4823 - Efficacy and biomarker analysis of patients (pts) with advanced renal cell carcinoma (aRCC) with sarcomatoid histology (sRCC): subgroup analysis from the phase 3 JAVELIN Renal 101 trial of first-line avelumab plus axitinib (A + Ax) vs sunitinib (S)

Background

Despite advances in clear cell RCC treatment, pts with sRCC have poor prognosis and are more resistant to VEGF-targeted therapy. In JAVELIN Renal 101 (NCT02684006), progression-free survival (PFS) was longer (median 13.8 vs 8.4 mo; HR 0.69; p < 0.001) and objective response rate (ORR) was higher (51% vs 26%) with A + Ax vs S; benefit was observed in pts irrespective of PD-L1 expression and across all prognostic risk groups (Motzer NEJM 2019; Choueiri ASCO-GU 2019). We report data from a post hoc analysis of JAVELIN Renal 101 pts with sRCC.

Methods

886 eligible pts with clear cell aRCC, no prior systemic therapy for aRCC, and ECOG PS 0-1 were randomised 1:1 to receive either A + Ax (N = 442) or S (N = 444) following a standard dose and schedule. PFS and ORR were assessed by independent review committee in pts irrespective of PD-L1 expression. Pts whose pathology report indicated sarcomatoid features were included in this post hoc analysis. Biomarker analyses included expression of PD-L1, genes and signatures, whole exome sequencing, and classification per criteria reported previously (Chen Cell Rep 2016).

Results

Of the 886 randomised pts, 108 (12.2%; 47 on A + Ax and 61 on S arm) had sRCC. Baseline characteristics were balanced between the 2 arms in this subgroup; 10.2%/62.0%/27.8% had favourable/intermediate/poor IMDC risk. In pts with sRCC, A + Ax improved PFS (median [95% CI], 7.0 [5.3, 13.8] vs 4.0 [2.7, 5.7] mo; HR 0.57 [95% CI, 0.325,1.003]) and ORR [95% CI] (46.8% [32.1, 61.9] vs 21.3% [11.9, 33.7]; complete response in 4.3% vs 0%) vs S. Ongoing biomarker analyses suggest that pts with sRCC have higher median expression levels of key immune markers, including PD-L1 and IFNG, and most are defined molecularly by the differentially expressed genes in M1-M4 TCGA subtypes as the M3 classification with historically poor prognosis.

Conclusions

Pts with sRCC who received A + Ax had PFS and ORR benefit over S, supporting the results in the overall trial population. This analysis provides insight into the biology of an aggressive subtype of RCC and suggests a potential new treatment option.

Clinical trial identification

NCT02684006 February 17, 2016.

Editorial acknowledgement

ClinicalThinking, funded by Pfizer Inc. and Merck Healthcare KGaA.

Legal entity responsible for the study

Pfizer Inc.

Funding

Pfizer Inc. in alliance with Merck Healthcare KGaA.

Disclosure

T.K. Choueiri: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Cerulean Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Prometheus Laboratories; Honoraria (self), Advisory / Consultancy: Alligent; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Corvus Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Alexion Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Honoraria (self), Advisory / Consultancy: Sanofi/Aventis; Honoraria (self), Advisory / Consultancy: EMD Serono; Research grant / Funding (institution): Seattle Genetics/Astellas; Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy, Leadership role: NCCN; Leadership role: Kidney Cancer Association; Honoraria (self), Advisory / Consultancy: UptoDate; Honoraria (self), Advisory / Consultancy: Michael J. Hennessy Associates; Honoraria (self), Advisory / Consultancy: ASCO; Honoraria (self), Advisory / Consultancy: Harborside Press; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Analysis Group; Honoraria (self), Advisory / Consultancy: PlatformQ Health; Honoraria (self), Advisory / Consultancy: Clinical Care Options; Honoraria (self), Advisory / Consultancy: Navinta Healthcare; Honoraria (self), Advisory / Consultancy: Kidney Cancer Journal; Honoraria (self), Advisory / Consultancy: Lpath; Honoraria (self), Advisory / Consultancy: NEJM; Honoraria (self), Advisory / Consultancy: Lancet Oncology; Honoraria (self), Advisory / Consultancy: HERON; Honoraria (self), Advisory / Consultancy: Lilly; Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Calithera Biosciences; Leadership role, Full / Part-time employment: Dana Farber Cancer Hospital. J.M.G. Larkin: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: GSK; Advisory / Consultancy: Kymab; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Secarna; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: EUSA Pharma. S.K. Pal: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Research grant / Funding (self): Medivation; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Aveo; Advisory / Consultancy: Myriad Pharmaceuticals; Advisory / Consultancy: Genentech; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai. R.J. Motzer: Honoraria (self), Research grant / Funding (institution): Pfizer Inc.; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Incyte; Research grant / Funding (institution): Bristol-Myers Squibb (BMS); Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Merck. B. Venugopal: Honoraria (self), Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self): Eusa Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb. B.Y. Alekseev: Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Ferring; Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi. G. Gravis: Travel / Accommodation / Expenses: Janssen Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Astellas Pharma; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Ipsen. M.A. Bilen: Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy: GenomicHealth; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Incyte; Speaker Bureau / Expert testimony: AstraZeneca; Research grant / Funding (institution): Tricon Pharmaceuticals; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Pfizer. A. Chudnovsky: Full / Part-time employment: Pfizer Inc. K.A. Ching: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Pfizer Inc. M. Mariani: Full / Part-time employment: Pfizer Inc. P.B. Robbins: Full / Part-time employment: Pfizer Inc. B. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. A. di Pietro: Full / Part-time employment: Pfizer Inc. L. Albiges: Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Peloton Therapeutics; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis. All other authors have declared no conflicts of interest.