Abstract
Purpose
Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non–small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized.
Methods
We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed.
Results
We included 67 patients—38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation.
Conclusion
There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.
INTRODUCTION
Performing repeat biopsies to study molecular mechanisms of acquired resistance to tyrosine kinase inhibitors (TKIs) in EGFR (epidermal growth factor receptor) -mutant non–small cell lung cancer (NSCLC) has been one of the cornerstones of developing next-generation treatment strategies, including the T790M-inhibitor osimertinib and combinations of EGFR and MET inhibitors.1,2 Repeat biopsy cohorts have also elucidated that approximately 3% to 10% of acquired resistance to EGFR TKIs is associated with histologic transformation to small-cell lung cancer (SCLC).3,4 Even more rarely, activating EGFR mutation can be identified among de novo SCLCs.5
Significant progress has been made in the past few years toward understanding the genetic mechanisms associated with such histologic transformation. For example, Niederst et al6 demonstrated that whereas the founder EGFR mutation is still uniformly found at the DNA level in transformed cancers, expression of the EGFR protein is significantly diminished, thus rendering the transformed tumors unresponsive to EGFR TKIs. Work by Lee et al7 suggests that the SCLC clone branches off from the founder clone early—in some cases even before initial clinical cancer diagnosis—and that cancers prone to transformation may show inactivation of both TP53 and Rb1 at initial NSCLC diagnosis.
Despite these advances, little is known about the clinical course of patients with EGFR-mutant cancer after SCLC transformation, which leads to uncertainty about appropriate treatments and prognostic implications for clinicians. Here, we describe clinical outcomes from a large retrospective cohort of patients with EGFR-mutant SCLC transformed cancers.
METHODS
We performed a retrospective chart review of patients with a history of EGFR-mutant SCLC or high-grade neuroendocrine carcinoma—henceforth collectively termed SCLC—who were seen at eight North American cancer centers. Institutional review board approval was obtained independently at each center.
Data that were collected included demographic information, tumor histology and molecular pathology, and clinical treatments and outcomes. Genotyping was performed with a variety of assays, including allele-specific polymerase chain reactions, next-generation sequencing (NGS), and whole-exome sequencing. For some cases with tissue available, older (narrower) genotyping results were expanded and updated using more modern assays for this project. Response and progression assessments were estimated to the best of the investigator’s judgment using radiology reports and, when unavailable, physician's notes; formal Response Evaluation Criteria in Solid Tumors (RECIST) measurements or confirmation of response were not obtained. Nevertheless, the general principles that support the RECIST classification, including the magnitude of lesion size variation that defines response and progression, were used to guide the investigators.8 In addition, as this cohort was analyzed retrospectively, there was no defined or standard time interval for obtaining response assessments.
Descriptive statistics were developed and time-to-event outcomes were analyzed using the Kaplan-Meier method.
RESULTS
Baseline Characteristics
A total of 67 patients with a history of EGFR-mutant SCLC who were treated between 2006 and 2018 were identified at eight cancer centers. The cohort included 38 women and 29 men with a median age at diagnosis of 56 years, a racial makeup of 49% white and 42% Asian, with 73% never smokers (Table 1). Fifty-eight patients (87%) had NSCLC histology at the time of the initial lung cancer diagnosis, predominantly adenocarcinoma, whereas nine patients (13%) had de novo SCLC or a mixed histology, including SCLC at diagnosis. All patients had EGFR mutations, including 46 (69%) with exon 19 deletion mutations and 17 (25%) with L858R. Genotyping platforms used historically at the time of diagnosis for this cohort rarely included the assessment of tumor suppressor genes associated with high-grade neuroendocrine cancers, such as TP53 and Rb1, but the prevalence of mutations in these genes was high among the small subset of patients who were tested using NGS (TP53, 100% [n = 7]; Rb1, 50% [n = 4]; Appendix Table A1, online only).
TABLE 1.
Demographics of the Study Population
Pretransformation Course
The 58 patients with NSCLC at diagnosis received a median of two lines of systemic therapy before SCLC transformation (range, one to six lines), including at least one EGFR TKI in all cases (Table 2). Of note, osimertinib was used as first-line therapy in only one patient. Seventeen patients (29%) acquired an EGFR T790M mutation and 23 (40%) received more than one EGFR TKI before transformation. Median total time on EGFR TKIs before transformation was 15.8 months (range, 1.3 to 53.4 months), and median time since diagnosis of advanced NSCLC to SCLC transformation was 17.8 months (95% CI, 14.3 to 26.2 months; Fig 1A). Nearly all patients (n = 53 [93%]) were receiving an EGFR TKI at the time of transformation.
TABLE 2.
Treatments Received
FIG 1.
Time to event analyses. (A) Time since diagnosis to transformation to small-cell lung cancer (SCLC) and overall survival (OS) since the time of diagnosis. (B) Progression-free survival (PFS) of SCLC-transformed patients treated with platinum-etoposide. (C) PFS of SCLC-transformed patients treated with taxanes. (D) OS since the time of SCLC transformation.
SCLC Characteristics
At the time of transformation—for the 58 patients who started with NSCLC—or diagnosis—for the nine de novo SCLC cases—histology was reported as classic SCLC in 97% of cases and as large-cell neuroendocrine carcinoma in the remaining two cases. Additional pathology findings at the time of transformation are summarized in Appendix Table A2 (online only). The founder EGFR mutation was confirmed in all transformed cases that underwent genotyping (Appendix Table A3, online only). Only five SCLC transformed samples harbored an EGFR T790M mutation, including one patient who was known to have had de novo T790M since initial diagnosis, three with prior acquisition of T790M after TKI therapy, and one without any prior documentation of T790M. Mixed NSCLC-SCLC histology was noted in two SCLC cases with T790M. Conversely, at the time of transformation, T790M was not found in 15 (79%) of 19 patients with prior evidence of the mutation, including in one patient with de novo T790M at initial diagnosis.
The most common mutations identified in SCLC samples were TP53 (38 [79%] of 48 patients), Rb1 (18 [58%] of 31 patients), and PIK3CA (14 [27%] of 52 patients). Frequency of TP53 mutations increased dramatically when considering only samples genotyped by NGS (32 [91%] of 35 patients), which highlights the low sensitivity of allele-specific polymerase chain reaction assays in detecting non–hot spot mutations in this tumor suppressor (Table 3). No other genes were mutated in a significant portion of cases, with BRCA1 (n = 3) being the next most frequently mutated gene in the cohort (Appendix Table A3). Of note, none of the three observed BRCA1 point mutations—Ile1568Met, Ser1294Gly, and Glu686Lys—are thought to be associated with a cancer predisposition syndrome.
TABLE 3.
Frequency of Common Mutations Within Small-Cell Lung Cancer Cases, by Testing Method
Post-Transformation Course
After SCLC transformation—or after diagnosis for patients with de novo SCLC—patients received a median of two lines of systemic treatment (range, zero to six lines; Table 2). As expected, platinum-etoposide was the most commonly used regimen (n = 53, including 10 patients who previously received a platinum doublet regimen). Among patients with enough retrospective data for investigators to estimate a response to treatment (n = 46), the clinical response rate to platinum-etoposide was 54%. A high clinical response rate to the combination (eight [80%] of 10 patients) was achieved even in the subset of patients who had previously received platinum chemotherapy for adenocarcinoma. Median estimated progression-free survival on platinum-etoposide was 3.4 months (95% CI, 2.4 to 5.4 months; Fig 1B).
No responses were observed among 17 patients who received a checkpoint inhibitor, either a single-agent programmed death-1 or programmed death-ligand 1 inhibitor (n = 9) or as part of the combination ipilimumab-nivolumab regimen (n = 8). Indeed, none of the 17 patients even seemed to derive clinical benefit from these therapies, as the longest time to progression was only 9 weeks.
Taxanes were administered to 21 patients, generally late in the course—median of two prior lines of therapy after SCLC transformation—and as single-agent therapy (14 of 21 patients received taxane monotherapy). Among 20 patients with sufficient data to estimate response, clinical response rate to taxane-containing regimens was 50%, including some marked responses (Fig 2). Median estimated progression-free survival on taxanes was 2.7 months (95% CI, 1.3 to 3.4 months; Fig 1C). Additional analysis by type of taxane revealed that both paclitaxel and nab-paclitaxel each elicited five responses among seven treated patients (clinical response rate, 71%), whereas no responses were observed among six patients who were treated with docetaxel.
FIG 2.
Example of a response to nab-paclitaxel in a SCLC-transformed cancer. (A and B) Significant response of an (A) adrenal metastastasis (red circle) and of (B) extensive thoracic involvement in a patient who had received eight prior lines of therapy for metastatic EGFR (epidermal growth factor receptor) -mutant lung cancer, including single-agent etoposide and a clinical trial of a BCL-2/BCL-XL inhibitor since SCLC transformation.
Although EGFR TKIs were administered in 52% of patients after SCLC transformation, they were frequently used in combination with cytotoxic chemotherapy per the treatment-beyond-progression strategy or as maintenance therapy after the conclusion of cytotoxic chemotherapy.9,10 Their varied pattern of use limits interpretation of clinical benefit, but a few responses were noted in cases in which concurrently active NSCLC clones were proven or highly suspected. Specifically, although serial biopsies after SCLC diagnosis were not performed in most cases, adenocarcinoma was identified in progressing lesions of at least four patients after SCLC transformation, which suggests more than one active clone concurrently in the same patient. In three of these patients, there seemed to be some degree of clinical benefit gained from EGFR TKI therapy.
As characteristically observed in de novo SCLC, there was a high rate of CNS involvement after SCLC transformation in our cohort. Thirty-eight (64%) of 59 patients with follow-up radiographic information after SCLC diagnosis experienced progression in the CNS at some point after SCLC diagnosis.
Median follow-up after transformation to SCLC was 8.1 months (range, 0 to 26.9 months) and 45 deaths (67%) have occurred. Median overall survival since the initial diagnosis of metastatic lung cancer was 31.5 months (95% CI, 24.8 to 41.3 months; Fig 1A), and median overall survival since the time of SCLC was 10.9 months (95% CI, 8.0 to 13.7 months; Fig 1D).
DISCUSSION
To our knowledge, this cohort represents the largest report to date of clinical outcomes for patients with EGFR-mutant lung cancers that either transform to or present initially as SCLC or large-cell neuroendocrine carcinoma. Whereas EGFR-mutated de novo SCLC cases are rare, they are likely part of the same biologic continuum as bona fide transformed tumors. Baseline demographic characteristics seem to be relatively similar among our cohort compared with the general population of patients with EGFR-mutant adenocarcinoma whose disease never undergoes such transformation. One characteristic that may distinguish patients with a higher chance of future transformation is the presence of baseline TP53 and/or RB1 mutations, as previously reported by Lee et al.7 We observed that SCLC transformation can manifest at any time during the disease course, seen as early as 2 months and as late as 5 years after the diagnosis of metastatic lung cancer, but that the median time to transformation was 17.8 months. After transformation, clinical behavior mimics classic (EGFR wild-type) SCLC on many levels, with frequent but transient responses to platinum-etoposide, frequent CNS metastases, and median overall survival of 10.9 months.
Although the response rate to immune checkpoint inhibitors in pretreated SCLC is relatively modest, complete absence of clinical response in our EGFR cohort, including to anti–programmed death-1/anti–cytotoxic T-cell lymphocyte-4 combinations, is noteworthy and reminiscent of the poor activity of immunotherapy in more classic EGFR-mutant adenocarcinoma.11-13 This suggests that these tumors are biologically more akin to the parental EGFR-mutant adenocarcinoma than to smoking-associated classic SCLC cases. As combination regimens with chemotherapy and immune checkpoint inhibitors have recently demonstrated more promise than single-agent checkpoint inhibitors in both EGFR-mutant adenocarcinoma and de novo SCLC, studying immunotherapy together with chemotherapy could be fruitful in EGFR-mutant transformed SCLC.14,15
Of equal interest was the relatively high clinical response rate to taxanes observed in EGFR-mutant transformed SCLC, notably to both paclitaxel and nab-paclitaxel (70% each), even among heavily pretreated patients. In classic SCLC, response rate to single-agent taxanes in pretreated patients is only 20% to 30%, albeit in small studies.16-18 It is possible that taxanes are more active in EGFR-mutant transformed SCLC because of residual NSCLC clones that also are responding well to a taxane. Alternatively, EGFR-mutant transformed SCLC cells could have a biologic basis for increased sensitivity to taxanes compared with de novo SCLC cases. Nevertheless, despite the small sample size, frequent responses to taxanes were noteworthy and future prospective studies should be considered for this population.
Genotyping was restricted by the historical assays performed and the limited access to additional tissue, although some interesting observations were still possible. Despite few patients tested initially with platforms broad enough to assess TP53 and RB1, high frequency of mutations in these tumor suppressors at diagnosis supports previously reported findings that alterations that affect both genes may strongly predispose to SCLC transformation.7 It was rare for SCLC-transformed samples to harbor EGFR T790M, even if it had been previously detected in the patient’s prior course, which suggests that the T790M gatekeeper mutation—the most common acquired resistance mutation to emerge after first and second-generation EGFR TKIs—tends to reside in a clone that is distinct from the SCLC transformed clone. In other words, the hypothesis of an early branching event between the SCLC clone and the initially predominant NSCLC clonal population,7 from which EGFR T790M-positive clones emerge, is consistent with these clinical observations. Mutations that affect TP53, Rb1, and PIK3CA were frequent in the SCLC samples in our cohort, as in other reports.3,4,7 Of importance, as a result of the high variability of assays and techniques used in this multicenter cohort, caution should be used when comparing the frequency of mutations with published studies.
Ferrer and colleagues19 recently reported on a cohort of 48 EGFR-mutant SCLC transformed cases collected from centers in Europe. Although the cohort had fewer genotyping data available compared with our North American cohort, many similar clinical themes were observed, including a median time since diagnosis to SCLC transformation of 16 months and a median survival after transformation of 9 months.
Our study is limited by its retrospective nature and the fact that treatments and response assessments were not standardized across the cohort. Central review was not performed for pathology slides, nor for radiology scans; however, given the rarity of EGFR-mutant SCLC transformations, the size of the cohort we have collated is significant enough to draw conclusions and inform the treatment of patients in the absence of prospective data. Unfortunately, the current study cannot provide answers to some other relevant questions related to SCLC transformation, such as the impact of first-line use of osimertinib on its frequency or the absolute risk of transformation associated with TP53 and Rb1 mutations at the initial diagnosis of adenocarcinoma. Examining the closely related question of whether there is a signature mutational spectrum of adenocarcinomas that go on to transform to SCLC was limited by access to archival tissue, as many patients from this cohort were initially treated in a community setting and were referred to participating centers later in the course of their disease.
In summary, EGFR-mutant lung cancers that transform to SCLC or that have high-grade neuroendocrine histology at the time of diagnosis exhibit high response rates to platinum-etoposide, which should be considered the first-line therapy of choice, and also exhibit high response rates to taxanes. Conversely, these tumors do not respond well to checkpoint inhibitors and the use of these therapies outside of a clinical trial should currently be discouraged. In cases that transformed from initial NSCLC, the founder EGFR mutation was universally maintained and the SCLC and EGFR T790M-positive clonal subpopulations seemed to be distinct from each other. TP53, Rb1, and PIK3CA mutations are common in SCLC transformations, with the former two also frequent at initial diagnosis among patients whose disease eventually undergoes transformation. Of importance, given the increasing use of cell-free DNA analysis at the time of acquired TKI resistance, our data emphasize the continued role of tissue biopsy at progression for histologic examination, especially in cases in which no genetic resistance mechanism is identified by noninvasive means. Additional investigation and ongoing multicenter collaborations are needed to better elucidate optimal strategies for this group.
Appendix
TABLE A1.
Frequency of TP53 and Rb1 Mutations in Baseline Tissue, by Testing Method
TABLE A2.
Summary of Available Pathology Findings of All SCLC Cases
TABLE A3.
Genetic Findings of All SCLC Cases
Footnotes
Presented at the 2018 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 1-5, 2018, and at the International Association for the Study of Lung Cancer 19th World Conference on Lung Cancer, Toronto, ON, Canada, September 23-26, 2018.
Funded by National Institutes of Health Grant No. 2R01CA137008, LungStrong, Targeting a Cure for Lung Cancer, Be A Piece of the Solution, and the Susanne E. Coyne Memorial Fund (L.V.S.), as well as by STOP Cancer Carrie Scott Grant (K.L.R.).
Processed as a Rapid Communication manuscript.
The current manuscript was offered priority review by Thomas Stinchcombe, MD.
AUTHOR CONTRIBUTIONS
Conception and design: Nicolas Marcoux, Scott N. Gettinger, Salvatore del Prete, Frances A. Shepherd, Zofia Piotrowska, Lecia V. Sequist
Administrative support: Karen L. Reckamp
Provision of study materials or patients: Kathryn C. Arbour, Tracey L. Evans, Julie R. Brahmer, Philip D. Bonomi, Salvatore del Prete, Anna Wurtz, Anna F. Farago, Dora Dias-Santagata, Karen L. Reckamp, Helena A. Yu, Heather A. Wakelee, Frances A. Shepherd, Lecia V. Sequist
Collection and assembly of data: Nicolas Marcoux, Scott N. Gettinger, Grainne O’Kane, Kathryn C. Arbour, Joel W. Neal, Hatim Husain, Tracey L. Evans, Julie R. Brahmer, Philip D. Bonomi, Anna Wurtz, Anna F. Farago, Dora Dias-Santagata, Mari Mino-Kenudson, Karen L. Reckamp, Helena A. Yu, Heather A. Wakelee, Frances A. Shepherd, Zofia Piotrowska, Lecia V. Sequist
Data analysis and interpretation: Nicolas Marcoux, Scott N. Gettinger, Grainne O’Kane, Joel W. Neal, Hatim Husain, Tracey L. Evans, Julie R. Brahmer, Alona Muzikansky, Philip D. Bonomi, Dora Dias-Santagata, Mari Mino-Kenudson, Karen L. Reckamp, Helena A. Yu, Heather A. Wakelee, Frances A. Shepherd, Zofia Piotrowska, Lecia V. Sequist
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Nicolas Marcoux
Honoraria: Bristol-Myers Squibb
Scott N. Gettinger
Consulting or Advisory Role: Bristol-Myers Squibb, Alexion Pharmaceuticals, Pfizer
Research Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), Ariad Pharmaceuticals (Inst), Incyte (Inst), Pfizer (Inst)
Travel, Accommodations, Expenses: Merck
Joel W. Neal
Consulting or Advisory Role: Ariad Pharmaceuticals, Takeda, AstraZeneca, Genentech, Eli Lilly, Exelixis, Loxo, Jounce Therapeutics
Research Funding: Genentech (Inst), Merck (Inst), Novartis (Inst), Boehringer Ingelheim (Inst), Exelixis (Inst), Ariad Pharmaceuticals (Inst), Takeda (Inst), Nektar (Inst)
Hatim Husain
Consulting or Advisory Role: AstraZeneca, AbbVie, Foundation Medicine
Speakers' Bureau: AstraZeneca, Merck, Bristol-Myers Squibb
Research Funding: Pfizer (Inst)
Travel, Accommodations, Expenses: AstraZeneca, Merck, Bristol-Myers Squibb, Foundation Medicine, AbbVie
Tracey L. Evans
Honoraria: Genentech, Genentech (I), Merck, AstraZeneca
Consulting or Advisory Role: Genentech, Genentech (I), AstraZeneca
Speakers' Bureau: Genentech (I), Genentech, Merck, AstraZeneca
Travel, Accommodations, Expenses: Genentech, Genentech (I)
Julie R. Brahmer
Consulting or Advisory Role: Bristol-Myers Squibb, Eli Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech
Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Incyte (Inst), Janssen Oncology (Inst)
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Merck
Other Relationship: Bristol-Myers Squibb, Merck
Alona Muzikansky
Consulting or Advisory Role: Sofregen Medical
Philip D. Bonomi
Honoraria: AstraZeneca, Bristol-Myers Squibb, Biodesix, Merck, Pfizer, Genentech, Trovagene, Eli Lilly
Consulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, Biodesix, Merck, Pfizer, Genentech, Eli Lilly
Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Corvus Pharmaceuticals (Inst), Five Prime Therapeutics (Inst), Biodesix (Inst), Genentech (Inst), Eli Lilly (Inst), Merck (Inst), Pfizer (Inst)
Anna F. Farago
Honoraria: Foundation Medicine, DAVAOncology, Clinical Care Options, Medical Learning Institute
Consulting or Advisory Role: PharmaMar, Takeda, AbbVie, Loxo, Stemcentrx, Genentech, Bayer
Research Funding: PharmaMar (Inst), AbbVie (Inst), AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Merck (Inst), Loxo (Inst), Ignyta (Inst), Amgen (Inst), Genentech (Inst), Novartis (Inst), Bayer (Inst)
Travel, Accommodations, Expenses: PharmaMar, Stemcentrx, AbbVie, Bayer, Loxo, DAVAOncology, Genentech
Mari Mino-Kenudson
Consulting or Advisory Role: Merrimack Pharmaceuticals, H3 Biomedicine
Karen L. Reckamp
Consulting or Advisory Role: Amgen, Ariad Pharmaceuticals, Astellas Pharma, Euclises, Tesaro, Boehringer Ingelheim, Takeda
Research Funding: Bristol-Myers Squibb (Inst), Pfizer (Inst), Ariad Pharmaceuticals (Inst), Xcovery (Inst), Adaptimmune (Inst), Genentech (Inst), Boehringer Ingelheim (Inst), AbbVie (Inst), ACEA Biosciences (Inst), Loxo (Inst)
Helena A. Yu
Consulting or Advisory Role: AstraZeneca, Eli Lilly
Research Funding: Clovis Oncology (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Eli Lilly (Inst), Novartis (Inst), Pfizer (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Eli Lilly
Heather A. Wakelee
Honoraria: Novartis, AstraZeneca
Research Funding: Genentech (Inst), Pfizer (Inst), Eli Lilly (Inst), Celgene (Inst), AstraZeneca (Inst), MedImmune (Inst), Exelixis (Inst), Novartis (Inst), Clovis Oncology (Inst), Xcovery (Inst), Bristol-Myers Squibb (Inst), Gilead Sciences (Inst), Pharmacyclics (Inst), ACEA Biosciences (Inst)
Travel, Accommodations, Expenses: AstraZeneca
Frances A. Shepherd
Stock and Other Ownership Interests: Eli Lilly, AstraZeneca
Honoraria: Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck Sharp & Dohme, Merck Serono, Boehringer Ingelheim
Consulting or Advisory Role: Eli Lilly, AstraZeneca, Boehringer Ingelheim, Merck Serono
Research Funding: Eli Lilly (Inst), Pfizer (Inst), Bristol-Myers Squibb (Inst), AstraZeneca (Inst), MedImmune (Inst), Roche Canada (Inst), Merrimack Pharmaceuticals (Inst)
Zofia Piotrowska
Consulting or Advisory Role: Boehringer Ingelheim, AstraZeneca, Ariad Pharmaceuticals, Takeda, Superdimension, Guardant Health, Novartis, AbbVie
Research Funding: Novartis (Inst), Ariad Pharmaceuticals (Inst), Takeda (Inst), Guardant Health (Inst)
Lecia V. Sequist
Honoraria: AstraZeneca
Consulting or Advisory Role: AstraZeneca, Genentech, Bristol-Myers Squibb, Pfizer, Merrimack Pharmaceuticals
Research Funding: Boehringer Ingelheim (Inst), Clovis Oncology (Inst), Genentech (Inst), Merrimack Pharmaceuticals (Inst), Novartis (Inst), AstraZeneca (Inst), Johnson & Johnson (Inst), Merck (Inst), Pfizer (Inst), Guardant Health (Inst), Incyte (Inst)
No other potential conflicts of interest were reported.
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