ASCO 2020: Emerging Unmet Needs in RCC: An Ideal Sequential Strategy and the Post-Immunotherapy Space

( As a discussant at the 2020 American Society of Clinical Oncology Virtual Annual Meeting, Dr. Laurence Albiges provided an assessment of emerging unmet needs in advanced renal cell carcinoma following the presentation of four related abstracts. Before getting to those data, it is important to highlight the current landscape of immunotherapy in advanced renal cell carcinoma (RCC). Immunotherapeutics, including combinations of checkpoint inhibitors and a checkpoint inhibitor combined with a tyrosine kinase inhibitor, have now been established in the first-line treatment of metastatic kidney cancer. However, treatment optimization including the potential role of monotherapy and response-driven treatment adaptation, as well as treatments following progression on first-line immune checkpoint inhibition remain to be assessed. To this end, each of these four abstracts provides interesting and important data.

1. OMNIVORE: In this Phase II response-adaptive trial, Dr. Rana McKay and colleagues sought to assess whether treatment de-escalation could be efficacious. While CheckMate 214 demonstrated the efficacy of combined nivolumab and ipilimumab, OMNIVORE sought to assess whether nivolumab monotherapy, followed by ipilimumab in patients who failed to respond could provide reasonable outcomes. Further, they discontinued therapy in those with a complete or partial response and observed these patients with treatment reinitiated at progression.

OMNIVORE key inclusion criteria

Dr. McKay and colleagues found relatively low rates of partial response to monotherapy (nine of 83 patients, 11%). Eleven patients (nine with partial response, one with unconfirmed partial response, and one with stable disease) underwent observation of whom five remained off therapy for at least one year. Of those who failed to respond and received ipilimumab, two converted to a partial response. These data suggest that an initial combination approach is likely preferable.

2. HCRN GU16-260: Dr. Michael Atkins and colleagues asked a similar question and, in this study, treated 123 patients with treatment-naïve advanced RCC with nivolumab monotherapy induction. Those with progressive disease or stable disease received salvage nivolumab and ipilimumab combination therapy. The objective response rate was 29% with five patients achieving a complete response, 29 achieving a partial response, 47 having stable disease, and 36 having progressive disease. While 60 patients were eligible for salvage therapy, 28 were unable to receive it due to therapeutic toxicity or symptomatic disease burden.

Across three trials now including TITAN presented at ESMO 2019 and these two presented at ASCO 2020, the objective response rate for nivolumab monotherapy ranges between 17 and 32% in the first-line setting. The addition of ipilimumab as a rescue strategy resulted in objective response rates between 4 and 13%. Notably, OMNIVORE used a two cycle rescue while the other two trials used a four cycle rescue and this may explain some of the differences in the response rate between these trials.

TITAN vs OMNIVORE clinical trials

Dr. Albiges concluded by emphasizing that, in her opinion, a nivolumab monotherapy approach with rescue as needed cannot be recommended as there is a relatively limited activity demonstrated and many patients will not be eligible for rescue as a result of toxicity from nivolumab monotherapy.

3. FRACTION-RCC: To briefly summarize this trial, the authors sought to assess whether patients who had progressed on prior PD-1 therapy could be rescued with nivolumab and ipilimumab combination therapy. While there are many other aims of this trial, the data presented to date have shown an objective response rate of 15% for patients receiving this approach suggesting that durable partial responses may be induced from combination immunotherapy, even following prior anti-PD-1 therapy. However, this was a single armed series without a comparator.

4. Finally, Dr. Lee and colleagues presented their Phase II trial of lenvatinib plus pembrolizumab for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC). Lenvatinib is a multi-kinase VEGFR inhibitor that has been previously approved in combination with everolimus for patients progressing following VEGF-targeted therapy.

FRACTION RCC key inclusion criteria

Among 104 enrolled patients, the majority had been pre-treated with 58% having seen at least two lines of therapy. The objective response rate was 51% and median progression-free survival was 11.7 months. Again, these are non-randomized data but they suggest benefit in a heavily pre-treated population.

ipi nivo fraction

Dr. Albiges highlighted that while a complete response was not seen with either treatment approach (nivolumab + ipilimumab or lenvatinib + pembrolizumab), partial responses and stable disease were not uncommon.

In summary, while reducing the burden of treatment is laudable, Dr. Albiges highlighted that combination therapy would be the first-line standard of care with single-agent nivolumab monotherapy restricted to those who are not eligible for combination therapy. A randomized trial assessing this question is currently pending. Further, a biomarker-based decision approach is also pending (BIONIKK) and may allow for rationale treatment de-intensification for patients likely not to experience adverse oncologic outcomes as a result. Ongoing trials including CONTACT-03, MK6482-005, and PDIGREE will help to define optimal treatment for patients progressing after first-line therapy including immune checkpoint inhibition. However, monotherapy TKI is currently the standard of care.

Presented by: Laurence Albiges, MD, PhD, Vice Chair, Department of Cancer Medicine, Gustave Roussy Institute, Villejuif, France

Written by: Christopher J.D. Wallis, MD, PhD, Urologic Oncology Fellow, Vanderbilt University Medical Center, Nashville, Tennessee, Twitter: @WallisCJD, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020

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