Negative Survival Data From CONTACT-03 Call ICI Rechallenge in Advanced RCC Into Question

Treatment with atezolizumab (Tecentriq) plus cabozantinib (Cabometyx) after initial disease progression on a prior frontline immune checkpoint inhibitor (ICI)–based regimen did not produce superior survival benefit for patients with advanced renal cell carcinoma (RCC), providing prospective evidence that PD-L1 inhibitor rechallenge may not be an optimal treatment strategy for this patient population, according to Toni K. Choueiri, MD.

Findings from the phase 3 CONTACT-03 trial (NCT04338269) presented at the 2023 ASCO Annual Meeting showed that patients given cabozantinib plus atezolizumab achieved a median progression-free survival (PFS) of 10.6 months (95% CI, 9.8-12.3) compared with 10.8 months (95% CI, 10.0-12.5) for cabozantinib alone. Additionally, the median overall survival (OS) was 25.7 months (95% CI, 25.1–not evaluable [NE]) with the combination vs NE (95% CI, 21.1-NE) with cabozantinib alone. The similarity in PFS between both arms was observed across the majority of prespecified subgroups.

Moreover, the incidence of grade 3/4 treatment-related adverse effects (TRAEs) was 55.3% with the combination vs 47.3% with the monotherapy. The incidence of any-grade TRAEs was comparable in both arms at 96.2% and 97.3%, respectively.

“The primary end points of PFS and OS were negative, [as were] key secondary end points of overall response rate [ORR] and duration of response,” Choueiri said. “In conclusion, PD-L1 inhibitor [use] after progression on prior ICIs does not seem to work.”

In an interview with OncLive^®, Choueiri highlighted findings from CONTACT-03 and their clinical significance, as well as the need for continued investigation of PD-1 inhibitor rechallenge despite the negative trial results with cabozantinib and atezolizumab.

Choueiri serves as medical director of International Strategic Initiatives, director of the Lank Center for Genitourinary Oncology, co-leader of the Kidney Cancer Program, and senior physician at Dana-Farber Cancer Institute. He is also the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: Could you discuss the rationale for investigating the use of cabozantinib and atezolizumab following progression on an ICI in patients with advanced RCC?

Choueiri: In practice, we've seen the use of ICIs after tumor progression on prior ICIs. We know PD-1/PD-L1 inhibitors are a cornerstone of cancer therapy, but what to do after progression on prior PD-1/PD-L1 inhibitors remains unknown. [Currently for patients with advanced RCC,] we use VEGF TKIs such as cabozantinib, but [should] we rechallenge with ICIs? [Current] practice is all over the place. To answer this question, we attempted to do a rigorous phase 3 trial in [patients with advanced RCC] post-progression on a PD-1/PD-L1 inhibitor. Patients [were] [randomly assigned] to cabozantinib at 60 mg once a day vs the combination of cabozantinib plus the PD-L1 inhibitor atezolizumab.

What key findings from this study were presented at the meeting?

We did not see [superior] activity [with the combination]. PFS, OS, and ORR by independent central review and investigator assessment were negative, and toxicity was even higher [with the combination vs cabozantinib alone].The practice of using ICIs, specifically atezolizumab, after progression on a prior ICI should be looked at with caution. This may apply to other solid tumors where we see it in practice.

Are there any other investigations of ICI rechallenge in advanced RCC being planned or conducted?

We now have a [phase 3] study that finished accrual called TiNivo-2 [NCT04987203]. That study [randomly assigned] patients to tivozanib [Fotivda] vs tivozanib plus nivolumab [Opdivo]. This study will also ask the important question of whether rechallenge with a PD-1 inhibitor rather than a PD-L1 inhibitor has any merit.

What is the clinical significance of this research?

[This study emphasizes] the importance of [conducting] phase 3 trials and sticking to [available] data when selecting [a treatment strategy].When we started this journey, people were polarized. Some felt that we should not even do this study, because the results were a given to be positive, or [vice versa]. When we looked at the literature, there was no large, randomized phase 3 trial [assessing ICI rechallenge] in any solid tumor. We were the first here, and I think that's important, [although these data] don't answer all the questions. The question of PD-1 rechallenge remains relevant. Hopefully we'll be able to answer that with TiNivo-2.

Disclosures: Choueiri reported stock ownership and honoraria with Curesponse, Osel, Pionyr Immunotherapeutics, Precede Bio, and Tempest Therapeutics; and consulting or advisory roles with Alkermes, Analysis Group, Aravive, Arcus Biosciences, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Clinical Care Options, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, Gilead Sciences, GlaxoSmithKline, Harborside Press, Infinity Pharmaceuticals, Ipsen, Janssen Oncology, Kanaph Therapeutics, Lancet Oncology, Lilly, Merck, MJH Life Sciences, Navinata Health, NCCN, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Precede Bio, Prometheus, Roche/Genentech, Sanofi/Aventis, Scholar Rock, Tempest Therapeutics, The New England Journal of Medicine, and UpToDate.

He also reported research funding from Agensys, Arcus Biosciences, AstraZeneca, AVEO, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, Exelixis, GlaxoSmithKline, Ipsen, Merck, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and TRACON Pharma; and patents and royalties from Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, ctDNA technologies, and PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response.

He also reported travel expenses from Alexion Pharmaceuticals, Allegiant, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath Therapeutics, Merck, MJH Life Sciences, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, The New England Journal of Medicine, and UpToDate; and that medical writing and editorial assistance support may have been funded by communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, and Parexel.

Reference

Choueiri TK, Albiges L, Tomczak P, et al. Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study. J Clin Oncol. 2023;41(suppl 17):LBA4500. doi:10.1200/JCO.2023.41.17_suppl.LBA4500