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Abstract
Background Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest.
Methods Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell–inflamed gene expression profile (TcellinfGEP) and 11 other gene signatures were evaluated by RNA sequencing. TMB, hotspot mutations in PIK3CA (oncogene), and deleterious mutations in PTEN and TP53 (tumor suppressor genes) were evaluated by whole-exome sequencing (WES).
Results 93 and 79 patients were included in the RNA-sequencing-evaluable and WES-evaluable populations, respectively. No statistically significant associations were observed between any of the RNA-sequencing signature scores and objective response rate or progression-free survival. Area under the receiver operating characteristic curve values for response ranged from 0.39 to 0.54; all 95% CIs included 0.50. Responses were seen regardless of TMB (≥175 or <175 mutations/exome) and mutation status. There were no correlations between TcellinfGEP and TMB, TcellinfGEP and microvessel density (MVD), or MVD and TMB.
Conclusions This analysis demonstrated efficacy for lenvatinib plus pembrolizumab regardless of biomarker status. Results from this study do not support clinical utility of the evaluated biomarkers. Further investigation of biomarkers for this regimen is warranted.
Trial registration number NCT02501096.
- Tumor Biomarkers
- Immunotherapy
Data availability statement
Data are available upon reasonable request. Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the USA and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country-specific or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Previous analyses across multiple solid tumor types, including endometrial cancer, have demonstrated associations between biomarkers (eg, T-cell–inflamed gene expression profile (TcellinfGEP), tumor mutational burden (TMB)) and response to pembrolizumab monotherapy.
WHAT THIS STUDY ADDS
We evaluated potential associations between clinical outcomes and gene expression signature scores in patients with advanced endometrial carcinoma enrolled in Study 111/KEYNOTE-146.
Additionally, we descriptively summarized response in biomarker subpopulations defined by TMB and by DNA variants for individual genes of interest (including PIK3CA, PTEN, and TP53) in these patients.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY
The biomarkers evaluated in this study should not be used to predict response to the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma.
Introduction
Endometrial cancer is one of the most common gynecologic cancers among women worldwide,1 and its incidence and prevalence has increased globally over the past three decades.2 A 5-year survival rate of only 17% was estimated among women with distant metastases,3 and patients with microsatellite stable (MSS) tumor status have a particularly poor prognosis.4 Although first-line treatment with carboplatin plus paclitaxel may provide some benefit in patients with recurrent or advanced endometrial cancer (eg, median progression-free survival (PFS) of 13 months and median overall survival (OS) of 37 months in the phase 3 GOG0209 study),5 many patients develop resistance to chemotherapy6 and have limited treatment options in the second-line and later settings. In the phase 1b/2 Study 111/KEYNOTE-146, combination therapy with the multi-kinase inhibitor lenvatinib7 plus the anti-programmed cell death protein 1 (PD-1) monoclonal antibody pembrolizumab resulted in an objective response rate (ORR) at week 24 (primary endpoint) of 38.0% (95% CI 28.8% to 47.8%) among the 108 patients (MSS/mismatch repair-proficient, n=94; microsatellite instability-high/mismatch repair-deficient, n=11; unknown status, n=3) with previously treated advanced endometrial cancer.8 Similar response rates were reported in patients with programmed cell death ligand 1 (PD-L1)–positive (combined positive score ≥1, 35.8%) and PD-L1–negative (combined positive score <1, 39.5%) tumors, and antitumor activity was seen across the histologic subtypes including clear cell and serous adenocarcinoma.8 More recently, in the phase 3 Study 309/KEYNOTE-775, lenvatinib plus pembrolizumab demonstrated significant improvements in PFS and OS compared with physician’s choice of chemotherapy in patients with advanced endometrial cancer whose disease had progressed or recurred after receipt of at least one previous platinum-based chemotherapy regimen.9 Clinically meaningful benefits were observed in both the mismatch repair-proficient (n=697) and mismatch repair-deficient (n=130) populations.9 In both Study 111/KEYNOTE-1468 and Study 309/KEYNOTE-775,9 the toxicity profile of lenvatinib plus pembrolizumab was generally consistent with the known profiles of the individual agents.10 The combination is approved in the USA for the treatment of patients with advanced endometrial cancer that is not microsatellite instability-high or mismatch repair-deficient and who have disease progression following prior systemic therapy.11 In Europe, the combination is approved for the treatment of all comers with advanced or recurrent endometrial cancer who have disease progression following prior platinum-containing therapy.12
Given the clinical benefit associated with lenvatinib plus pembrolizumab among patients with previously treated endometrial cancer, there is considerable interest in biomarkers that can identify patients with a greater likelihood of response to treatment. Several analyses have evaluated the association between biomarkers and the response to pembrolizumab monotherapy. The T-cell–inflamed gene expression profile (TcellinfGEP) is comprised of 18 genes that are indicative of a T-cell−activated tumor microenvironment (TME).13 Higher TcellinfGEP scores have demonstrated positive associations with response to pembrolizumab monotherapy across a wide variety of solid tumor types13–16; in some instances, these analyses have included patients with endometrial cancer.14 15 Additionally, other gene expression signatures reflective of the TME and tumor biology, including key cell types (eg, granulocytic myeloid-derived suppressor cells (gMDSC), monocytic myeloid-derived suppressor cells (mMDSC), and stromal cells),17 18 oncogenic pathways (eg, MYC and RAS),19 and biological processes (eg, angiogenesis, glycolysis, hypoxia, proliferation, and WNT),19–23 may play a role in cancer progression and response to immunotherapy. Cristescu et al recently reported negative associations between several of these signature scores (angiogenesis, mMDSC, and stroma/epithelial-mesenchymal transition (EMT)/transforming growth factor β (TGFβ)) and the response to pembrolizumab monotherapy across multiple solid tumor types.16 Another biomarker of interest is tumor mutational burden (TMB), which is a quantifiable measure of multiple types of DNA mutations.24 Higher levels of TMB have been shown to independently predict response to pembrolizumab and other anti−PD-(L)1 monotherapies in patients with advanced solid tumors,14 15 25–28 including in analyses that have included patients with endometrial cancer.14 15 27 The antitumor activity of lenvatinib has been attributed to a reduction in microvessel density (MVD).29 An elevated MVD could therefore potentially serve as a biomarker for predicting response to this agent.
The objective of the current analysis was to evaluate potential associations between clinical outcomes and gene expression signature scores in patients with advanced endometrial carcinoma enrolled in Study 111/KEYNOTE-146. Additionally, we descriptively summarized response in biomarker subpopulations defined by TMB and by DNA variants for individual genes of interest (including PIK3CA, PTEN, and TP53, which are among the most frequently mutated genes in endometrial cancer30) in these patients.
Methods
Methods for this study were previously published8 31 and are briefly summarized below.
Study design, patients, and treatment
Study 111/KEYNOTE-146 (NCT02501096) was a phase 1b/2, multicenter, open-label, single-arm study in patients with select advanced solid tumors. Patients in the endometrial carcinoma cohort were ≥18 years of age with pathologically confirmed metastatic disease that was measurable according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).32 Patients had an Eastern Cooperative Oncology Group performance status score of 0 or 1, adequately controlled blood pressure, and life expectancy of ≥12 weeks. Previous treatment with ≤2 systemic therapies was permitted; however, patients who previously received lenvatinib or any anti−PD-(L)1 drug were excluded. The endometrial carcinoma cohort was expanded from 20 to ~120 patients per protocol amendment 3 based on the efficacy results demonstrated at the first and second interim analyses. All patients provided written informed consent before enrollment. The protocol was approved by the institutional review board/ethics committee at each study center, and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.
All patients received the combination of oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks in 3-week cycles. Treatment continued for up to 35 cycles or until disease progression, unacceptable toxicity, or withdrawal of consent.
Assessments
Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. Fresh biopsies were limited to readily accessible tumor lesions (including liver metastases accessible with CT guidance). RNA-sequencing data for the 18-gene TcellinfGEP and 11 other signatures (angiogenesis, glycolysis, gMDSC, hypoxia, mMDSC, MVD, MYC, proliferation, RAS, stroma/EMT/TGFβ, and WNT) were analyzed. Methodology was previously described in detail.16 Briefly, RNA-sequencing was performed using the HiSeq 4000 platform (Illumina, San Diego, California, USA), and gene signatures associated with TcellinfGEP were identified based on the Merck-Moffitt and The Cancer Genome Atlas databases. The TcellinfGEP score was calculated as the weighted sum of the predictor genes determined during the development of the TcellinfGEP on the NanoString platform (NanoString Technologies, Seattle, Washington, USA). Other signature scores were calculated as the average of the genes (log scale) in each signature gene set.
TMB, hotspot mutations in PIK3CA (oncogene), and deleterious mutations in PTEN and TP53 (tumor suppressor genes) were evaluated by whole-exome sequencing (WES) as previously described in detail.28 Briefly, WES was performed using ImmunoSELECT-RUO (Personal Genome Diagnostics, Baltimore, Maryland, USA) or ACE Cancer Exome (Personalis, Menlo Park, California, USA). DNA was isolated using the QIAamp DNA FFPE Tissue Kit (Qiagen, Valencia, California, USA) and quantitated using the Qubit assay (Invitrogen, Carlsbad, California, USA), with quality assessed using the QuantideX qPCR DNA QC Assay (Asuragen, Austin, Texas, USA). TMB was determined by counting the number of mutations (synonymous and non-synonymous) across an 0.8 Mb region spanning 324 genes with computational germline status and oncogenic driver filtering. The focus of the TMB analysis was on the 175-mut/exome cut-off, which aligns with the 10-mut/megabase FoundationOneCDx cut-off. Microsatellite instability genotype was determined by applying mSINGS on WES data from tumor samples and confirmed by PCR using the MSI Analysis System, V.1.2 (Promega, Madison, Wisconsin, USA).
Statistical analyses
The association between each RNA gene signature score and ORR and PFS per irRECIST was evaluated using logistic regression and Cox proportional hazards, respectively, with and without adjustment for TcellinfGEP. P values were adjusted for multiplicity using the Hochberg step-up procedure. P values were one-sided for TcellinfGEP and two-sided for all other signatures, with significance prespecified at α=0.05. The area under the receiver operating characteristic (AUROC) curve for discriminating response was evaluated for each biomarker. Spearman correlation (ρ) was used to assess the correlation between TcellinfGEP and TMB, TcellinfGEP and MVD, and MVD and TMB. The association between TMB status and DNA variants for individual genes and ORR was evaluated descriptively. Statistical analyses were performed in R.
Results
Patients
A total of 124 patients were enrolled and treated on or before the data cut-off date of August 18, 2020. All patients received the combination of lenvatinib plus pembrolizumab. Ninety-three patients were included in the RNA-sequencing–evaluable population and 79 patients were included in the WES-evaluable population. Failures were primarily driven by sample availability and quality. In the RNA-sequencing‒evaluable population, 40.9% were responders and median PFS was 7.4 months (table 1). Mean age was 65.8 years; most patients had endometrioid adenocarcinoma (50.5%) and had MSS (89.2%) and PD-L1 CPS ≥1 (53.8%) tumors. Results were similar in the WES-evaluable population (table 1).
Baseline characteristics in the overall and biomarker populations
RNA sequencing
There were no statistically significant associations between any of the RNA-sequencing signature scores (ie, TcellinfGEP, angiogenesis, glycolysis, gMDSC, hypoxia, mMDSC, MVD, MYC, proliferation, RAS, stroma/EMT/TGFβ, and WNT) and ORR or PFS. Results were consistent before and after adjusting for TcellinfGEP, with all p values at or above 0.308 (table 2). RNA-sequencing signature scores were similar in responders and non-responders (figure 1). The AUROC curve values for response ranged from 0.39 (95% CI 0.27 to 0.51) for MYC to 0.54 (95% CI 0.42 to 0.67) for hypoxia, with all 95% CIs including 0.50 (figure 2).
P values for association between RNA-sequencing signature scores and clinical outcomes in all patients
RNA-sequencing signature box plots by responder status for all patients. EMT, epithelial-to-mesenchymal transition; gMDSC, granulocytic myeloid-derived suppressor cell; mMDSC, monocytic myeloid-derived suppressor cell; MVD, microvessel density; TcellinfGEP, T-cell−inflamed gene expression profile; TGF, transforming growth factor.
RNA-sequencing signature AUROC curves for response for all patients. For AUROC curves, 1 minus specificity (x axis) is the false-positive rate and sensitivity (y axis) is the true-positive rate. AUROC, area under the receiver operating characteristic; EMT, epithelial-to-mesenchymal transition; gMDSC, granulocytic myeloid-derived suppressor cell; mMDSC, monocytic myeloid-derived suppressor cell; MVD, microvessel density; TcellinfGEP, T-cell−inflamed gene expression profile; TGF, transforming growth factor.
WES: TMB and single gene mutations
In all patients, ORR was 77% (10/13) in patients with TMB ≥175 mutations (mut)/exome and 33% (22/66) in patients with TMB <175 mut/exome. The AUROC for response was 0.66 (95% CI 0.53 to 0.79) (figure 3A). In the MSS group, ORR was 100% (4/4) in patients with TMB ≥175 mut/exome and 34% (22/64) in patients with TMB <175 mut/exome. The AUROC for response was 0.63 (95% CI 0.48 to 0.77) (figure 3B).
TMB box plots by responder status and TMB AUROC curves for response for all patients (A) and the MSS group (B). For AUROC curves, 1 minus specificity (x axis) is the false-positive rate and sensitivity (y axis) is the true-positive rate. AUROC, area under the receiver operating characteristic; MSS, microsatellite stable; TMB, tumor mutational burden.
Responses were observed in patients with and without hotspot mutations in PIK3CA (oncogene) and deleterious mutations in PTEN or TP53 (tumor suppressor genes). Results were consistent in all patients and the MSS group (table 3).
Objective response rates by status of select genes
Correlations
There were no correlations between TcellinfGEP and TMB, TcellinfGEP and MVD, or MVD and TMB. For TcellinfGEP versus TMB, the Spearman correlation coefficient was −0.01 in all patients and −0.03 in the MSS group (figure 4A). Spearman correlation coefficients were 0.34 for TcellinfGEP versus MVD (figure 4B) and −0.03 for MVD versus TMB (figure 4C) in all patients.
Scatterplots of TcellinfGEP versus TMB in all patients (left panel) and the MSS group (right panel) (A), TcellinfGEP versus MVD in all patients (B), and MVD versus TMB in all patients (C). Dotted vertical/horizontal lines represent the biomarker cut-offs. MSS, microsatellite stable; MVD, microvessel density; TcellinfGEP, T-cell−inflamed gene expression profile; TMB, tumor mutational burden.
Discussion
To our knowledge, this is the largest analysis in any cancer type that explored whether an association exists between clinical outcomes and gene expression signature scores in patients treated with the combination of lenvatinib plus pembrolizumab. All patients had advanced endometrial carcinoma and received lenvatinib plus pembrolizumab predominantly in the second-line or third-line setting; nearly 90% of the population had MSS tumors. None of the biomarkers evaluated by RNA sequencing (TcellinfGEP and 11 other signatures) or WES (TMB and variants in PIK3CA, PTEN, and TP53) predicted response to treatment in our patient population.
In contrast with the current findings, previous pan-tumor analyses have shown that TcellinfGEP,13–16 other signatures (ie, angiogenesis, mMDSC, and stroma/EMT/TGFβ),16 and TMB14 15 25–28 can predict response to agents targeting the PD-1 pathway, including pembrolizumab. All patients in our study received the combination of lenvatinib plus pembrolizumab and thus direct comparison of outcomes with the individual monotherapies was not possible. Data examining the relationship between clinical outcomes and gene expression signature scores in patients treated with lenvatinib plus pembrolizumab are limited. Our results are consistent with those for 80 patients with metastatic renal cell carcinoma enrolled in Study 111/KEYNOTE-146.33 The finding that lenvatinib plus pembrolizumab resulted in a clinically meaningful response rate regardless of TMB status (based on WES) is consistent with smaller analyses in patients with other cancer types.34 35 Lee et al found no significant relationship between TMB (stratified by the median) and PFS among 24 patients with advanced renal cell carcinoma treated with this combination (p=0.14).34 A retrospective analysis by Dierks et al assessed somatic mutations and TMB per WES in a small cohort of eight patients with metastatic anaplastic or poorly differentiated thyroid carcinoma who received lenvatinib plus pembrolizumab.35 The four patients who achieved a complete response had 19, 29, 138, and 1447 somatic mutations and a TMB (per next-generation sequencing) of 3, 3.3, 5.6, and 81.9 mut/Mb, respectively. Although the patient with the highest number of somatic mutations and highest TMB had the longest duration of complete response (30 months), responses were noted in patients with a much lower mutation burden, and the sample size was too small to draw any conclusions.35 In a recent study, patients with stage IV non−small-cell lung cancer treated with lenvatinib plus pembrolizumab were categorized based on levels of both TcellinfGEP and TMB.36 In that analysis, ORR was greatest (57.1% (12/21)) when both biomarkers were high (≥−0.16 and ≥5 mut/Mb, respectively) and least (12.0% (3/25)) when both biomarkers were low (<−0.16 and <5 mut/Mb, respectively),36 although further study is needed to assess whether this combination of biomarkers might predict response in this or other patient populations.
A limitation of our analysis was that, depending on accessibility, tumor tissue samples could have been obtained from metastatic or recurrent sites, which may have a different TME than the primary tumor. Results from the previously mentioned phase 3 Study 309/KEYNOTE-775, which evaluated treatment with lenvatinib plus pembrolizumab in the second-line or later setting,9 and the ongoing phase 3 ENGOT-en9/LEAP-001 study, which is evaluating the same therapy in the first-line setting,37 may provide additional insights into the utility of biomarkers to predict response to this combination in patients with endometrial cancer. Both studies include prespecified objectives for exploratory analyses of molecular (genomic, metabolic, and/or proteomic) determinants of response or resistance to treatment using blood and tumor tissue samples.
Substantial proportions of patients with and without hotspot mutations in PIK3A (oncogene) and deleterious mutations in PTEN or TP53 (tumor suppressor genes) responded to combination therapy in our study. Comparable findings were observed in the cohort of patients with metastatic renal cell carcinoma from Study 111/KEYNOTE-146.33 Patients with mutations in VHL, PBRM1, BAP1, or SETD2, which are among the most commonly mutated genes in clear cell renal cell carcinomas,38 had ORRs ranging from 60% to 70%, while patients without mutations had similar ORRs ranging from 57% to 68%.33
The lack of a correlation between TcellinfGEP and TMB in the current study is consistent with previous pan-tumor analyses suggesting that these biomarkers capture distinct features of T-cell activation and neoantigenicity.14 15
In conclusion, no statistically significant associations were observed between any of the RNA-sequencing signature scores and ORR or PFS. Responses were seen regardless of TMB status and PIK3CA, PTEN, and TP53 mutation status. There were no correlations between TcellinfGEP and TMB, TcellinfGEP and MVD, or MVD and TMB. Previous results showed clinical benefits in patients regardless of DNA mismatch repair status, PD-L1 status, and histology.9 Taken together, studies have been unable to identify putative biomarkers associated with benefit from lenvatinib plus pembrolizumab in patients with endometrial carcinoma. Results do not support clinical utility of the evaluated biomarkers, although further investigation of biomarkers for this regimen is warranted.
Data availability statement
Data are available upon reasonable request. Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the USA and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country-specific or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Institutional Review Board/Privacy Board (IRB/PB) (Memorial Sloan Kettering Cancer Center, Assurance Number FWA00004998, IRB Registration Number - A (OHRP/FDA) IRB00000273, IRB Registration Number - B (OHRP/FDA) IRB00009377, IRB Registration Number - C (OHRP/FDA) IRB00013747. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
This study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Eisai Inc., Nutley, NJ, USA. We thank the patients and their families and caregivers for participating in this study, along with all investigators and site personnel. We would also like to thank Michael Nebozhyn (Merck & Co., Inc., Rahway, NJ, USA), Yasuhiro Funahashi (Eisai Inc., Nutley, NJ, USA), and Shuyu Li (Eisai Inc., Nutley, NJ, USA) for their contributions to the study. Medical writing assistance was provided by Michael S. McNamara, MS, of ICON plc (Blue Bell, PA, USA), which was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
References
Footnotes
Collaborators Not applicable.
Contributors Conception, design or planning of the study: CA, ALC, ZAC, RC, PJ, LD, JM, CED, and YM. Acquisition of the data: MHT, CA, ALC, MSB, CDS, RC, PJ, LD, CED, YM, and MJM. Analysis of the data: MHT, ZAC, LS, RC, LD, CED, and MJM. Interpretation of the results: VM, MHT, ALC, ZAC, LS, AL, RC, RO, LD, CED, YM, and MJM. Drafting the manuscript: VM, RC, and PJ. Reviewing or revising the manuscript for important intellectual content: All authors. Reviewed the version of the manuscript submitted and agree with its content and submission: All authors. Accountability: All authors. Guarantor: VM.
Funding This study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Eisai Inc., Nutley, NJ, USA.
Competing interests VM is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748. Study support (all funding to institution)/unpaid consultancy/advisory board membership from AstraZeneca, Clovis, Duality, Eisai, Faeth, Genentech, GSK, Immunocore, iTEOS, Kartos, Karyopharm, Moreo, Morphosys, MSD, Novartis, Takeda, and Zymeworks. MHT received honoraria for consulting/advisory board participation from Bristol-Myers Squibb, Eisai Inc, Novartis, Merck & Co., Inc., Pfizer, Bayer, Sanofi/Genzyme, Regeneron, LOXO Oncology, Blueprint Medicines, Immune-onc, Exelixis, and Cascade Prodrug. MHT received honoraria for participation in speakers' bureaus from Bristol-Myers Squibb, Eisai Inc, Blueprint Medicines, and Merck & Co., Inc. Research funding to Dr Taylor’s institution was provided by Bristol-Myers Squibb, Eisai, Merck & Co., Inc., Pfizer, Immune-Onc, and Simcha. CA: Clinical trial funding (to institution): AbbVie, Artios Pharma, AstraZeneca, Clovis, and Genentech/Roche; Advisory board (fees): Merck; Advisory board (no fees): Blueprint Medicine; Data Monitoring Committee: AstraZeneca; Leadership role: GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) and NRG Oncology, Board of Directors (unpaid). CA is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748. ALC: Honoraria: Amgen; Expert Testimony: Department of Justice. MSB: Consulting/advisory board member (honoraria paid to me): Eisai Inc, Exelixis, Loxo Oncology, Eli Lilly, and Bayer Pharmaceuticals. CDS: Nothing to disclose. ZAC, AL, RC, PJ, and RO: Employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholders in Merck & Co., Inc., Rahway, NJ, USA. LS: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. LD, JM, and CED: Employees of Eisai Inc., Nutley, NJ, USA. YM: Employee of Eisai Co. Ltd., Tsukuba, Japan, and a stockholder in Eisai Co., Ltd. MJM: Nothing to disclose.
Provenance and peer review Not commissioned; externally peer reviewed.