Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial

Abstract

Background: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC.

Methods: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses.

Results: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification.

Conclusions: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC.

Keywords: JAVELIN Renal 101; avelumab; axitinib; renal cell carcinoma; sarcomatoid.

Conflict of interest statement

Disclosure TKC reports grants received from Pfizer during the conduct of the study; personal fees received from Agensys, Alexion, Alligent, American Society of Clinical Oncology, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Celldex, Cerulean, Clinical Care Options, Corvus, Dana-Farber Cancer Institute, EMD Serono, Inc., Eisai, Exelixis, Foundation Medicine, Genentech/Roche, GSK, Harborside Press, Heron, Ipsen, Kidney Cancer Association, Kidney Cancer Journal, Lpath, Lancet Oncology, Lilly, Merck & Co., Michael J. Hennessy Associates, National Comprehensive Cancer Network, Navinata Health, New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus Laboratories, Sanofi, Seattle Genetics/Astellas, and UpToDate outside the conduct of the study; grants received from AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Cerulean, Corvus, Eisai, Exelixis, Foundation Medicine, Genentech/Roche, GSK, Ipsen, Merck & Co., Novartis, Peloton Therapeutics, Pfizer, Prometheus Laboratories, Takeda, and TRACON outside the conduct of the study; and medical writing and editorial assistance provided by ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel, funded by pharmaceutical companies. JL reports personal fees from Eisai, EUSA Pharma, GSK, Kymab, Pierre Fabre, Roche/Genentech, and Secarna and grants and personal fees from Bristol Myers Squibb, Merck & Co., Novartis, and Pfizer outside the submitted work. SP reports personal fees from Astellas Pharma and Novartis and personal fees and grants from Medivation. RJM reports serving as a consultant or advisor for and research funding from Pfizer, Novartis, Eisai, and Genentech/Roche, serving as a consultant or advisor for Exelixis, Lilly, Merck & Co., and Incyte, and receiving travel, accommodation, and expenses and research funding from Bristol Myers Squibb outside the submitted work. BIR reports grants and personal fees from AVEO Oncology, Bristol Myers Squibb, Genentech/Roche, Merck & Co., and Pfizer; grants from AstraZeneca; and personal fees from 3D Medicines, Alkermes, Arravive, Inc., Compugen, Corvus Pharmaceuticals, Exelixis, Merck & Co., Novartis, Peloton, Surface Oncology, and Synthorx. BV reports grants and personal fees from Bristol Myers Squibb, personal fees from Merck & Co. and Pfizer, and grants from Merck & Co. during the conduct of the study; and personal fees from EUSA Pharma, Ipsen, and Janssen outside the submitted work. BA reports personal fees from Amgen and Ferring, grants and personal fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck & Co., Pfizer, Roche, and Sanofi, and grants from Ipsen outside the submitted work. GG reports receiving travel, accommodation, and expenses from Astellas, Bristol Myers Squibb, Ipsen, Janssen Oncology, and Pfizer. MAB reports grants from AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, Incyte, Peleton Therapeutics, Pfizer, and TRACON; personal fees from EMD Serono, Inc., Exelixis, Genomic Health, and Sanofi; and grants and personal fees from Nektar. AC reports employment at Pfizer at the time when the study was conducted. SH, KAC, XJM, MM, PBR, BH, AdiP report employment at Pfizer. LA reports consulting fees compensated to their institution from Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus Pharmaceuticals, Exelixis, Ipsen, Merck KGaA, Merck & Co., Novartis, Peloton Therapeutics, Roche, and Pfizer outside the submitted work. HM has declared no conflicts of interest. Data sharing Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (i) for indications that have been approved in the USA and/or EU or (ii) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Antitumor activity in patients with sRCC. (A) Progression-free survival and (B) mean duration of response based on BICR assessment. In (B), the difference (avelumab + axitinib versus sunitinib) in mDR was 2.4 months (95% CI, 0.9-3.9 months), and the truncation time was 12.5 months; duration of response = PFS time − time to response/PD/death (whichever is earlier). BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; mDR, mean duration of response; PD, progressive disease; PFS, progression-free survival; sRCC, sarcomatoid renal cell carcinoma. a Comparison versus sunitinib.

Figure 2

An overview of the biomarker profile of patients with sRCC showing (A) presence of CAFs and Treg cells, (B) lower expression of key VEGF signaling molecules, and (C) elevated CD274, CD8A, IFNG, and FOXP3 gene expression. Triangle symbol in the boxes represents the mean and the horizontal line represents the median; upper and lower box lines represent the 3rd and 1st quartile, respectively. Sample numbers per group are given above each plot. Two-sided P values calculated using a nonparametric Wilcoxon rank-sum test. CAF, cancer-associated fibroblasts; TPM, transcripts per million; Treg, regulatory T cell; sRCC, sarcomatoid renal cell carcinoma; VEGF, vascular endothelial growth factor.

Figure 3

Differences in expression and progression-free survival in the combination arm between sarcomatoid and nonsarcomatoid samples according to (A) WGCNA clusters, (B) Hallmark pathways, and (C) cell type-specific signatures. For the expression analysis, there were 97 sarcomatoid samples and 618 nonsarcomatoid samples; for the progression-free survival analysis, there were 39 sarcomatoid samples and 310 nonsarcomatoid samples. A positive coefficient indicates that the signature/pathway is expressed at higher levels in sarcomatoid versus nonsarcomatoid samples, and a negative coefficient indicates that a signature/pathway is expressed at higher levels in nonsarcomatoid versus sarcomatoid samples. Dots above the dashed line denote gene expression pathways or signatures that were statistically different (P ≤ 0.05) in expression between sarcomatoid and nonsarcomatoid samples. Blue dots indicate a significantly shorter progression-free survival in sarcomatoid samples with higher pathway score (P ≤ 0.05), whereas purple dots indicate a significantly shorter progression-free survival in nonsarcomatoid samples with higher pathway score (P ≤ 0.05). For (C), only positive coefficients (signatures/pathways that are expressed at higher levels in sarcomatoid versus nonsarcomatoid samples) are shown. EMT, epithelial–mesenchymal transition; IL-6, interleukin-6; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; NF-κB, nuclear factor kappa B; NK, natural killer; PI3K, phosphoinositide 3-kinases; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TNF, tumor necrosis factor; WGCNA, weighted gene coexpression network analysis.

Figure 3

Differences in expression and progression-free survival in the combination arm between sarcomatoid and nonsarcomatoid samples according to (A) WGCNA clusters, (B) Hallmark pathways, and (C) cell type-specific signatures. For the expression analysis, there were 97 sarcomatoid samples and 618 nonsarcomatoid samples; for the progression-free survival analysis, there were 39 sarcomatoid samples and 310 nonsarcomatoid samples. A positive coefficient indicates that the signature/pathway is expressed at higher levels in sarcomatoid versus nonsarcomatoid samples, and a negative coefficient indicates that a signature/pathway is expressed at higher levels in nonsarcomatoid versus sarcomatoid samples. Dots above the dashed line denote gene expression pathways or signatures that were statistically different (P ≤ 0.05) in expression between sarcomatoid and nonsarcomatoid samples. Blue dots indicate a significantly shorter progression-free survival in sarcomatoid samples with higher pathway score (P ≤ 0.05), whereas purple dots indicate a significantly shorter progression-free survival in nonsarcomatoid samples with higher pathway score (P ≤ 0.05). For (C), only positive coefficients (signatures/pathways that are expressed at higher levels in sarcomatoid versus nonsarcomatoid samples) are shown. EMT, epithelial–mesenchymal transition; IL-6, interleukin-6; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; NF-κB, nuclear factor kappa B; NK, natural killer; PI3K, phosphoinositide 3-kinases; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TNF, tumor necrosis factor; WGCNA, weighted gene coexpression network analysis.

Figure 3

Differences in expression and progression-free survival in the combination arm between sarcomatoid and nonsarcomatoid samples according to (A) WGCNA clusters, (B) Hallmark pathways, and (C) cell type-specific signatures. For the expression analysis, there were 97 sarcomatoid samples and 618 nonsarcomatoid samples; for the progression-free survival analysis, there were 39 sarcomatoid samples and 310 nonsarcomatoid samples. A positive coefficient indicates that the signature/pathway is expressed at higher levels in sarcomatoid versus nonsarcomatoid samples, and a negative coefficient indicates that a signature/pathway is expressed at higher levels in nonsarcomatoid versus sarcomatoid samples. Dots above the dashed line denote gene expression pathways or signatures that were statistically different (P ≤ 0.05) in expression between sarcomatoid and nonsarcomatoid samples. Blue dots indicate a significantly shorter progression-free survival in sarcomatoid samples with higher pathway score (P ≤ 0.05), whereas purple dots indicate a significantly shorter progression-free survival in nonsarcomatoid samples with higher pathway score (P ≤ 0.05). For (C), only positive coefficients (signatures/pathways that are expressed at higher levels in sarcomatoid versus nonsarcomatoid samples) are shown. EMT, epithelial–mesenchymal transition; IL-6, interleukin-6; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; NF-κB, nuclear factor kappa B; NK, natural killer; PI3K, phosphoinositide 3-kinases; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TNF, tumor necrosis factor; WGCNA, weighted gene coexpression network analysis.