IASLC Lung Cancer News - V1, N4

LUNG CANCER

NEWS

V1/ N4 / NOVEMBER 2016

FOR THORACIC SPECIALISTS www.iaslc.org

INSIDE 3 6

IASLC 2016 WCLC New from 2016 ESMO Clinical Guidelines NICE: It Takes Two to Tango

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Breaking News Briefs

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Richard B. Gaynor Interview

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FDA Corner 7th Latin American Conference on Lung Cancer Epidemiology of Lung Cancer in Developing Countries In Memoriam: Robert B. Livingston

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Lung Canceer in Women: Different or Not?

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NCI Corner

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Teenage Smoking: An Interview with Michael Kulik, MS

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Names and 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 GLOBAL RESEARCH REPORT

Changing Landscape of Front-line Immunotherapy

By Naiyer A. Rizvi

The rapid development of anti-PD-1 and PD-L1 antibodies in cancer underscores the tremendous impact they have had on the cancer landscape and for our patients. The first publication in 2010 forever changed our notion of “immunogenic” and “non-immunogenic” tumors.1 In this landmark paper, nivolumab, an immunotherapy agent, demonstrated activity not just in melanoma, but tumor regression was also observed in a patient with non-small cell lung cancer (NSCLC).

Furthermore, tumor cell surface expression of B7-H1 (PD-L1) showed a correlation with the likelihood of response to treatment.

Fast-forward to 2015 and nivolumab has now been approved in the US for second-line therapy for both squamous and non-squamous lung cancer inde-

pendent of PD-L1 expression.2,3 Also in 2015, pembrolizumab initially received accelerated approval for PD-L1-positive NSCLC4,5; and, as of October 24, 2016, it was approved in the first-line, treatmentnaive NSCLC setting for individuals with PD-L1 expression ≥50% and in the secondline setting in those with PD-L1 scores of 1% or higher; Figure 1 displays high levels of PD-L1 expression on a tumor.

Herein lies the controversy of PD-L1 as a biomarker for response to NSCLC. Although it is (mostly) clear that tumoral PD-L1 expression improves the likelihood of response to anti-PD-1 antibodies, many questions remain as to the optimal assay and cutoff. This controversy has proven less relevant in the second-line NSCLC setting where standard chemotherapy has limited efficacy and moderate toxicity; however, one must ask if measuring PD-L1 expression can help anti-PD-1 antibodies selectively displace

Figure 1. High levels of PD-L1 expression on a tumor. Reprinted with permission, N Engl J Med. 2015;372: 2018-28.

chemotherapy in the first-line chemotherapy-naive setting.

Given the higher efficacy of chemotherapy in the first-line setting, PD-L1 expression has become relevant as a biomarker; two phase 3 trials comparing anti-PD-1 vs. first-line chemotherapy were presented at ESMO 2016 to address this very question. KEYNOTE 24 (KN 24)6 compared pembrolizumab with first-line chemotherapy and CheckMate 26 (CM 26) compared nivolumab with first-line chemotherapy. The key difference between the two trials was the cutoff continued on page 9

PERSPECTIVE

S P OT L I G H T O N T H O R AC I C O N CO LO G Y R E S E A R C H

New Findings in Malignant Pleural Mesothelioma (MPM)

The Lung Master Protocol (Lung-MAP)

How one investigator’s passion and devotion to science led to discovery of the “ghost gene” in MPM

Lung-MAP (S1400), is a unique master multi-study protocol that incorporates genomic testing of tumors through a next-generation sequencing (NGS) platform (Foundation Medicine) and biomarker-driven therapies for patients with squamous cell lung cancer (SCC) after progression on first-line therapy. This effort represents a unique private-public partnership supported by the National Cancer Institute (NCI) and the National Clinical Trials Network (NCTN), the Foundation for the National Institutes of Health (FNIH), and Friends of Cancer Research (FOCR). The overall aim of the Lung Master Protocol is to find new agents and companion diagnostics for precisely defined molecular subsets of patients with advanced squamous cell cancer, for whom there are few effective therapeutic options and a major need for new targeted drugs. With the exception of the newly approved nivolumab and pembrolizumab, in the second-line setting, which occurred after the launch of Lung-MAP in June of 2014, and necitumumab in the first-line setting, there have been few other FDA approvals specifically for squamous lung cancer.

Research studies like The Cancer Genome Atlas (TCGA) have detected a large number of somatic gene mutations/amplifications in patients with this disease.

Many of these are targetable by investigational agents (examples: PIK3CA, BRAF, FGFR2 are mutated while EGRF and MET are amplified). However, the frequency of these changes in these patients is low (5%–20%), making recruitment and treatment very challenging in the traditional single-agent trial setting. Hence, the LungMAP strategy is to use a common platform (Next Generation DNA Sequencing) to enable a single “umbrella screening protocol” to efficiently find patients with diverse

By Vassiliki A. Papadimitrakopoulou, MD

with Michele Carbone, MD Q: Many laboratories are now working on the link between BAP1 and mesothelioma. How did you come up with the idea that there was genetic susceptibility to developing mesothelioma?

A: Only a fraction of individuals exposed to asbestos develop mesothelioma, so we believed that if we could identify the reasons some people are more susceptible than others, we could develop preventive strategies. To this end, we studied an epidemic of mesothelioma in Cappadocia, Turkey, where about 50% of the population exposed to erionite fibers dies of mesothelioma. Over the course of 14 years, we discovered that susceptibil-

ity to mesothelioma was transmitted in a Mendelian fashion; we formulated the hypothesis that the cause of the epidemic environmental interaction with gene X. Q: Who funded these studies?

A: Initially, I paid out of my own pocket, and I spent whatever vacation time I had working in Cappadocia. Then, after compiling preliminary data, I was awarded a grant from the American Cancer Society.

Those studies allowed me to be awarded an NCI-P01 grant in 2006 to identify the hypothetical mesothelioma susceptibility gene(s), which we later identified as BAP1. continued on page 4

continued on page 5

INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER

Conquering Thoracic Cancers Worldwide Through education, international collaboration, and groundbreaking research, the IASLC is the leader in the global fight against lung cancer.

More information at IASLC.org.

Lung Cancer Awareness Month is the month of November.

Join the fight.

More information at LCAM.org.

The IASLC Foundation supports global research discovering new approaches to conquer thoracic cancers.

IASLC.org/Foundation

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IASLC LUNG CANCER NEWS / NOVEMBER 2016

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MEETING HIGHLIGHT

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

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 quarterly 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.

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 World Conference on Lung Cancer 2016 Together Against Lung Cancer

By Lori L. Alexander, MTPW, ELS, MWC

The 17th IASLC World Conference on Lung Cancer (WCLC) promises to offer new data and exciting new developments on a wide range of topcs in lung cancer care. A host of scientific abstract presentations and invited sessions will be offered within the three major topics of the conference: active prevention, accurate diagnosis, and advanced care.

December 4-7, 2016

Vienna

Active Prevention

Given that tobacco use is the most common preventable cause of cancer, tobacco control dominates under the topic of active prevention. “A major goal of WCLC 2016 will be to unite in order to become a stronger global voice for tobacco control,” says Robert Pirker, MD, Vienna, Austria, Chair of the Conference. Monday’s Plenary session will feature several prominent speakers on tobacco control, including Dr. Tabaré Vázquez, President of Uruguay, who will discuss his country’s success in implementing tobacco control measures. In addition, Vera da Costa e Silva, Secretariat of the World Health Organization’s Framework Convention on Tobacco Control, will discuss the impact of the Framework on global health. Several other sessions will focus on the current status of tobacco control in various regions of the world, in particular, Central Europe, Middle East, China, and Africa. Other sessions will address tobacco use in youth and new challenges in tobacco control, such as water pipes and e-cigarettes.

Accurate Diagnosis

Screening and staging are just two of the highlights. Once again this year, an all-day screening workshop will be held the day before the start of the conference. The goal of the workshop, led by Prof. John K. Field, the University of Liverpool, UK, and James L. Mulshine, MD, Rush University, Chicago, USA, will be to provide recommendations to IASLC on how it can best support leadership in the arena of lung cancer screening globally. In addition, invited sessions will address advances in lung cancer screening and precision screening. The new 8th edition of the TNM Staging Manual will be featured during Tuesday’s Plenary Session, with a discussion centering on how the new classification will change clinical practice. “The 8th edition will help us refine prognosis both at clinical and pathologic staging and stratify tumors in future clinical trials, but will require more attention from us in measuring tumor size, determining nodal disease status, searching for metastases, and using clinical judgment to recommend treatment,” says Ramon Rami-Porter, MD, Chair of the IASLC Staging and Prognostic Factors Committee.

IASLC

I N T E R N A T I O N A L

Advances in Care

Recent studies have underscored the burgeoning promise of immunotherapy in lung cancer. Several sessions will include reports on emerging data on immune checkpoint inhibitors, alone, and in combination with each other immunotherapeutics, as well ascombinations with chemotherapy and radiation therapy. In addition, speakers in invited sessions will discuss the selection and monitoring of patients for immune checkpoint inhibitors, a crucial aspect of care for this class of drugs. Presentations on targeted therapies are also drawing attention, with new data on third-generation EGFR tyrosine kinase inhibitors, such as osimertinib; new ALK inhibitors, such as ceritinib and brigatinib; Hsp90 inhibitors, such as ganestespib; as well as other novel agents. Speakers will also discuss the use of targeted therapies and immunotherapies in earlier disease stages with the aim of enhancing cure rates.

At the conference, please keep up to date by reading synopsies of presented studies in WCLC Daily News, the on-site newspaper. Also, look for highlights from the conference in the February 2017 issue of IASLC Lung Cancer News. ✦

» » » » » »

A S S O C I A T 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

Multidisciplinary Hands-On Live Learning: Molecular Testing and Personalized Therapy in Lung Cancer.

Tobacco Control, Smoking Cessation Pathology Medical Oncology Radiation Oncology Pulmonology Surgery

San Francisco January 7, 2017 Registration fee: $25 for IASLC members $35 for non-IASLC members Limited space maximum 35 participants per meeting

FOR MORE INFORMATION PLEASE GO TO WWW.IASLC.ORG OR PIA.HIRSCH@IASLC.ORG

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IASLC LUNG CANCER NEWS / NOVEMBER 2016

Perspective from page 1 Q: How did you find the gene?

A: Initially, in the pre-NGS era, the gene eluded us. Dr. Nasu and other postdocs in my lab manually sequenced miles and miles of DNA looking for the putative mesothelioma-gene. I traveled around the country to be in the operating room of patients with a family history of mesothelioma to diagnose their tumors and to harvest tumor cells, from which I extracted the DNAs that Dr. Nasu and others sequenced. Four years into the grant, we had ruled out several DNA regions that genetic linkage analyses and comparative genomic hybridization—done by our P01 collaborators Dr. Cox at the University of Chicago and Dr. Testa at Fox Chase Cancer Center—had identified as possibly harboring a mesothelioma gene. We had significantly narrowed down potential chromosomal regions indicated by linkage analyses, but we were in the last year of the P01 with not enough time to sequence them all. We knew that we had little hope of renewing the grant and continuing this work, since we had nothing to show for it. There was also increasing skepticism that a mesothelioma gene existed. At a Chicago ASCO meeting, I was introduced with these words: “Now Dr. Carbone will tell us about his hunt for the ghost gene.” I started thinking that maybe I had committed a terrible error and that there was no such thing as a mesothelioma gene.

The epiphany came when I received a phone call from Louisiana: a member of one of the families I was studying had developed an eye melanoma and a mesothelioma. I asked my colleague at University of Hawaii Cancer Center, biostatistician Dr. Pagano, “What is the chance of these two very rare tumors occurring in the same person, and of multiple mesotheliomas and eye melanomas in the same family?” He answered, “About

2 of 10 million cases.” I then concluded that this could not be a coincidence.

I pulled out Principles and Practice of Oncology from my bookshelf, and found that eye melanomas and mesotheliomas shared frequent deletions in chromosome 3p, a region that was on Dr. Nasu’s to-do list, based on genetic linkage studies. A few days later, my collaborators Giovanni Gaudino and Haining Yang at the University of Hawaii Cancer Center walked into my office showing me a new paper by Dr. Harbour reporting a high incidence of somatic BAP1 mutations in eye melanoma, and Dr. Testa sent me an email about the same paper. BAP1 was on 3p. Was it BAP1? We were all quite excited. We discussed the possibility in a videoconference meeting with my P0-1 collaborator Dr. Pass at New York University. We were running out of grant time and this was our last chance, so we decided to focus sequencing on 3p. Dr. Testa’s lab helped speed up the process.

The first clue came a few weeks later from Dr. Testa’s lab when he and his colleagues identified a truncating BAP1 mutation; soon after, Dr. Nasu in my lab obtained his sequence results and discovered the same mutation. There was still a possibility that this was a fluke, but that possibility was ruled out in the following weeks when DNA sequencing perfectly matched all affected members of two separate US families with BAP1 mutations, while none of the non-affected family members had inherited these mutations.

Same results, two separate laboratories.

Moreover, among 23 sporadic mesothelioma blood samples that Harvey Pass and Mary Hesdorffer at Mesothelioma Applied Research Foundation (MARF) sent us, we found germline mutations in two: the only two patients who previously had developed uveal melanoma.

After more than 14 years of research, I could hardly believe that it was true. With

Karain, Turkey, 2010. Left, Dr. Carbone reviewing X-rays, Dr. Berkant Ozpolat (standing); Center, Dr. H.I. Pass talking to patients.

Drs. Gaudino and Yang we reviewed all the data to rule out any possible mistake: they were very solid. We published that BAP1 was the mutated gene that caused mesothelioma and eye melanoma in some families. In the same issue of Nature Genetics, Speicher’s team reported that inherited BAP1 mutations caused benign melanocytic tumors. We checked our patients: they had those melanocytic lesions. Speicher and colleagues checked the family history of their patients and found several mesotheliomas. This was all quite reassuring!

Q: Why mesothelioma and uveal melanoma?

A: Using a BAP1+/- mouse model, we demonstrated that these mice develop mesothelioma following exposure to very low doses of asbestos. So we think that germline BAP1 mutation carriers may be more susceptible to even small amounts of asbestos exposure. Similarly, BAP1 mutations may increase sensitivity to ultraviolet (UV)-induced mutagenesis.

Therefore, BAP1 is the first gene shown to modulate mineral fiber and environmental carcinogenesis.

Q: Do BAP1 mutation carriers develop other malignancies?

A: Yes. Subsequent to our research, other scientists have linked germline BAP1 mutations to renal cell and gallbladder carcinomas, basal cell carcinomas, various types of sarcomas, etc. I think BAP1 mutant carriers may be prone to many types of cancer, especially to cancers caused by environmental carcinogens.

We named this condition “the BAP1 cancer syndrome.”

Q: What is the incidence of cancer in carriers of this BAP1 cancer syndrome?

Sarihidir, Turkey, 2008. Left, standing, former mayor of Sarihidir, sitting Dr. Carbone, Dr. Baris, a mesothelioma patient, her niece—who translates in English and her son, standing behind, and Dr. S. Emri.

A: So far, all carriers we studied have developed one or more cancers during their lifetime. However, we discovered that mesothelioma and other cancers

that develop in a background of BAP1+/germline mutations are often associated with prolonged survival of five to 10 or more years, which we think this may be related in part to early detection, since these families are closely monitored, and in part to a possibly less aggressive tumor phenotype.

Q: How many BAP1 families are there?

Are there other genes that cause mesothelioma?

A: We have studied over 50 families in which several family members developed mesothelioma and often also other malignancies. Some of them do not have BAP1 mutations. Now, with support from a US Department of Defense grant, we are trying to identify a second mesothelioma gene. In a paper in press in PNAS, we identified novel genes that contribute to sporadic mesothelioma; we are now testing whether they are also mutated in the germline.

Q: How do BAP1 mutations originate?

A: The mutations are inherited and can be traced through centuries of ancestry.

We identified four families who share the same BAP1 point mutation. We discovered that the four families are related and descend from a German couple who immigrated to the US in the early 1700s. From this extended family, we have built a family tree encompassing ~80,000 people, and we are identifying additional branches of this family who carry the mutation.

Q: How can medicine help carriers of BAP1 mutations?

A: Genetic counseling is imperative to inform carriers about prevention. Such individuals should avoid UV sunlight and trades in which asbestos exposure may occur. Patients should understand that their tumors are usually less aggressive than the same tumors when they occur sporadically. Moreover, we are enrolling

IASLC LUNG CANCER NEWS / NOVEMBER 2016

BAP1+/- carriers in screening programs for early detection of eye and skin melanoma, which are cancers that are curable when detected early, and for biomarkers studies. We will soon start a prospective HMGB1 study following a recent discovery by Dr. Yang that this biomarker may allow us to identify asbestos-exposed individuals and those among them who are more likely to develop mesothelioma.

Q: Who helped you the most in this research?

A: The members of the high-risk mesothelioma families deserve most of the credit. Among them, the Cappadocia families in Turkey, and the Wisconsin and Louisiana families. Without their help, we would have never discovered that mesothelioma had a genetic component first, and later identified the gene.

Q: In your scientific team, who deserves most credit for this discovery?

A: Our success was the result of teamwork, and we would not have succeeded without the participation of all the scientists listed in our papers. I will also mention that some team members spent significant time traveling and working

with me in Cappadocia, exposing themselves to the potent carcinogenic erionite fibers following my “crazy” idea that there was a mesothelioma gene to be found and that we could reduce the incidence of mesothelioma. They did it because of their passion and because they wanted to make a difference. To them, I am most grateful. Moreover, Dr. Murat Tuncer, then Director of Cancer Control at the Turkish Ministry of Health in Turkey, upon our request built a clinic in the village of Tuzkoy to help mesothelioma patients and our research.

Q: What lessons have you learned in Cappadocia?

A: Many. Probably the most important was to listen to my heart rather than logic and to never give up. Once, as I was about to leave for Turkey a senior colleague, said, “Michele, if I were you, rather than wasting time looking for a ghost gene in Cappadocia, I would go to the Caribbean for the next few months.”

Everybody around us laughed. But I had met the mesothelioma families in Cappadocia and in the US, I wanted to do something about their problem, and I hoped (although I was not sure) that my hypothesis of a meso-gene was cor-

rect. I was not after a grant: I wanted to fix a problem. Similarly, a few years later, with my Turkish collaborators Drs. Baris, Dogan and Emri we went to the Turkish Ministry of Health and asked them to build two new villages in Cappadocia and to relocate the residents of the erionite-containing villages to prevent further exposure in a population that was predisposed to mesothelioma. We never thought they would have listened to us, yet we wanted to try: we waited one week in Ankara to talk to the Ministry.

Well, the Ministry listened to us, and they built two new erionite-free villages, likely saving many future lives from mesothelioma! ✦ Bibliography

Baumann F, Buck BJ, Metcalf RV, et al. The presence of asbestos in the natural environment is likely related to mesothelioma in young individuals and women from Southern Nevada. J Thorac Oncol. 2015; 10:731-737.

Baumann F, Flores E, Napolitano A, et al. Mesothelioma Patients with Germline BAP1 Mutations Have SevenFold Improved Long-term Survival. Carcinogenesis.

2015; 36:76-81.

Carbone M, et al. Consensus Report of the 2015 Weinman International Conference on Mesothelioma.

J Thorac Oncol. In press.

Carbone M, Baris YI, Bertino P, et al. Erionite exposure in North Dakota and Turkish villages with mesothelioma. Proc Natl Acad Sci USA. 2011; 108:13618-13623.

Carbone M, Emri S, Dogan U, et al. A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes. Nature Reviews Cancer.

2007; 7:147-154.

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Carbone M, Ferris LK, Baumann F, et al. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med. 2012;10:179.

Carbone M, Flores EG, Emi M, et al. Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred, tracing back nine generations to a common ancestor from the 1700s. PLoS Genetics. 2015; 11(12):e1005633.

Carbone M, Yang H, Pass HI, et al. Bap1 and cancer.

Nat Rev Cancer. 2013; 13:153-159.

Dogan UA, Baris YI, Dogan M, et al. Genetic Predisposition to Fiber Carcinogenesis Causes a mesothelioma Epidemic in Turkey. Cancer Res. 2006; 66:5063-5068.

Napolitano A, Antoine DJ , Pellegrini L, et al. HMGB1 and its hyper-acetylated isoform are sensitive and specific serum biomarkers to detect asbestos exposure and to identify mesothelioma patients. Clin Cancer Res. 2016; 22:3087-3096.

Napolitano A, Pellegrini L, Dei A, et al. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene. 2016; 35:1996-2002.

Nasu M, Emi M, Pastorino S, et al. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. J Thorac Oncol. 2015;10:565-576.

Roushdy-Hammady I, Siegel J, Emri S, et al. A geneticsusceptibility factor malignant mesothelioma in the Cappadocian region of Turkey. The Lancet. 2001; 357:444-445.

Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011; 43:1022-1025.

Yang H, Rivera Z, Jube S, et al. Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proc Natl Acad Sci USA. 2010; 107:12611-12616.

Yoshikawa Y, Emi M, Hashimoto-Tamaoki T, et al.

High-density array-CGH with targeted NGS unmask multiple non-contiguous minute deletions on chromosome 3p21 in mesothelioma. Proc Natl Aca Sci USA. 2016; in press.

Lung-MAP from page 1 uncommon molecular changes. According to their profile, these patients are assigned to a “matched” trial with an investigational drug or combination of drugs for the target. Thus, the Master Protocol has a single entry point under its “umbrella” but then allows for multiple simultaneous studies with a single Institutional Review Board (IRB) approval. Based on the need for study assignment of patients whose tumor does not harbor targetable alterations and the rapid therapeutic establishment of the efficacy of immunotherapy, a non-match trial that tests nivolumab plus ipilimumab vs nivolumab alone has been included in the umbrella protocol. Current biomarker-driven studies include: S1400B evaluating taselisib, a PI3K inhibitor, and S1400D evaluating AZD4547, an FGFR inhibitor, while S1400A evaluating the activity of durvalumab, an anti-PD-L1 antibody, was closed in December 2015 and S1400C evaluating palbociclib, a CDK 4/6 inhibitor, was closed in September of 2016 (Figure 1).

As of September 2016, 1,003 patients were registered to S1400, with accruals from ALIIANCE, ECOG-ACRIN, NRG, and the leading group SWOG, while 723 patients were notified of their sub-study assignment and 364 patients were registered to a sub-study. Principal investigators from all cooperative groups are leading the individual studies (see Acknowledgement). Patients can enter the trial either at progression on prior therapy or can be prescreened while they are receiving front-line therapy and prior to progression with the option to request study assignment at progression.

Several sub-studies are currently under development, including a study exploring the activity of talazoparib, a PARP inhibitor for patients with homologous recombination deficient tumors, and a study exploring the activity of the combination of durvalumab and tremelimumab for patients with immunotherapy relapsed or refractory tumors as shown in the schema (Figure 2). Genomic screening is feasible in the majority of patients, and findings so far are confirming the anticipated prevalence of targeted alterations. ✦

Biomarker-Driven Sub-Studies

Single Arm Phase II Randomized Phase III

Non-Match Sub-Study

S1400B PI3K+

S1400C CCGA+

S1400D FGFR+

GDC-0032

Palbociclib

AZD4547

GDC-0032 vs TBD

Palbociclib vs TBD

AZD4547 vs TBD

S1400I Checkpoint Naive

Nivolumab/ Ipilimumab

Nivolumab

Figure 1. Current Lung-MAP schema. CCGA = Cell Cycle Gene Alteration

Non-Match Sub-Study

Biomarker-Driven Sub-Studies

Single Arm Phase II Potential for Randomized Phase III

S1400B PI3K+

S1400D FGFR+

S1400G HRRD+

GDC-0032

AZD4547

BMN673

GDC-0032 vs TBD

AZD4547 vs TBD

BMN673 vs TBD

S1400I Checkpoint Naive

S1400F Checkpoint Refractory

MEDI4736 Nivolumab/Ipilimumab Tremelimumab vs Nivolumab

Figure 2. Lung-MAP upcoming protocol schema. HRRD = Homologous Recombinant Repair Deficiency

Acknowledgment. The leadership team for this study includes: Roy Herbst, MD, PhD; Mary W. Redman, PhD; David R. Gandara, MD; Fred R. Hirsch, MD, PhD; Philip C. Mack, PhD; Hossein Borghaei, DO; Corey J. Langer, MD; James L. Wade, MD; Martin Edelman, MD; Kathy Albain, MD; Primo Lara Jr, MD; Charu Aggarwal , MD; Mark A. Socinski, MD; Scott N. Gettinger, MD; Lyudmila A. Bazhenova, MD; Shakun Malik, MD; Vince Miller, MD; Ellen V. Sigal; and Karen Kelly, MD.

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IASLC LUNG CANCER NEWS / NOVEMBER 2016

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

What’s New from the 2016 ESMO Clinical Guidelines

By Matteo Giaj Levra, MD, and Silvia Novello MD, PhD

In September, the 2016 ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up of metastatic nonsmall cell lung cancer (NSCLC) were published. These guidelines outline many new recommendations updated from the 2014 version, following trends of innovation during the last 2 years in the field of thoracic oncology.

Without question, the big “revolution” and major change in this field is represented by immunotherapy: nivolumab, the PD-1 immune-checkpoint-inhibitor antibody, is now approved by the European Medicines Agency (EMA) after failure of first-line treatment for both squamous cell carcinoma (SCC) and non-squamous NSCLC. The results of the CheckMate 017 study showed a significant improvement in overall survival (OS) for patients with SCC treated with nivolumab (3 mg/kg every 2 weeks) compared with docetaxel (9.2 versus 6 months, HR 0.59, p < 0.001), together with a better toxicity profile.1 In non-squamous NSCLC, the results of CheckMate 057 study also showed a benefit for OS compared with docetaxel (12.2 versus 9.4 months, HR 0.73, p=0.002), despite a small excess of early progression and/or death in the nivolumab arm.2 A retrospective, unplanned analysis revealed an association between efficacy of nivolumab and PD-L1 tumor membrane expression, but

nivolumab is approved in non-squamous NSCLC regardless of PD-L1 status.

Recently, the FDA and EMA also approved another anti-PD-1 antibody, pembrolizumab (2 mg/kg every 3 weeks), for the treatment of NSCLC regardless of histology after failure of first-line in patients with tumors expressing PD-L1.3 Immunotherapy is only one of the new components in the updated guidelines: oncogene-addicted tumors are the other side of the coin in metastatic NSCLC with the advent of new therapeutic approaches. For EGFR-mutant tumors that progress after first-line tyrosine kinase inhibitors (TKIs), the approval of osimertinib in patients with the exon 20 T790M resistance mutation has changed how we approach these patients and has raised the challenge of tumor re-biopsy at progression as well as the issue of tissue availability. In the new guidelines, liquid biopsy constitutes a new strategy for tumor genotyping, and is now an approved diagnostic approach to detect the resistance mutation and enable us prescribe the targeted drug.4,5 Without doubt, this is a major change for a disease where tissue is still the issue.

With a significant delay from the FDA approval, in the ALK-rearranged disease, crizotinib should be administered first-line according to the results of the PROFILE 1014 study, which showed a relevant benefit for progression-free

survival (PFS) and overall response rate (ORR) compared with standard chemotherapy.6 The advent of new anti-ALK agents such as ceritinib and alectinib will definitively change our treatment scenarios in the “ALK disease,” especially in patients with brain metastases.

We eagerly await EMA approval for these second-generation agents.7,8 First-line treatment for the nononcogene addicted disease is still the province for chemotherapy, and the new guidelines consider a new targeted agent, necitumumab, for treatment-naive SCC; this has been approved in combination with cytotoxic agents. Necitumumab is an IgG1 human antibody against EGFR, which in combination showed a significant OS (11.5 versus 9.9 months, HR 0.84, p=0.01) and PFS improvement compared to the chemotherapy doublet alone. A retrospective analysis showed that tumors with positive EGFR expression by immunohistochemistry (IHC) benefited from triplet treatment, leading to the approval of necitumumab in this set of patients.9 Europe is extremely heterogeneous, and the diverse approval processes and country-based drug reimbursement systems make the management of advanced NSCLC even more complicated as new agents descend on the market. These new findings, however, underscore the critical need of generating updated common guidelines. ✦

Matteo Giaj Levra

Silvia Novello

References 1. 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.

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. 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; 387:1540–1550.

4. Douillard J-Y, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, singlearm study. Br J Cancer. 2014;110(1):55-62.

5. Oxnard GR, Thress KS, Alden RS, et al. 135O_ PR: Plasma genotyping for predicting benefit from osimertinib in patients (pts) with advanced NSCLC. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2016;11(4 Suppl):S154.

6. Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177.

7. Kim DW, Mehra R, Tan DS, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): Updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016; 17:452–463.

8. Ou S-HI, Ahn JS, De Petris L, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-SmallCell Lung Cancer: A Phase II Global Study. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(7):661-668.

9. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763-774.

ECONOMICS OF LUNG CANCER CARE

NICE: It Takes Two to Tango

By Sanjay Popat, FRCP, PhD

United Kingdom Healthcare System

The United Kingdom (UK) has a unique healthcare system: the National Health Service (NHS), a publicly funded, singlepayer system. Founded by the Labour government in 1948, its unique identity is constitutionally defined as a comprehensive service delivered to all, based on clinical need and not on ability to pay, and funded by general taxation. In practice, this means that healthcare is free at point of use for most services, including cancer treatment.1 So, if cancer care is free in the UK, who decides which treatments are funded (reimbursed) and which ones aren’t? The answer is surprisingly complex, geographically different, and very much depends on treatment type; for example, cancer surgery is funded dif-

ferently from new anti-cancer drugs.

The key organization to manage cancer commissioning, though, is the National Institute for Health and Care Excellence (NICE).

This is a non-departmental public body established by primary legislation, accountable to the UK Department of Health, but operationally independent of it, with a remit only technically for England, but with arrangements in place for the devolved nations (Wales, Scotland, and Northern Ireland).2

What Does NICE Do?

As the NHS is funded through general taxation, with a fixed budget allocated to the Department of Health from the gov-

ernment, some entity therefore needs to decide if new drugs should be funded, and if so, on what grounds: enter NICE. NICE is extremely active. It provides evidence-based guidelines, information services for commissioners and clinicians, and defines quality standards and performance metrics. However, perhaps the most important oncological role of NICE is providing funding approvals. In this regard, NICE issues decrees on the cost-effectiveness of new “technologies” (e.g., a new anti-cancer drug, medical device, diagnostic test) to the NHS.

How Does NICE Appraise New Drugs?

The process by which NICE appraises new drugs has changed recently, but the principles remain similar. Previously,

NICE would only appraise a new indication after EMA licensing, a process that often took over a year to complete in practice. Given that EMA licensing often took many months after presentation of phase 3 trial data, the net effect was that patients were potentially denied access to effective anti-cancer therapy, frequently for over 1 year, assuming that NICE eventually recommended funding. Reacting to this, the government initially established the Cancer Drugs Fund (CDF) and ultimately reformed NICE processes.

So how exactly does NICE determine cost-effectiveness? This is the critical issue.

NICE determines the most likely cost per quality-adjusted life-year (QUALY) by principally receiving evidence from the manufacturer and a commissioned independent academic “evidence review

IASLC LUNG CANCER NEWS / NOVEMBER 2016

RECENT APPROVALS: Pembrolizumab (Keytruda) was approved by the FDA for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1.

The following indications for pembrolizumab were added for metastatic NSCLC: (1) tumors that have high PD-L1 expression (>50%), with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC, and (2) tumors that express any degree of PD-L1, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab. This is the first FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer. This approval also expands the indication in second-line treatment of lung cancer to include all patients with PD-L1-expressing NSCLC. Both approvals are based on published phase III randomized trials. (As of October 24, 2016.)

Atezolizumab (Tecentriq) was approved by the FDA for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab. This approval is based on results from the randomized phase III OAK and phase II POPLAR studies. The phase III trial showed a significant improvement in overall survival in patients with locally advanced or metastatic NSCLC, regardless of PD-L1 status, after previous cytotoxic therapy.

(As of October 18, 2016.)

The indication labeling for erlotinib (Tarceva) was modified by the FDA to limit the its use to patients with non-small cell lung cancer (NSCLC) whose tumors have specific epidermal growth factorreceptor activating mutations. The labeling change applies to patients with NSCLC receiving maintenance or second- or greater-line treatment. These indications will be limited to patients whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations. The first-line indication previously has already been limited to patients with EGFR exon 19 deletions or exon 21 substitution mutations. Its prior approval, independent of mutation status, in the second- and third-line setting after failure of one or two chemotherapy regimens has been rescinded. (As of October 18, 2016.)

Nivolumab (Opdivo) was approved by the Scottish Medicines Consortium (SMC) as treatment for locally advanced or metastatic non-squamous NSCLC, where the disease has progressed after prior chemotherapy. This recommendation means that Scottish patients on the National Health Service will become the first in the United Kingdom to be offered treatment with nivolumab. SMC previously (July 2016) approved nivolumab for locally advanced or metastatic squamous NSCLC after prior chemotherapy. (As of October 10, 2016.)

Osimertinib (Tagrisso) was recommended in draft guidance by National Institute for Health and Care Excellence (NICE) as a second-line option for patients with

group.” The QUALY threshold is not fixed

by NICE but from analyses of historical outcomes; this seems to be around £40K per QUALY.3 This assessment method may be problematic for modern therapeutics since considerable uncertainties in determining the true QUALY often exist, particularly when the magnitude of the survival benefit afforded is unknown and or needs estimation (e.g., TKIs where patients crossed over, either per trial or in routine care, or for single-arm phase 2 data). In addition, the manufacturer’s base cost of most drug indications submitted usually prices nearly all indications beyond NICE’s historical approvals

thresholds. As a result, either indications are rejected/decommissioned by NICE (e.g., erlotinib in the BR.21 indication), or substantial delays ensue prior to ultimate approval by NICE while manufacturers negotiate confidential discounted NHS pricing, or manufacturers simply decide not to submit appraisals (e.g., bevacizumab or alectinib).

What’s the Solution?

NICE undoubtedly performs an essential function by rationing a fixed budget, driving down the cost of new medicines for the NHS, and by allowing confidential discounts from manufacturers. Several

7

advanced NSCLC that is EGFR T790M-positive. The final draft guidance issued by NICE says osimertinib should be made available through the Cancer Drugs Fund (CDF), after a financial agreement was reached with AstraZeneca. It is the first drug to be approved under the updated CDF. (As of October 4, 2016.)

A label extension was approved by the FDA for the cobas® EGFR Mutation Test v2 with plasma samples as a companion diagnostic for second-line osimertinib (Tagrisso) therapy in the treatment of T790M positive advanced NSCLC. Previously, the FDA granted approval of the cobas® EGFR Mutation Test v2 for use with plasma or tissue DNA as a companion diagnostic for erlotinib (Tarceva) as first-line therapy for EGFR mutation-positive advanced NSCLC. The test is the only FDA-approved companion diagnostic for the detection of the EGFR mutations in plasma DNA. (As of September 9, 2016.)

Crizotinib (Xalkori) was approved by the European Commission for the treatment of ROS1-positive advanced NSCLC. In the European Union (EU), as in China, Japan, the US, and numerous other countries, crizotinib is also indicated for treatment of adults with ALK-positive advanced NSCLC. Crizotinib has previously been approved in the USA for first-line treatment of ROS1-positive advanced NSCLC. (As of August 31, 2016.)

Pemetrexed (Alimta) was approved by the NICE for the maintenance treatment for locally advanced or metastatic non-squamous non-small-cell lung cancer (NSCLC) after four cycles of pemetrexed and cisplatin induction therapy. Pemetrexed was already recommended by NICE as maintenance treatment for those who had received a platinum doublet chemotherapy not containing pemetrexed and for first-line therapy in combination with cisplatin. (As of August 24, 2016.)

Crizotinib (Xalkori) was approved by NICE as a first-line treatment for anaplastic lymphoma kinase (ALK)-positive advanced NSCLC. Previously, crizotinib was only recommended for use after standard chemotherapy (as of September 26, 2016).

The Scottish Medicines Consortium (SMC) has also recommended crizotinib for use in the first-line, treatment-naive setting for ALK positive NSCLC. (As of August 23, 2016.)

BREAKTHROUGH THERAPY DESIGNATION: Alectinib (Alecensa) was granted breakthrough therapy designation by the FDA on October 4, 2016 for first-line treatment of individuals with ALK-positive NSCLC who have not received prior treatment with an ALK inhibitor. This second breakthrough therapy designation was based on the results of the open-label, randomized phase III J-ALEX study, which was presented at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting in June and which showed a significant improvement in response rate and PFS compared with “standard” crizotinib. Alectinib received its first FDA breakthrough therapy designation in June 2013 for people with ALKpositive NSCLC whose disease had progressed on treatment with or were intolerant to crizotinib and was formally approved for this purpose on December 11, 2015.

improvements to the NICE process have been made recently; NICE now reviews potential indications parallel to licensing with three potential outcomes: the drug is approved for funding, rejected, or recommended for a limited period in a new Cancer Drugs Fund (if there is uncertainty for cost-effectiveness) pending reappraisal. Additionally, a new Early Access to Medicines Scheme (EAMS) has been developed, allowing prelicensing access to promising innovative medicines. All of these changes are deeply welcome. Nevertheless, the fundamental issues of eye-watering drug base costs and NICE cost-effectiveness methodol-

ogy remain unchanged. While progress has been made, it is clear that the dance between NICE and manufacturers leaves patients and clinicians in a difficult position. “It takes two to tango” is a common English idiom. Let’s hope that the dance is over quickly! ✦ References 1. https://www.gov.uk/government/publications/thenhs-constitution-for-england. Accessed September 23, 2016.

2. https://www.nice.org.uk/about/what-we-do.

Accessed September 23, 2016.

3. Dakin H, Devlin N, Feng Y, Rice N, O'Neill P, Parkin D. The Influence of Cost-Effectiveness and Other Factors on NICE Decisions (2015): 24;10: 1256–1271.

8

IASLC LUNG CANCER NEWS / NOVEMBER 2016

THOUGHT LEADER INTERVIEW

Richard B. Gaynor, MD

“We thank Dr. Gaynor for his long-standing support and significant contributions to lung cancer research, to the

On September 14, Eli Lilly and Company announced the retirement effective January 1, 2017, of Richard B. Gaynor, MD, senior vice president, Global Development & Medical Affairs for Lilly’s Oncology business. Before joining Lilly, Dr. Gaynor served as a faculty member at the University of California, Los Angeles, School of Medicine and the University of Texas Southwestern Medical Center. He currently sits on the boards of directors of the Damon Runyon Cancer Research Foundation and the Walther Cancer Foundation. IASLC Lung Cancer News recently spoke with Dr. Gaynor about his career and the future of cancer research.

Q: What are the most remarkable developments that you have seen in lung cancer research during your time at Lilly?

A: The remarkable developments in the treatment of lung cancer have included

a better understanding of the biology of lung cancer, such as the identification of specific driver mutations, and the recognition of the role of histology in clinical outcomes. These developments include the design of targeted agents for EGFR and ALK mutations, the ongoing development of immune checkpoint inhibitors, the use of maintenance therapy in non-progressing patients, and the increasing use of liquid biopsy to monitor genetic changes during therapy.

lung cancer community, and most of all to the many patients with lung cancer who have—and will—benefit from his contributions,” says Fred R. Hirsch, MD, PhD, IASLC CEO.

“The addition of pemetrexed to our therapeutic arsenal in the first- and second-line setting and as maintenance therapy in advanced non-squamous cell NSCLC has made an indelible difference in many patients' lives. The simple addition of vitamins B12 and folic acid to this agent mitigated its toxicity and helped save it from the scrap heap,” says Corey J. Langer, MD, IASLC Lung Cancer News Editor. “Dr. Richard Gaynor had no small part in pemetrexed's development, as well as the development of other agents in advanced NSCLC that have permanently improved the odds of meaningful survival. He should be saluted for his efforts.”

Q: What do you consider your greatest accomplishment regarding drug development in non-small cell lung cancer (NSCLC)?

A: While at Lilly, it has been very rewarding to participate in the development of

Alimta (pemetrexed) for the treatment of non-squamous NSCLC, help establish its use as maintenance therapy, and collaborate to better understand its role in combination with checkpoint inhibitors. In addition, the registration of Cyramza (ramucirumab) in second-line NSCLC, Portrazza (necitumumab) for the frontline treatment of squamous NSCLC, and ongoing studies, including a Phase 3 trial of the CDK 4 and CDK 6 inhibitor abemaciclib in KRAS-mutant NSCLC, and combinations of targeted agents with immune checkpoint inhibitors have been important in Lilly's ongoing commitment to develop new therapies for lung cancer patients.

Q: What about partnerships with other companies?

A: Collaborations with other pharmaceutical companies and academic investigators

have been crucial in our studies of novel drug combinations including studies with immune checkpoint inhibitors. As the field of precision medicine evolves, genetic profiling of tumors will continue to help guide patient selection and therapeutic interventions. There will continue to be further emphasis on the identification of biomarkers and, in some cases, the development of companion diagnostics to better select patients for therapy.

Q: Where do you see the therapy for NSCLC in the next 5 to 10 years?

A: The recent data on the efficacy of new treatments in lung cancer patients with

high tumor expression of PD-L1 is an exciting example of the use of biomarker selection of patients to improve outcomes for patients treated with immunotherapy.

In the future, combinations of immunologic agents and targeted agents will likely be important in addressing tumor heterogeneity and drug resistance. The continued advances in genetics and analysis of large data sets, coupled with analysis of realworld evidence, will likely help shape drug development. It is always interesting to speculate when and where the next scientific breakthroughs will occur, but in this dynamic environment with exceptional academic and pharmaceutical investigators, it is more a question of when, not if, such advances will occur. ✦

IASLC Foundation Creates the

Fellowship Matching Challenge The IASLC and IASLC Foundation Board Members have joined together to create the Fellowship Matching Challenge. Between now and December 31, 2016, the Board Members will match dollar for dollar any new or increased contributions up to $16,500.

As someone who wishes to be better educated about lung cancer, you understand the importance of people working to improve what is currently medically possible. You understand why fellowship funds are needed to facilitate time for research, to empower breakthroughs in how lung cancer is diagnosed, to allow focus to be given to the possibilities of treatment, to enable longer lives for those affected, and to offer hope for a better future for all lung cancer patients.

Since 2000, the IASLC has provided more than 80 researchers with fellowships. Fellowship grants have been awarded to medical doctors and scientists throughout the world including Italy, the United States, Japan, Spain, Australia, France, China, Denmark, Ireland, Taiwan, Germany, Thailand, Poland, and Canada. We want to continue to grow these opportunities by awarding an increased number of fellowships to encourage even more groundbreaking research and worldwide collaboration.

To do that, we need your help.

We hope you will partner with us in making this challenge a success. This is a unique opportunity to double the impact of your donation while helping to create the opportunity for more fellowships to be funded.

To make a tax-deductible gift, you can visit www.IASLC.org or mail donations to 13100 East Colfax Avenue, Unit 10, Aurora, CO 80011.

For more information, please email the IASLC Foundation at Foundation@IASLC.org

IASLC LUNG CANCER NEWS / NOVEMBER 2016

BY ERIK J. MACLAREN, P H D

In May 2016, the U.S. Food and Drug Administration (FDA) finalized the deeming rule that extended the agency’s regulatory authority to include all tobacco products, including e-cigarettes, cigars, and hookah, and pipe tobacco. IASLC Drug Cancer News spoke with Mitch Zeller, JD, Director of the FDA Center for Tobacco Products to learn more about the impact of this new rule on tobacco product regulation.

Q: What is the future of tobacco product regulation in the United States?

A: The deeming rule marked a new chapter in the agency’s efforts to end preventable

tobacco-related disease and death. Provisions aimed at restricting youth access took effect immediately upon the rule’s effective date of August 8, 2016, effective date, and on September 15, the FDA took action against 55 tobacco retailers by issuing the first warning letters regarding selling newly regulated tobacco products to minors.

The rule provided the foundation for the FDA to regulate tobacco products that young people were using at an alarming rate, and that had previously gone largely unregulated. Among other requirements, the rule requires manufacturers of newly regulated products to meet the applicable public health standard set forth in the Family Smoking Prevention and Tobacco Control Act (TCA) and in the deeming rule, and to receive the FDA’s marketing authorization, unless the product was on the market as of February 15, 2007. The FDA has provided a staggered compliance time frame for industry to submit applications for this type of authorization.

The FDA plans additional steps to protect youth, including issuing a separate proposed rule to extend the existing flavor ban on cigarettes to cover cigars with characterizing flavors, including premium cigars, little cigars, and cigarillos. The agency also intends to issue rules to require nicotine exposure warnings and childresistant packaging for products with e-liquids.

Q: How have tobacco companies responded to the expansion of the FDA’s regulatory authority under the deeming rule?

A: Since the deeming rule’s May 2016 finalization, the FDA has received about 6,000

inquiries by phone or email from manufacturers and retailers about the deeming rule and about the requirements to comply. Steps the FDA has taken to proactively support regulated industry have included: • Redesigning the Center for Tobacco Products’ online information about deeming to clearly set forth the rule’s provisions and delineate compliance requirements; • Hosting webinars on various deeming-related topics; • Preparing guidances to discuss the agency’s current thinking on regulatory topics related to deeming; and • Assisting small businesses through the Center for Tobacco Products’ Office of Small Business Assistance.

Q: What is the FDA’s perspective on Electronic Nicotine Delivery Systems (ENDS) products as potential smoking cessation devices?

A: The FDA recognizes some tobacco products have the potential to be less

harmful than others. The agency believes ENDS products have potential benefits and risks, and that more scientific evidence is needed about these. By reviewing individual applications, the FDA will be able to answer important questions about what ingredients are in ENDS products, to help establish whether they are beneficial or harmful and to whom.

Certain ENDS may have reduced toxicity compared to conventional cigarettes, they may encourage current smokers to switch completely, and/or they may have the potential to reduce disease and death if not widely used by youth. However, if any of these products prompt young people to become addicted to nicotine, diminish their interest in quitting cigarettes, and/or lead to long-term dual usage with other tobacco products, the public health impact could be negative.

If an ENDS product is marketed for tobacco cessation or any other therapeutic purpose, the product will be regulated as a drug or device, rather than as a tobacco product.

CORNER

INTERVIEW WITH MITCH ZELLER, JD /

9

Q: What types of research are useful in supporting the FDA’s regulatory decision-making relating to tobacco products and especially ENDS?

A: In support of its mission to protect the public health, the FDA is commit-

ted to continually learning more about the potential health impacts—whether beneficial or harmful—of ENDS and other products in the evolving tobacco marketplace. The science base is developed through extensive research on important factors such as product toxicity, appeal, and initiation, including studies the agency itself conducts and supports, and through the information that companies submit to comply with the TCA and deeming rule requirements.

For those companies submitting a premarket tobacco product application (PMTA) for e-cigarettes—the pathway that the FDA expects to be the most common for these products—the agency has developed a draft industry guidance that is available for public comment. The “Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems” draft guidance includes information the agency recommends be submitted in a PMTA for an ENDS product, to show whether permitting the new tobacco product to be marketed is appropriate for the protection of the public health. For example, the PMTA ENDS draft guidance discusses circumstances when a new clinical trial might be helpful and when it might be less necessary; the FDA looks forward to comments in this area.

Another, more general draft guidance titled “Applications for Premarket Review of New Tobacco Products” is also available; this covers the types of information that the FDA proposed be included in a new tobacco product application.

The agency is currently reviewing comments received on this draft guidance. ✦

Front-Line Immunotherapy from page 1 to define positivity; KN 24 employed a cutoff of 50% PD-L1 expression (prevalence of 30%) and CM 26 employed a cutoff of 5% (50% prevalence); both were designed to demonstrate superiority in progression-free survival (PFS) with antiPD-1 therapy. CM 26 failed to meet its primary endpoint; however, KN 24 demonstrated superiority for pembrolizumab compared to standard chemotherapy for both PFS and overall survival (OS). This remarkably positive trial demonstrated a response rate of 45% for pembrolizumab compared to 28% with chemotherapy, including a nearly 10% complete response rate. PFS was 10.3 vs. 6 months and 1-year landmark survival was 70 vs. 54%. These differences were statistically significant.

The high response rate and complete response rate in KN 24 raise the question as to the potential greater efficacy of immunotherapy in the first-line setting.

Does immunotherapy work better firstline versus second-line in NSCLC? Does prior chemotherapy impede the magnitude of immune response in some way?

These data have opened the door for broader immunotherapy indications in the first-line setting beyond the high positive PD-L1 subset. As we look to the future NSCLC landscape, trials combining chemotherapy with anti-PD-(L)1 antibodies are underway, as are trials combining antiCTLA-4 with anti- PD-(L)1 antibodies.

These trials may help us extend the application of immunotherapy in the first-line

setting beyond the high PD-L1 positive patients; the results are eagerly awaited.

Questions certainly remain as to whether immunotherapy can be applied to every patient with NSCLC. KN 24 inclusion criteria included ECOG 0-1, no corticosteroid use, and no history of autoimmune disorders—the real-world application is yet to be defined. Nevertheless, in 2016, the landscape of NSCLC has irrevocably changed. The treatment paradigm will now include PD-L1 testing for every patient with advanced NSCLC at diagnosis. For patients with PD-L1 expression ≥ 50%, first-line pembrolizumab has displaced platinum-based doublet chemotherapy and represents the new standard of care. ✦

References

1. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol.

2010;28:3167-3175.

2. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous NonSmall-Cell Lung Cancer. N Engl J Med. 2015;373:16271639.

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;373:123-135.

4. Herbst RS, Baas P, Kim DW, 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;387:15401550.

5. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer.

N Engl J Med. 2015;372:2018-2028.

6. Reck M, Rodríguez-Abreu D, Robinson AG, et al.

Pembrolizumab versus Chemotherapy for PD-L1Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Oct 8. [Epub ahead of print]

10

IASLC LUNG CANCER NEWS / NOVEMBER 2016

MEETING SUMMARY

7th Latin American Conference on Lung Cancer

By Edgardo S. Santos Castillero, MD, and Roberto I. Lopez, MD

Today, liquid biopsy represents an alternative besides tumor tissue specimens to discover druggable molecular pathways.

DNA (ctDNA) plasma NGS test, was used to genotype 5206 advanced-stage NSCLC patients. In this cohort, 85% of samples were ordered at clinical progression and 15% at baseline in patients who had insufficient tumor specimen for analysis.

Somatic ctDNA alterations were detected in 86% of cases; most common ones included EGFR (25%) and KRAS (17%).

Among driver oncogenes, the alteration pattern was highly consistent with those previously described in the tissue sequencing compendia (e.g., TCGA). Dr. Gandara pointed out that the accuracy of ctDNA sequencing (PPV) found in the 229 consecutive samples matched with their tissue testing report was 100% for EGFR L858R, 98% for EGFR exon 19 deletion, 96% for ALK, RET or ROS-1 fusions, and 100% for KRAS mutations.

In 63% (229/362) of consecutive NSCLC cases, tissue was insufficient or undergenotyped. More importantly, alterations not previously identified were found via ctDNA NGS in 24% (51/229) of these cases. For those patients who were tested at progression, resistance mutations in 1111 EGFR mutant NSCLC cases were identified via ctDNA NGS at frequencies consistent with published literature: 47% had EGFR T790M, 5% MET amplification, 5% ERBB2 amplification, 3% NF1 inactivation and RB1 inactivation, 2.5% PTEN inactivation, 1.9% KRAS mutations, 1.8% BRAF mutations, and others. Dr. Gandara concluded that ctDNA NGS is capable of identifying new druggable alterations at progression and when tumor tissue is insufficient. This

technology also opens the possibility of serial testing for evolution of resistant alterations in lung cancer.

Among the highest rank abstracts, we report a study on cost-effectiveness of immune checkpoint inhibitors in NSCLC relative to PD-L1 expression. This analysis was presented by Dr. Gilberto Lopes (Brazil) et al. With the advent of checkpoint blockade, there is tremendous pressure from health insurance companies, government, patient advocacy groups, and regulatory authorities due to the high cost of these novel agents and the impact on the healthcare system.

Conversely, these agents have also been shown to improve overall survival in firstline (e.g., KEYNOTE 024 trial) and second-line therapy (e.g., CheckMate 017, CheckMate 057, KEYNOTE 010 trials) in advanced NSCLC patients. A decisionanalytic model to determine the costeffectiveness of PD-L1 assessment and second-line therapy with nivolumab or pembrolizumab vs docetaxel was developed by the investigators. The model used outcomes data from 3 randomized clinical trials (RCTs) and drug acquisition costs from the US. For squamous NSCLC, the incremental quality-adjusted life-years (QALY) of nivolumab was 0.23. The incremental cost-effectiveness ratios (ICER) was USD $128,000. PD-L1 expression improved incremental QALY

only for patients with PD-L1 > 5% and > 10%. Among all non-squamous NSCLC, the incremental QALY of nivolumab was 0.12 and ICER was USD $121,000.

PD-L1 expression improved incremental QAYL for patients with PD-L1 > 1%, > 5%, > 10%. This led to a drop in the ICER in all 3 groups of patients stratified

by PD-L1 expression. KEYNOTE-010 study included patients with at least 1% or higher PD-L1 expression; the incremental QALY was 0.13 for pembrolizumab. The ICER was USD $116,000.

For those patients whose tumors had a PD-L1 > 50%, the incremental QALY was improved by 18% and the ICER dropped to USD $98,000 (Figure 1). Lopes concluded that the use of PD-L1 expression as a biomarker for patient selection improves the cost-effectiveness of treatment with PD-1 inhibitors and has the potential to decrease the total cost of therapy with these agents in both Brazil and in the United States; however, this improvement comes at a cost. By using PD-L1 as a biomarker, fewer patients are treated and the total life years gained is likely to be lower than if we treat all patients. ✦

Brazil: Cost-effectiveness with and without PD-L1 Expression US Dollars (thousands)

(14.7%), MET amplification (8.8%), and others. Interestingly, these patients were still sensitive to other therapies after progression (overall response rate [ORR], 47.1%).

Today, liquid biopsy represents an alternative besides tumor tissue specimens to discover druggable molecular pathways. Dr. David Gandara (US) et al presented the results of largest cohort of plasma next generation sequencing (NGS) performed in advanced non-small cell lung cancer (NSCLC) and its clinical correlations. Guardant360, a highly accurate, deep-coverage circulating tumor

$264

ICER NIVO vs DOC SQ ICER NIVO vs DOC NSQ

$129

$150

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ICER PEMBRO vs DOC

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$137

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1%

$112

$116

$109

$58

$63

5%

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50%

PD-L1 Expression

USA: Cost-effectiveness with and without PD-L1 Expression US Dollars (thousands)

In August 2016, the 7th Latin America Conference on Lung Cancer (LALCA) was held in Panama City, Republic of Panama. More than 500 healthcare professionals gathered to discuss the latest advances in prevention, detection, diagnosis, and treatment for lung cancer. This congress, which was sponsored by the IASLC, takes place every 2 years in different countries of the region. The meeting was led by Drs. Roberto I. Lopez, Local Chair, and Edgardo S. Santos Castillero, International Chair. This was the first LALCA meeting where trainees from different disciplines (thoracic surgery, radiation oncology, pathology, radiology, pulmonary, and medical oncology) had the chance to attend the “School of Thoracic Oncology”; this 1-day workshop led by Drs. Luis E. Raez and Suresh Ramalingam offered trainees the opportunity to interact and learn the basics of lung cancer diagnosis, prognosis, and pathology, as well as the role of surgery, radiation, and new targeted therapies, at no cost. In addition, LALCA Panama opened its doors to cancer patients and their relatives. This new Patient Advocacy session provided experts in the field with the opportunity to talk to patients and families about current treatments available, the importance of genetic testing, drug availability, costs, and other topics.

Two lung cancer survivors with stage IV disease also participated as guest speakers and shared their experiences fighting lung cancer. Both sessions were well received by the participants. The LALCA meeting agenda also included educational conferences, a roundtable session to discuss major topics with experts in the field, poster display and discussion, and oral presentations.

Several significant abstracts were presented at the conference. In an international effort involving several Latin America countries, Dr. Oscar Arrieta (Mexico) et al presented their results on acquired resistance, clinical characteristics, and survival outcomes of patients whose disease progressed on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in EGFR mutant (+) lung adenocarcinoma among Hispanics. In this prospective registry study, 34 patients with acquired resistant to TKI were identified over a period of 4 years. After progression, all patients were re-biopsied; similar to what has been found in Caucasian patients, T790M was the most common cause of acquired resistance (47.1%), followed by PI3K mutations (14.7%), EGFR amplification

ICER NIVO vs DOC SQ

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Figure 1. Cost-Effectiveness of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Relative to PD-L1 Expression. Courtesy of Dr. Gilberto Lopes, Oncoclinicas do Brasil, São Paulo/Brazil.

IASLC LUNG CANCER NEWS / NOVEMBER 2016

11

PERSPECTIVE

Epidemiology of Lung Cancer in Developing Countries

By Jyoti Malhotra, MD, MPH and Paolo Boffetta, MD, MPH

Lung cancer is the most frequent malignant neoplasm in most countries worldwide, and the main cause of cancer death in both sexes.1,2 As per GLOBOCAN, lung cancer accounted for an estimated 1,242,000 new cases among men, which is 17% of all cancers excluding non-melanoma skin cancer, and 583,000 (9%) of new cancer cases among women in 2012.

Approximately 58% of all cases occur in middle and low income countries.3 Lung cancer also accounts for 19% of all cancer deaths.4 Among both women and men, the incidence of lung cancer is low in persons under age 40 and increases up to age 75 to 80 in most populations.

Based on figures from World Health Organization (WHO), age-standardized mortality rates from lung cancer (at all ages) increased in most developing countries worldwide except for Central American countries (Mexico, Panama) between 2002 and 2012. For men, overall lung cancer mortality between 2002 and 2012 decreased in several countries worldwide.5,6 Thus, the declines in lung cancer mortality rates in men have continued over recent years, and are projected to persist for the near future.7 Overall female lung cancer mortality has been lower than in men, but has been increasing up to the recent years in most countries.

Trends in lung cancer mortality can be interpreted in terms of different patterns of smoking prevalence in subsequent cohorts of people in various countries,8,9 as tobacco smoking remains the major cause of all major histologic types of lung cancer in developing countries as well. An increase in tobacco consumption is paralleled a few decades later by an increase in the incidence of lung cancer. Similarly, the temporal lag in trends in female and male lung cancer mortality reflects historical differences in cigarette smoking between subsequent female and male cohorts.10,11 The higher rate of lung cancer among African Americans as compared to other ethnic groups in the United States is probably explained by their higher tobacco consumption.12 The lower risk of lung cancer among smokers in China and Japan as compared to Europe and North America might be due to relatively recent introduction of regular heavy smoking in Asia, although differences in the composition of traditional smoking products and in genetic susceptibility might also play a role.13 The importance of tobacco smoking in the causation of lung cancer

Jyoti Malhotra

Paolo Boffetta

complicates the investigation of the other causes, because tobacco smoking may act as a powerful confounder or modifier.

Although cigarettes are the main tobacco product smoked in western countries, an increased risk of lung cancer has also been shown following consumption of local tobacco products, such as bidi and hookah in India and khii yoo in Thailand, and the use of water pipes in China.14 Chronic inflammation seen with infections more prevalent in developing countries may also play a role in lung carcinogenesis. Patients with pulmonary tuberculosis have been found to be at increased risk of lung cancer.15 In the most informative study, involving a large cohort of tuberculosis patients from Shanghai, China,16 the risk of lung cancer exceeded twofold in the subjects with a history of tuberculosis within the last 20 years. Six studies exploring risk of lung cancer among individuals with markers of Chlamydia pneumoniae infection have also consistently detected a positive association.17 Other notable risk factors for lung cancer in developing countries include indoor air pollution and occupational exposures. Indoor air pollution is especially a major risk factor for lung cancer in never-smoking women living in several regions of Asia. This includes coal burning in poorly ventilated houses, burning of wood and other solid fuels, as well as fumes from high-temperature cooking using unrefined vegetable oils such as rapeseed oil.18 In many low- and medium-resource countries, occupational exposure remains widespread, with the most important occupational lung carcinogens reported to be asbestos, silica, radon, heavy metals, and polycyclic aromatic hydrocarbons (PAHs).19,20 For lung cancer prevention worldwide, control of tobacco smoking is the most important preventive measure.

Other priorities for the prevention of lung cancer include control of occupational exposures as well as indoor and outdoor air pollution, and understanding the carcinogenic and preventive effects of other lifestyle factors. ✦

2. Malvezzi M, Carioli G, Bertuccio P, Rosso T, Boffetta P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2016 with focus on leukemias. Ann Oncol 2016.

3. Foreman D, Bray F, Steliarova-Founcher E, Ferlay J, Brewster D. Cancer Incidence in Five Continents IARC Scientiĺc Publication 1o 164 Lyon: International Agency for Research on Cancer 2014: X. 4. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015: 136(5): E359-386.

5. World Health Organization Statistical Information System. WHO mortality database. Available at: http://www3.who.int/whosis/menu.cfm/ [last accessed: December 2015].

6. Malhotra J, Malvezzi M, Negri E, La Vecchia C, Boffetta P. Risk factors for lung cancer worldwide.

Eur Respir J 2016.

7. Malvezzi M, Bosetti C, Rosso T, Bertuccio P, Chatenoud L, Levi F, Romano C, Negri E, La Vecchia C. Lung cancer mortality in European men: trends and predictions. Lung Cancer 2013: 80(2): 138-145.

8. Graham H. Smoking prevalence among women in the European community 1950-1990. Soc Sci Med 1996: 43(2): 243-254.

9. Franceschi S, Naett C. Trends in smoking in Europe. Eur J Cancer Prev 1995: 4(4): 271-284.

10. Thun M, Peto R, Boreham J, Lopez AD. Stages of the cigarette epidemic on entering its second century.

Tob Control 2012: 21(2): 96-101.

11. Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2012. Ann Oncol 2012: 23(4): 1044-1052.

12. Devesa SS, Grauman DJ, Blot WJ, Fraumeni JF. Cancer surveillance series: changing geographic

patterns of lung cancer mortality in the United States, 1950 through 1994. Journal of the National Cancer Institute 1999: 91(12): 1040-1050.

13. Yuan J-M, Koh W-P, Murphy SE, Fan Y, Wang R, Carmella SG, Han S, Wickham K, Gao Y-T, Mimi CY. Urinary levels of tobacco-specific nitrosamine metabolites in relation to lung cancer development in two prospective cohorts of cigarette smokers.

Cancer research 2009: 69(7): 2990-2995.

14. World Health Organization IAfRoC. Tobacco smoke. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol 83 Tobacco Smoke and Involuntary Smoking. Lyon, France, Lyon, France, 2004; pp. 51–1187.

15. Aoki K. Excess incidence of lung cancer among pulmonary tuberculosis patients. Japanese journal of clinical oncology 1993: 23(4): 205-220.

16. Zheng W, Blot W, Liao M, Wang Z, Levin L, Zhao J, Fraumeni Jr J, Gao Y. Lung cancer and prior tuberculosis infection in Shanghai. British journal of cancer 1987: 56(4): 501.

17. Littman AJ, Jackson LA, Vaughan TL. Chlamydia pneumoniae and lung cancer: epidemiologic evidence. Cancer Epidemiology Biomarkers & Prevention 2005: 14(4): 773-778.

18. International Agency for Research on Cancer WHO. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 95. Household use of solid fuels and high-temperature frying.

IARC, Lyon, France, 2006.

19. Cogliano VJ, Baan R, Straif K, Grosse Y, LaubySecretan B, El Ghissassi F, Bouvard V, BenbrahimTallaa L, Guha N, Freeman C, Galichet L, Wild CP. Preventable exposures associated with human cancers. J Natl Cancer Inst 2011: 103(24): 1827-1839.

20. Humans IWGotEoCRt. Chemical agents and related occupations. IARC Monogr Eval Carcinog Risks Hum 2012: 100(Pt F): 9-562.

IN MEMORIAM

Robert B. Livingston, MD The lung cancer research community lost a respected leader and significant contributor to the field with the passing of Robert B. Livingston, MD, a Professor of Medicine and Hematology-Oncology at the University of Arizona Cancer Center. He died at home in Tucson, Arizona, on September 8, 2016, at age 75.

Dr. Livingston embarked on his career after graduating from the University of Oklahoma College of Medicine in Oklahoma City, Oklahoma, and completing a residency there in internal medicine in 1971. He then undertook a fellowship in developmental therapeutics at the University of Texas MD Anderson Cancer Center until 1973. Dr. Livingston spent more than 30 years investigating both lung and breast cancers during his career in clinical research, and he was known as a leading international advocate and expert on both clinical research and clinical trials. Dr. Livingston formerly chaired the Lung Cancer and the Breast Cancer Committees of the Southwest Oncology Group, and in 2008, he was chosen by his peers as one of the “Best Doctors in America.” Among his many scientific contributions to oncology, Dr. Livingston was among the first to introduce the use of concurrent chemotherapy and radiation for limited small cell lung cancer and stage 3 non-small cell lung cancer.

“Though Bob was among the most respected leaders in the fields of both lung and breast cancer for decades and was in high demand for both when I began working with him, he generously shared his time and wisdom because he enjoyed teaching as much as he enjoyed working with his patients. Beyond what the oncology literature told us, he shared the clinical pearls you can only get from working closely with someone day after day who has deep experience. That he was also such a kind and humble person only made me more grateful for that opportunity.”

– H. Jack West, MD

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015: 65(1): 5-29.

Medical Director, Thoracic Oncology Program, Swedish Cancer Institute

12

IASLC LUNG CANCER NEWS / NOVEMBER 2016

POINTS OF CONTROVERSY

Lung Cancer in Women: Different or Not?

By Julien Mazières, MD, PhD, and Julie Milia, PhD

Once considered a “man’s disease,” lung cancer no longer discriminates. During the last decade, lung cancer in women has become the most common cause of cancer death in women in the US, surpassing breast cancer, and the second leading cause of cancer death in women in Europe. Lung cancer in women displays specific epidemiological, radiological, clinical, and pathological characteristics that differentiate it from lung cancer in men. Moreover, both prognosis and response to treatment appear to be different from men. In line with these findings, lung carcinogenesis is, at least in part, distinct in women and involves different mechanisms and signaling pathways. We therefore believe that specific therapeutic strategies should be considered in women harboring lung cancer.

of adenocarcinoma (64% for women vs 48% for men) and a higher incidence of tumors with a lepidic component.3 There is a higher proportion of non-smokers among women with lung cancer than in men: 30% vs 10%, respectively. This rate can rise as high as 80% in Asia.4 Finally, females have a generally better prognosis and their tumors are more chemosensitive in comparison to males.5

and tumor cell lines and tissues. Estrogen can directly stimulate the transcription of estrogen-responsive genes in the nucleus of lung cells, and it can also transactivate growth factor signaling pathways, in particular the epidermal growth factor pathway12 (Figure 1). Moreover, treatment with hormonal substitutes negatively affects the prognosis of women with stage IV lung cancer.13

Potential Risk Factors

Genetics Routine molecular profiling of patients with advanced NSCLC has been conducted in France, and the results underscore differences based on gender: 54% of women carry known genetic alterations, whereas these are present in only 39% of men, except for KRAS, which is more frequent for men14 (Table 1).

Tobacco Smoking accounts for about 90% of global lung cancer deaths in men and 70% of the deaths in women.6 Tobacco remains the major risk factor for women today. Women appear to be more sensitive to carcinogens; for the same quantity of tobacco consumption, they will

“The incidence and mortality of lung cancer are still increasing in Asian females, who are mostly never-smokers, and presents as adenocarcinoma. Druggable oncogenic drivers are more prevalent in Asian females, so their disease has a higher opportunity to use targeted therapy. The identification of specific genetic alterations or normal profiles may serve as new therapeutic targets.

Therapeutic Strategies

To date, there are no recommendations to treat men and women differently.

Nevertheless, the incidence of molecular alteration is higher in women and led

Julien Mazières

Julie Milia

tomore frequent use of targeted therapies (Table 1). EGFR-activating mutation is found in around 20% of the women, with the incidence as high as 40% in non-smokers. Tyrosine kinase Inhibitors (TKIs) are now the standard treatment for the care of EGFR-mutated patients.15 ALK rearrangements are also found more often in women than in men: 5.4% vs 2.7%, according to the biomarkers study performed in France.14 The HER2 mutation is also more frequently found in women. The use of antibodies targeting HER2 for these patients seems to yield promising overall response rates.16 Hormones are also known to play an important role in oncogenesis and development of NSCLC because estrogen can stimulate cell proliferation and antiestrogens can cause inhibition of proliferation. We have increasing data on the interactions between estrogen receptors

—Caicun Zhou, PhD, MD Shanghai Pulmonary Hospital, Shanghai, China, IASLC Lung Cancer News Associate Editor

Epidemiology

Lung cancer is the most common cancer in men worldwide (1.2 million), with the highest rates in central and eastern Europe (53.5 per 100,000) and eastern Asia (50.4 per 100,000). In women, the incidence rates are generally lower. The highest estimated rates are in northern America (33.8), northern Europe (23.7), and eastern Asia (19.2), compared to much lower rates in western and middle Africa (1.1 and 0.8, respectively).1 Denmark has the highest rate of lung cancer in women, followed by Canada and US. In the US, the rate of new lung cancer cases over the past 37 years has dropped for men (28% decrease), while it has risen for women (98% increase).

The number of lung cancer deaths worldwide will increase from 1.6 million in 2012 to 3 million in 2035. Consequently, the number of lung cancer deaths will almost double in both men (1.1 million in 2012 to 2.1 million in 2035) and in women (0.5 million in 2012 to 0.9 million in 2035).2

Presentation

Lung cancer in females exhibits some specificity such as a higher frequency

”

develop more cancer than men. This may be explained in part by lower expression of DNA repair genes such as ERCC, BRCA1, and RRM1 in women as compared to men.7 5

Environment In Asia, lung cancer in women has been correlated to the Kang use (charcoal oven); and in Denmark, more lung cancers have been detected in women bus and tramway drivers.8 In other countries, no real links have been made between a specific “women’s environment” and lung cancer incidence.

Hormones: Women diagnosed with lung cancer have better clinical outcomes compared to men within the same strata of stage and histology. Several studies support a link between female hormones and lung cancer: early menopause, less than three pregnancies, a short menstrual cycle, use of estrogenic substitutes, and a family history of hormone-dependent cancers.3,9,10,11 Estrogens may be involved in lung cancer carcinogenesis, and estrogen receptors (ERs), mainly ERbeta, are present and functional in normal lung

Figure 1: Interaction of ER and EGFR pathways (E2 – estradiol; ER – estrogen receptor; EGFR – epidermal growth factor)

Table 1. Incidence of Molecular Alteration According to Gender (from14) Biomarker

Men

Women

Drugs

EGFR

3.9

16.8

EGFR-TKI

ALK

2.7

5.4

ALK-TKI

KRAS

27.9

25.3

BRAF

1.5

2.0

BRAF inh.

PI3K

2.5

2.9

PI3K inh.

HER2

0.5

1.5

HER2-TKI, HER-mAb

Total

39%

53.9%

MEK inh., CDK4 inh,

Targeted therapy

IASLC LUNG CANCER NEWS / NOVEMBER 2016

By Stephanie R. Land, PhD

Tobacco cessation assistance, imperative for tobacco users who seek medical care,1 takes on even greater urgency for individuals who are undergoing cancer screening or treatment. Cigarette smoking and other tobacco use in these settings raise important questions about how tobacco use affects patients and their cancer therapy, how to design cessation interventions for delivery with cancer screening and treatment, and how lung cancer screening affects tobacco use behavior at the individual and population level. For patients, quitting tobacco use can be the single most effective, cost-saving, toxicityfree means to prevent cancer or improve their outcomes after diagnosis.

Smoking Cessation Services in the Context of Lung Cancer Screening

The release of US Preventive Services Task Force recommendations for lung cancer screening with lowdose computed tomography (LDCT) and inclusion of LDCT screening in the US Medicare preventive benefits have led to a marked increase in the number of radiology clinics that deliver this service.2 NCI now plans to provide $18.4 million for a set of 6 5-year studies aimed at determining the key characteristics and implementation strategies of effective smoking cessation interventions designed for the LDCT setting. Smoking cessation treatment during LDCT screening offers great potential to reduce tobacco use rates and smoking-related morbidity and mortality.

Tobacco Use After Cancer Diagnosis

Cigarette smoking is prevalent among patients with lung and head and neck cancers, with rates as high as 40% to 60% at diagnosis. Studies comparing cancer patients who smoke cigarettes at the time of diagnosis to cancer patients who are former or neversmokers have demonstrated that current smokers have higher all-cause and cancer-specific mortality as

and EGFR signaling pathways, as well as on the additive antitumor effect of antiestrogens (tamoxifen and fulvestrant) combined with tyrosine kinase inhibitors (gefitinib, erlotinib, and vandetanib).12,17 Thus, future treatment may add antihormonal drugs to targeted therapies. Some trials such as LADIE-IFCT1003 trial (NCT01556191) are currently testing this hypothesis.

In summary, we think that lung cancer in women, at least in part, is a distinct entity with distinct carcinogenesis.

We propose that improving knowledge of its biology will permit the identification of specific genetic alterations or hormonal profiles that may serve as new therapeutic targets. ✦

well as higher risk of tobacco-related second primary cancer, and may also have higher risk of recurrence, poorer response to treatment, and increased toxicity.3 For patients in clinical trials, tobacco can be doubly damaging—affecting both response to experimental therapy and the ability of researchers to interpret trial results when interactions with tobacco use are not accounted for. A patient’s host factors, including tobacco use, are particularly important in the era of precision medicine.4 Tobacco use during and after cancer treatment should be recorded, and all patients should be offered cessation assistance.5 In a recent effort by NCI in collaboration with the American Association for Cancer Research (AACR), the NCI-AACR Cancer Patient Tobacco Use Assessment Task Force identified a priority research agenda regarding tobacco use after cancer diagnosis.

The Task Force also designed and tested the Cancer Patient Tobacco Use Questionnaire (C-TUQ), a key tool for initial and follow-up assessments in cancer clinical trials.6,7 The C-TUQ includes a “Core” short form of 4 smoking status and history items for routine use in cancer research, and an “Extension” to capture more detailed history, use of other tobacco products, cessation, and secondhand exposure. The Extension also includes smoking behavior during time periods specific to the cancer treatment trajectory, providing important data not available from general population questionnaires.

The Task Force recommends that tobacco use be assessed at the patient’s entry to a clinical trial and at the end of cancer treatment, and if possible, during treatment (e.g., before and after cancer surgery and on day 1 of each chemotherapy cycle). Broad use of the C-TUQ will enable researchers to gather and pool data on tobacco use by cancer patients, which will advance the scientific agenda identified in the Task Force recommendations. In August 2016, NCI awarded supplemental funding to selected investigators in the National Cancer Trials Network and the NCI Community Oncology Research Program

References 1. Ferlay J, Soerjomataram I, Dikshit R, et al: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer 136:E35986, 2015.

2. Didkowska J, Wojciechowska U, Manczuk M, et al: Lung cancer epidemiology: contemporary and future challenges worldwide. Ann Transl Med 4:150, 2016.

3. Zatloukal P, Kubik A, Pauk N, et al: Adenocarcinoma of the lung among women: risk associated with smoking, prior lung disease, diet and menstrual and pregnancy history. Lung Cancer 41:283-93, 2003.

4. Shafer D, Albain K: Lung cancer outcomes in women. Semin Oncol 36:532-41, 2009 5. Radzikowska E, Glaz P, Roszkowski K: Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival.

Population-based study of 20 561 cases. Ann Oncol 13:1087-93, 2002.

6. Ezzati M, Lopez AD: Estimates of global mortality attributable to smoking in 2000. Lancet 362:84752, 2003.

to facilitate implementation of C-TUQ assessments in their multi-center cancer trials.

As many as 50%–70% of patients who smoke at the time of diagnosis do quit, at least initially; however, many relapse during the course of treatment.

The limited availability of evidence-based cessation treatment in the cancer care setting and low patient utilization of such treatment are barriers to improving and sustaining cessation rates. NCI currently funds research regarding how to effectively deliver smoking cessation interventions to cancer patients after diagnosis, and how cessation after diagnosis improves cancer outcomes.

Globally, cancer screening and treatment hold great promise as opportunities to provide tobacco cessation assistance and reduce the burden caused by tobacco use worldwide. ✦

CORNER

Lung Cancer and Smoking Cessation: Opportunities for Progress

13

References 1. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence. 2008 Update. Clinical practice guideline. 2008; http://www.ahrq.gov/path/tobacco.htm#Clinic. Accessed Sept 14, 2016.

2. Mulshine J, Hirsch F, Field J. Update on low-dose CT lung cancer screening implementation in the United States. IASLC Lung Cancer News 2016; https://www.iaslc.org/sites/default/files/ wysiwyg-assets/News/ilcn_v1n2_june2016_1.pdf. Accessed Sept 14, 2016.

3. US Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General: United States Department of Health and Human Services. Public Health Service. Office of the Surgeon General;2014.

4. Ganz PA. Host factors, behaviors, and clinical trials: opportunities and challenges. J Clin Oncol. Aug 10 2012;30(23):2817-2819.

5. Morgan G, Schnoll RA, Alfano CM, et al. National Cancer Institute Conference on Treating Tobacco Dependence at Cancer Centers. J Oncol Pract. May 2011;7(3):178-182.

6. Land SR, Warren GW, Crafts JL, et al. Cognitive testing of tobacco use items for administration to patients with cancer and cancer survivors in clinical research. Cancer. Jun 1 2016;122(11):1728-1734.

7. Land SR, Toll BA, Moinpour CM, et al. Research Priorities, Measures, and Recommendations for Assessment of Tobacco Use in Clinical Cancer Research. Clinical cancer research : an official journal of the American Association for Cancer Research.

Apr 15 2016;22(8):1907-1913.

7. Planchard D, Loriot Y, Goubar A, et al: Differential expression of biomarkers in men and women. Semin Oncol 36:553-65, 2009.

8. Soll-Johanning H, Bach E, Olsen JH, et al: Cancer incidence in urban bus drivers and tramway employees: a retrospective cohort study. Occup Environ Med 55:594-8, 1998.

9. Seow A, Poh WT, Teh M, et al: Diet, reproductive factors and lung cancer risk among Chinese women in Singapore: evidence for a protective effect of soy in nonsmokers. Int J Cancer 97:36571, 2002.

10. Gao YT, Blot WJ, Zheng W, et al: Lung cancer among Chinese women. Int J Cancer 40:604-9, 1987.

11. Taioli E, Wynder EL: Re: Endocrine factors and adenocarcinoma of the lung in women. J Natl Cancer Inst 86:869-70, 1994.

12. Stabile LP, Lyker JS, Gubish CT, et al: Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects.

Cancer Res 65:1459-70, 2005.

13. Ganti AK, Sahmoun AE, Panwalkar AW, et al: Hormone replacement therapy is associated with

decreased survival in women with lung cancer.

J Clin Oncol 24:59-63, 2006.

14. Barlesi F, Mazieres J, Merlio JP, et al: Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet, 2016.

15. Rosell R, Carcereny E, Gervais R, et al: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239-46, 2012.

16. Mazieres J, Barlesi F, Filleron T, et al: Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Annals of Oncology, 2015.

17. Siegfried JM, Gubish CT, Rothstein ME, et al: Combining the multitargeted tyrosine kinase inhibitor vandetanib with the antiestrogen fulvestrant enhances its antitumor effect in non-small cell lung cancer. J Thorac Oncol 7:48595, 2012.

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IASLC LUNG CANCER NEWS / NOVEMBER 2016

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

Teenage Smoking: An Interview with Michael Kulik, MS

By Erik J. MacLaren, PhD

Tobacco smoking is a well-known risk factor for developing lung cancers, and the US Centers for Disease Control and Prevention has reported that nine out of 10 cigarette smokers began smoking by age 18.1 Michael Kulik, MS, a lecturer at the University of Pennsylvania in Philadelphia, Pennsylvania, teaches an academically based community service course called Preventing Tobacco Addiction in Urban Pre-adolescents.

IASLC Lung Cancer News recently spoke with Mr. Kulik about current trends in adolescent smoking and what can be done to prevent it.

Q: To what extent do genetics factor

Q: What predisposes teens to smoke?

Q: Are alternative forms of tobacco a

A: Physically, the brains of adolescents

are hyperplastic and, because of this, they are susceptible to making decisions that lead to smoking. Tobacco is more addictive than coffee, alcohol, or cocaine, but adolescents do not understand what addiction is all about until after they get addicted themselves. Peer pressure is also important, as it is for all adolescents concerning many behaviors. Teenagers want to fit in and do not want to be left out, so if their friends smoke, it is more likely that they are going to smoke as well. Kids all want to act cool; they all want to be grown-up. Smoking is an adult decision, so that alone is something that tempts kids to smoke.

Globally, cigarette smoking is common among youth.2 Most regular smokers initiate smoking before 20 years of age. Youth may have several reasons for starting tobacco use, including looking ‘cool,’ ‘mature,’ or ‘sociable,’ or believing that tobacco use is good for coping with stress and weight control. The factors increasing youth tobacco initiation may vary across countries, but some common factors are: tobacco use by parents or peers; exposure to tobacco advertising; acceptability of tobacco use among peers or in social norms advertised in movies or tobacco commercials; having depression, anxiety, or stress; and higher accessibility and lower prices of tobacco products.

Tobacco is also easy to get worldwide. Many urban convenience stores, especially in lower-income communities, sell what are sometimes called “loosies,” even though in the US it is illegal to sell single cigarettes. For adolescents, store signage that says personnel will check the identification of people buying tobacco often functions as a kind of challenge, daring teenagers to try to buy tobacco products.

into nicotine addiction?

A: There are basically three categories of

people: those who have never smoked, those who try it and don’t like it, and those who try it and keep going. There are genetic factors that have been shown to influence the uptake, continuing, or quitting of smoking. People with certain genotypes can metabolize nicotine faster, and they get more emotional and physiological pleasure from smoking, making it more likely that they will become addicted.

“gateway drug” that can lead to teen smoking?

A: Teenagers have a lot of alterna-

tives to choose from, including smokeless tobacco, little flavored cigars, and e-cigarettes. These are products that have become more popular as the taboo against combustion-type cigarettes has become stronger. Teens tend to think e-cigarettes are safe; I do not think they realize that a lot of the substances that are used in these devices have nicotine and can prove addictive.

One alternative I learned about while teaching 12th graders several years ago is the hookah pen. Hookah pens are a form of e-cigarettes that look like pens, and they come in different flavors and colors. Teenagers can have a backpack full of them and their parents would never know. Kids use hookah pens to inhale nicotine; it is a very common thing that is well known among adolescents. Many teens also smoke the little cigars that are flavored, which is attractive to kids; these cigars are also inexpensive and not regulated in the same way that cigarettes are.

Hookah smoking is huge among college students and on the rise. The last estimate I have seen indicates that 40%–50% of college students have engaged in hookah smoking in the last year, and my experience with students in the classroom has borne this out.

A number of manufacturers offer hookah pens for sale, but there does not seem to be any connection as yet to Big Tobacco. As of August 8, in the US Hookah pens are regulated by the US FDA, which has regulatory authority under a rule that is referred to as Electronic Nicotine Delivery Systems (ENDS).3 In a typical hookah session, the smoker takes 200 puffs of tobacco smoke and inhales about 150 times as much tobacco smoke as when smoking a cigarette. However, many young adults do not even realize that there is nicotine involved; plus, it is considered to be a fun social experience. There are hookah bars all around US college campuses, but they are fairly invisible to people who are not looking for them. The invisibility of some of these things is the most troubling aspect of these phenomena. They are out there, but most of us are unaware unless looking for them.

Q: Smoking rates among teens in the US have declined over the past 50 to 60 years. Why is that?

A: The primary reason is because the

norms have changed, and, for the most part, kids no longer grow up in households with smokers. But when they do, they perceive smoking as a normal adult behavior, and those kids are more likely to smoke. In addition, smoking bans are more prevalent, and cigarette prices have gotten much higher. Teens are also

Michael Kulik

switching to other alternatives, as we discussed earlier. Another reason cigarette smoking is becoming less popular is that the tobacco industry in the US has pretty much given up on trying to replace as many smokers as they did previously; it is now concentrating on other countries instead.

Q: What interventions work in preventing smoking in preadolescents and adolescents?

A: The most successful interventions,

which require a holistic approach, stem from an overall goal of having a healthy lifestyle involving a lot of physical activity.

It is pretty true of all negative behaviors that if you want teens to avoid them, you have to keep teens busy. Team sports are very good at keeping kids from smoking, in part because nicotine releases dopamine in the brain as does physical activity. So, in many cases, kids get the same kind of rush from playing sports. Now, on the other end of that, smokeless tobacco is kind of a rite of passage for some kids involved in sports.

The education we provide to teenagers seems to be most successful by showing kids that the tobacco industry is manipulating them. Teens are not persuaded by the fact that they might get cancer in 30 or 40 years. A lot of the teenagers we work with in disadvantaged neighborhoods have experienced death up close, so they are not worried about getting cancer. However, they do resent the tobacco industry trying to manipulate them, take advantage of them, and fool them. So, the most effective way we have found to keep kids from taking up smoking is to persuade them that the industry is only there to take their money. ✦

References

Flavored hookah pens available on eBay.

1. Centers for Disease Control and Prevention.

Youth and Tobacco Use. Fact Sheets 2016; http:// www.cdc.gov/tobacco/data_statistics/fact_sheets/ youth_data/tobacco_use/. Accessed July 2, 2016.

2. The Tobacco Atlas. World Lung Foundation. http:// www.tobaccoatlas.org/topic/smoking-amongyouth/ . Accessed July 13, 2016.

3. Extending Authorities to All Tobacco Products, Including E-Cigarettes, Cigars, and Hookah. US FDA website. http://www.fda.gov/TobaccoProducts/ Labeling/RulesRegulationsGuidance/ucm388395. htm. Accessed July 13, 2016.

IASLC LUNG CANCER NEWS / NOVEMBER 2016

Names and News David Ball, MD, FRANZCR, was appointed Director of the Lung Tumour Stream for The Royal Melbourne Hospital, The Royal Women's Hospital and the Peter MacCallum Cancer Centre, which are now part of the Victorian Comprehensive Cancer Centre Alliance. As reported in issue #3 of IASLC Lung Cancer News, the Peter MacCallum Cancer Centre recently moved into new facilities within the Victorian Comprehensive Cancer Centre building in Parkville, Victoria, Australia. Professor Ball is Chair of the multidisciplinary Lung Service at the Peter MacCallum Cancer Centre and a Professorial Fellow of the University of Melbourne.

Dr. Philip Bonomi completed his service as Director of the Division of Hematology, Oncology and Cell Therapy at Rush University Medical Center, Chicago, US, a position he has held since 2002.

Professor Bonomi is the Alice Pirie Wirtz Professor of Medical Oncology at Rush, where he continues his work as a lung cancer researcher and clinician.

Martin J. Edelman, MD, has been appointed Chairman of the Department of Hematology/Oncology and Deputy Director for Clinical Research at the Fox Chase Cancer Center in Philadelphia.

He will also be the G. Morris Dorrance Professor of Hematology/Oncology.

Prior to joining Fox Chase, Dr. Edelman was Head of the Section of Solid Tumor Oncology and Associate Director of the Division of Hematology/Oncology for the University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, US.

Richard B. Gaynor, MD, will retire as Senior Vice President, Global Development and Medical Affairs, Lilly Oncology as of January 2017. Prior to joining Lilly, Dr. Gaynor was a professor of medicine and microbiology at the University of Texas Southwestern Medical Center in Dallas, US. Editor note: See the interview with Dr. Gaynor on page 8.

Tony Mok, MD, has been selected by the American Society of Clinical Oncology (ASCO) as a candidate for the 2017 ASCO Board of Directors. Professor Mok is a professor in the Department of Clinical Oncology at the Chinese University of Hong Kong in Prince of Wales Hospital in Hong Kong. Professor Mok is also the Immediate-Past President of the IASLC.

Charles B. Simone II, MD, has been appointed the Medical Director of the Maryland Proton Treatment Center (MPTC).

Previous to this appointment, Dr. Simone was Associate Professor of Radiation Oncology at the Hospital of the University of Pennsylvania, Chief of the Thoracic Oncology Service, and Co-Director of the Penn Mesothelioma and Pleural Program at the University of Pennsylvania Health System, Pennsylvania, US.

Thomas Stinchcombe, MD, has been recruited to the Duke Cancer Institute (DCI) where he will be promoted to Professor of Medicine in Medical Oncology. Tom will help lead the thoracic oncology group in the Solid Tumor Therapeutics Program and serve as co PI for the Alliance in the DCI. Prior to this, Dr. Stinchcombe was director of the thoracic medical oncology program and Co-Director of the Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, Chapel Hill, NC.

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