight cancer, we surmount the life new boundary,” is the ultimate goal of club members, who suffer from the threat of death and torture of disease, both physiologically and spiritually. What does the Shanghai Cancer Club do? What systems are set up? The patients in our club who are declared recovered take part in voluntary services to help other club members and patients with cancer enhance their confidence to fight against cancer. The club has more than 16,000 members and a three-level management network, defined at the city, district, and activities station level. As the decisionmaking body of the club, the Members’ Congress sets up a Council and Board of Supervisors. Moreover, the club has 13 rehabilitation centers based on the types of cancer and 5 resource centers formed by cancer patients from the city’s highest-ranked hospitals (a class based on Chinese hospital management classification). An art troupe and different hobby groups (each group consists of 16 club members) were also founded by Shanghai Cancer Club. What do you hope to accomplish? We aim to publicize the concept of “group anti-cancer strategy” and to explore the potential role of non-drug intervention such as sports, psychology, and nutrition during cancer recovery. Our goal is to enhance the health literacy of those who suffer from cancer by means of health education and promotion. We hope to improve the quality of life and survival outcomes of our members so that they can possess the spirit of self-improvement, self-reliance and self-love in the face of adversity. Is this free? Or are fees involved? According to the club’s rules, each member is supposed to pay 50 RMB (USD$7.26 equivalent) as an annual
membership fee. The dues that come from our members enable the club to offer members diverse activities. Members can also participate in various activities free of charge, for instance attending lectures on physical rehabilitation and participating in activities organized by the disease guidance center, attending members’ interest groups, etc.
who give talks on their experience to club members), skin therapy, along with music and dance therapy, etc. are just some of the courses included in our club program. Furthermore, by integrating drum music therapy, drama healing, family care, and palliative care introduced from the US, we are trying to promote the ‘combination of education with recreation’ mode
Figure 1. Shanghai Cancer Recovery Club members, volunteers, and medical staff; Shanghai Pulmonary Hospital (12/31/15).
What are your greatest successes? The mental and physiological quality of our members’ lives has been significantly improved by taking part in various social activities that the club offers. Of note, with an average 5-year overall survival rate of 70%, our members get more survival benefits than other patients in China with cancer. In addition, we cooperate with institutions in China and abroad to support multiple scientific research and academic efforts. The Shanghai Cancer Recovery Club’s goal, as stated on their website is “To enhance patients’ confidence in recovery through methods of group therapy, so that after their recovery they can become volunteers and help other cancer patients.” Their motto is: “Don’t ask what society can give to us; ask what we give to society.” IASLC Lung Cancer News thanks the Shanghai Cancer Recovery Club for this profile and looks forward to sharing information about other international patient advocacy groups in future issues.✦ References
1. Shanghai Cancer Recovery Club website. http://chinadevelopmentbrief.cn/directory/shanghai-cancer-recovery-club-上海癌症康复俱乐部 / Accessed May 8, 2017.
Changing Treatment from page 5
References
Figure 2. Members of Shanghai Cancer Recovery Club after 'Health and Running' activities.
Is there any lobbying of governmental agencies involved? Or does the club mainly support patients through their cancer treatment? As an NGO, we get full support and help from Shanghai Charity Foundation, More Love Foundation, and community organizations. However, as an independent corporate body, we carry out the club management and operations independently. The club conducts health education and promotion by developing activities that include psychological counseling, nutrition guidance, and exercise training. This is supplemental care designed to improve the quality of life of patients who have already received standard treatment in the hospital. Guo Lin Qigong, psychological counseling, experience sharing by anti-cancer stars (successful fighters against cancer
of the cancer education. The mission of the club is to use science to cure disease, to devote great love and care to life, and, finally, to bring hope to patients with cancer. Are there separate groups for different cancers? For instance, is there a separate group for lung cancer vs colorectal cancer? Yes, the club has multiple recovery guidance groups based on different cancers, including lung cancer and colorectal cancer. Specifically, 400 lung cancer members created a WeChat (a social mobile app) group online to share their thoughts and experience. We have also established Cancer Patients Resource Centers in Shanghai Pulmonary Hospital and Shanghai Chest Hospital. More than 30 recovered lung cancer patients perform voluntary service there as well.
1. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703. 2. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemtherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167-2177. 3. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALKrearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33:1881-1888. 4. Shaw AT, Yeap BY, Solomon BJ, et al. Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls [abstract]. J Clin Oncol. 2011;29(Suppl 15):Abstract 7507. 5. Zhang I, Zaorsky NG, Palmer JD, et al. Targeting brain metastases in ALK-rearranged non-small-cell lung cancer. Lancet Oncol. 2015;16:e510-e521. 6. Friboulet L, Li N, Katayama R, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4:662-673. 7. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci USA. 2011;108:7535-7540. 8. Soria JC, Tan DS, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389:917-929. 9. Shaw AT, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive advanced ALKpositive non-small cell lung cancer (NSCLC): primary results of the global phase III ALEX study. 2017 ASCO Annual Meeting. Abstract LBA9008. Presented June 6, 2017. http://meetinglibrary.asco. org/record/153629/abstract. Accessed June 20, 2017. 10. Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 May 10. pii: S0140-6736(17)30565-2. doi: 10.1016/S01406736(17)30565-2. [Epub ahead of print].
IASLC LUNG CANCER NEWS / AUGUST 2017
INTERVIEW WITH JEFF ABRAMS, MD /
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BY ERIK T. M AC L AREN , P H D
CORNER
NCI Helping to Save Lives and Improve Cancer Survival Rates Scientific data from clinical trials are essential for evaluating new cancer treatments and setting new standards of care for patients. The National Cancer Institute (NCI) has supported clinical trials for over 50 years through the Cooperative Group Program, which has produced many important improvements in cancer care. Following recommendations in a report issued by the Institute of Medicine in 2010, the Cooperative Group Program has been reorganized into the National Clinical Trials Network (NCTN), with an increased emphasis placed on collaboration. NCI-funded Network trials have influenced state-of-the-art care in many treatment areas, including the introduction of new drugs, but also by conducting trials that are beyond the scope of the pharmaceutical industry. In 2011, the results of a phase 3 trial at the Radiation Therapy Oncology Group RTOG 9410 showed concurrent chemoradiation therapy conferred long-term survival benefits over sequential treatments in patients with stage III non-small cell lung cancer, an important improvement in outcomes that was achieved with currently existing treatments.1 In a study presented at the ASCO annual meeting this year, Joseph M. Unger, PhD, from the SWOG Statistical Center at the Fred Hutchinson Cancer Research Center in Seattle, WA, and colleagues tried to quantify the impact of NCI-funded cancer trials on patient survival.2 Dr. Unger and his coauthors estimated that through 2015, 3.34 million life-years were gained among US patients at a cost of $125 per life year, a survival improvement that could provide 5.6 more life-years to each of the approximately 600,000 individuals who died of cancer in the US in 2016.
Jeff Abrams, MD, Acting Director for Clinical Research and Associate Director of the Cancer Therapy Evaluation Program in the Division of Cancer Treatment & Diagnosis at the NCI, spoke with IASLC Lung Cancer News about this study as well as the broader benefits of the NCTN. Dr. Abrams noted that “there have been many positive Group trials showing an improvement in survival”; such successes include tamoxifen and aromatase inhibitors for adjuvant breast cancer treatment, trastuzumab for adjuvant breast cancer treatment, taxol for adjuvant breast cancer therapy, chemotherapy for adjuvant colon cancer therapy, and chemotherapy for low grade brain tumors, among others. However, the systematic approach of Unger et al. to look across all studies and diseases was a unique one. “This publicly supported trials Network aims to complement the treatment strategies that are supported by industry,” said Dr. Abrams. “Thus, this Network studies rare cancers and pediatric cancer, and does radiation and surgical trials, areas in which industry does not conduct many trials. It also does many drug trials in partnership with industry but tries to avoid duplicating trials industry would do by themselves. As the Unger paper demonstrates, over the many years of its existence, these Network trials have provided evidence that has served to save and prolong the lives of many Americans with cancer. It has done this at a cost for each year of life gained that seems well worth the investment.” Promoting collaborative efforts between industry and other partners is a crucial role of the NCI’s Network trials, and these partnerships are increasingly important in the age of precision medicine. Enrolling enough
patients with specific molecular profiles to test many targeted therapies is difficult for pharmaceutical companies, according to Dr. Abrams. “By working with NCI and the NCTN, these companies can cast a broad net to attract patients, leverage the NCI standing infrastructure, and cost-share regarding the diagnostic testing required to screen the tumors,” he said. “This provides ample incentives for the industry partners and provides patients with options they might not otherwise have.” Examples of such collaborations between government, academic, commercial, and nonprofits include the NCI Molecular Analysis for Therapy Choice (NCI-MATCH; EAY131) trial and the Lung-MAP (SWOG S1400) trial. Both of these trials are testing targeted therapies for cancer depending on genetic testing of the patients and the tumors. Enrolling patients with solid tumors, lymphomas, or myeloma that has progressed on standard treatment or for which there is no standard treatment, NCI-MATCH is a phase 2 precision medicine trial intended to identify targeted drugs or combinations of drugs that produce responses in these patients. Launched in August 2015, NCI-MATCH was spearheaded, in part, by Robert Comis, MD, Co-Chair of ECOG-ACRIN Cancer Research Group, whose death on May 10, 2017, was mourned by the cancer community. Dr. Comis worked with NCI to design and implement the MATCH trial, billed as “the largest, most scientifically rigorous precision medicine cancer trial to date.” Patients are assigned to treatment arms based on the mutational profile of their tumors, genomic sequencing, and other tests. There are over 24 different treatment
• Dabrafenib and trametidnib (Tafinlar and Mekinist) received FDA approval for use in combination for patients with metastatic non-small cell lung cancer (NSCLC) with BRAFV600E mutation as detected by an FDAapproved test. This is the first FDA approval specifically for treatment of patients with BRAFV600E mutationpositive metastatic NSCLC. (6/22/17)
• The FDA also approved the first multiple companion diagnostics nextgeneration sequencing (NGS)-based test (Oncomine Dx Target Test) to detect single gene mutations and deletions in 23 genes from DNA and fusions in ROS1 from RNA isolated from formalin-fixed, paraffin-embedded tumor tissue samples from patients with NSCLC. This test is currently indicated
to aid in selecting NSCLC patients for treatment with combination dabrafenib and trametinib, gefitinib, or crizotinib for BRAF and EGFR mutations and ROS1 fusions, respectively. With this test, physicians can now match patients to these therapies in days instead of several weeks, which often occurs when screening samples one biomarker at a time. (6/22/17)
Jeff Abrams
arms, and more are set to open later this year. The primary endpoint of NCI-MATCH is objective response rate, and treatments will be considered promising if ≥16% of patients have an objective response. The Lung-MAP trial (S1400) is another precision medicine trial involving collaborations between many partners, including the NCI, NCTN, SWOG, Friends of Cancer Research, the Foundation for the National Institutes of Health, a large number of pharmaceutical companies, Foundation Medicine, and several lung cancer advocacy organizations. In Lung-MAP, enrolled patients with advanced squamous cell lung cancer enter a master protocol in which the genotype of the tumor is used to sort patients into different treatment arms. This study will soon expand to include adenocarcinomas of the lung as well. ✦ References 1. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:1452-1460. 2. Unger JM, LeBlanc M, Blanke CD. The effect of positive SWOG treatment trials on survival of patients with cancer in the us population. JAMA Oncol. 2017 Jun 5. DOI: 10.1001/jamaoncol.2017.0762. [Epub ahead of print].
• Ceritinib (Zykadia) received European Commission approval for use in first-line treatment of patients with advanced NSCLC whose tumors are ALK-positive. This approval follows a positive opinion granted in May by the Committee for Medicinal Products for Human Use (CHMP), and is applicable to all 28 European Union member states plus Iceland, Lichtenstein, and Norway. (6/29/17)
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IASLC LUNG CANCER NEWS / AUGUST 2017
ADVOCACY AND SURVIVORSHIP
Ellen V. Sigal, PhD: Leading the Cancer Research Advocacy Community By Lori Alexander, MTPW, ELS, MWC®
Ellen Sigal’s unsurpassed passion for cancer research advocacy was ignited 30 years ago after the devastating loss of her younger sister Gale to breast cancer. Her drive to make a difference led her to establish Friends of Cancer Research (Friends), a nonprofit advocacy organization based in Washington, DC. Since then, Dr. Sigal has become a major leader and influence in the cancer research community, with service on the boards of several high-profile federal agencies, academic research centers, and other advocacy organizations. As a key player in the cancer research advocacy community over the past three decades, she has firsthand knowledge of how that community has changed, what it has achieved, and what challenges it still faces. “Cancer advocacy has evolved so that organizations today no longer exist solely to raise awareness of a problem; they are now catalysts to the solutions themselves. This shift provides cancer research organizations with a more active role of input, funding, prioritization, and strategy to benefit patients,” says Dr. Sigal. As founder and chair of Friends, Dr. Sigal is dedicated to using her voice to make sure the patient’s voice is heard. She supplements her compassion for the patient experience with strong leadership skills and a keen business acumen to develop partnerships and advocate for policies and research models that ensure that patients have access to treatments in the safest and quickest way possible. She notes that the rise of the patient voice is the greatest achievement in the cancer research community, with the patient voice becoming integral to drug development, outcomes research, and treatment decision-making. Access to Treatment Safely and Quickly Access to safe and effective drug treatments is the mission of Friends, and Dr. Sigal brings her passion for that mission beyond her organization. She serves as Chair of the inaugural board of directors of the Reagan-Udall Foundation, an independent nonprofit organization that works to modernize medical product development, accelerate innovation, and enhance product safety in collaboration with the US Food and Drug Administration (FDA). She is committed to ensuring that patients’ treatments are safe, even as treatment options begin to decrease and desperation for new treatments rises. She believes that patients with terminal disease deserve the right to access experimental treatments, but she
is not sure that new Right-to-Try legislation, which has been approved in more than 30 states in the United States, is the best answer to this complex problem. “It is universally agreed upon that dying patients should have access to promising experimental therapies when all other available options have been exhausted, and Right-to-Try legislation is a path toward achieving that goal. However, the FDA has a compassionate use process in place for such patients and approves more than 99% of these requests. Right-to-Try legislation, as it is currently written, seeks to remove FDA from this process, which could put us in dangerous territory, as it could unknowingly allow ill-intentioned individuals to enter the market and subject patients to significant harm. What we need is greater clarity on how to navigate the process and increased transparency and streamlining of processes for more rapid decisions on access in these difficult situations. The recently passed 21st Century Cures Act includes steps to address these concerns.” Dr. Sigal has also been involved in efforts to reshape clinical trials to accelerate the evaluation of targeted therapies. In an unprecedented public-private collaboration, Friends has worked with the National Cancer Institute (NCI), NCI’s National Clinical Trials Network, SWOG Cancer Research, the Foundation for the National Institutes of Health, and several pharmaceutical companies and lung cancer advocacy groups to establish the Lung Cancer Master Protocol (LungMAP) trial. The first-of-its-kind clinical trial design, developed through a series of workshops, forums, and working groups, involves the use of a multidrug, targeted screening approach to match patients with substudies testing investigational new treatments based on the patients’ unique tumor profiles. Dr. Sigal notes, “Since its implementation, we have been involved in constant review of the trial to ensure Lung-MAP is evolving in a manner that not only provides researchers and drug developers the information they need to effectively develop treatments but also provides patients with the best experimental treatments possible.” Drug Development “In recent years, the community has realized that patients’ voices are significant because no one else can better relay information as to how a drug or therapy is working and affecting quality of life than patients themselves,” says Dr. Sigal.
sions for the patient.” She adds that the research community needs an increased commitment from all sectors to collaboratively validate and rapidly implement instruments that add quality-of-life measures to clinical trials.
Ellen Sigal
“With advancements in technology, we now have better tools to help capture the patient voice and aggregate data on their experience. The capture of this type of data holds the potential for researchers and drug developers to generate more accurate information about what patients might expect from a treatment and even hold the potential for new trial designs that will assess endpoints that are most meaningful to patients.” Outcomes Research Dr. Sigal is currently serving her second 6-year term on the Board of Governors of the Patient-Centered Outcomes Research Institute (PCORI), an independent organization created by Congress to initiate research that helps patients, physicians, and caregivers make informed health care decisions by promoting comparative effectiveness research. As of March 2017, the institute has awarded $194 million to fund 65 comparative clinical effectiveness research studies and methods projects related to cancer. Lung cancer is the third most studied cancer type, with 10 projects currently dedicated to evaluating lung cancer from a comparative clinical effectiveness standpoint. Among the projects that PCORI has funded are pilot projects for engaging patients, doctors, and health care experts in creating guidelines for lung cancer screening, and creating a computerized decision-support program to help patients with cancer understand and manage their symptoms. Treatment Decision-Making “As precision medicine becomes more common and a reality for patients, they will want to be more involved in their treatment decisions,” says Dr. Sigal. “As a result, it will be more important for physicians to view their relationship with patients as a partnership, in which they provide information to patients so they have input on their treatment decisions. In turn, patients will need to provide comprehensive information on quality of life and the impact of treatment to their physicians so that together, as a team, they can make the best treatment deci-
Supporting the Patient Voice Dr. Sigal calls on IASLC members to support incorporation of the patient voice by making educational programs available to patients that will help them have meaningful conversations with physicians and researchers. One such program is the newly launched Friends initiative, ProgressForPatients.org. This initiative gives patients and their advocates the opportunity to participate in education that will help them communicate effectively with drug researchers, developers, and regulators, and ultimately will help patients learn when and where to add their voice and be better equipped to communicate their needs to advance health outcomes. “By providing their patients with the ability to participate in a program such as ProgressForPatients.org, physicians can be more open to embracing the patient voice.” Remaining Challenges and Opportunities The greatest remaining problem is the difficulty with sharing information, says Dr. Sigal. “Great progress is being made, but we still need all sectors to work together to solve this problem. Different systems, lack of sharing tissue, outcomes, and so on, is a major concern.” She adds that thoracic oncologists help support cancer research advocacy with their frontline work advancing the field through biomarker identification, immunotherapy, and combination therapy. Thoracic oncologists can further their support by engaging in open and detailed conversations with their patients. “This will open the door for patients to be more involved in their treatment decisions and provide the oncologist the opportunity to learn from the patient about the issues they are experiencing related to their treatment plan,” says Dr. Sigal. “Physicians should also have active and open dialogues with patients about the importance of participating in clinical trials and helping them navigate ongoing trials that meet their needs.” Dr. Sigal’s tireless efforts prove her point about the evolution of cancer advocacy: she has certainly been a catalyst to solutions within the cancer research community. ✦
SAVE THE DATE!
October 15â&#x20AC;&#x201C;18, 2017 | Yokohama, Japan
Hisao Asamura, MD Professor and Chief Division of Thoracic Surgery Keio University School of Medicine Tokyo, JAPAN
Keunchil Park, MD, Ph.D. Professor Division of Hematology/Oncology Samsung Medical Center Sungkyunkwan University School of Medicine Seoul, KOREA