Dr. McKay notes that therapy options for RCC after immunotherapy are conditional based on what modality of therapy was used in the first-line setting:
There is retrospective, phase 2, and subgroup phase 3 data suggesting that single-agent VEGF TKI post-IO is a feasible option in this disease space:
Data presented at 2021 GU ASCO by Marteau et al. showed that the objective response rate of cabozantinib (n=187) versus other TKIs (n=60) had better efficacy:
- ORR: 54% versus 38%, p = 0.0002
- Time to treatment discontinuation: median 6.2 months versus 3.1 months, p = 0.0052
- Overall survival: median 19.1 months versus 17.3 months, p = 0.8185
In the TIVO-3 trial, patients with metastatic clear cell RCC that had progressed on 2-3 prior regimens including at least 1 VEGF-TKI were randomized 1:1 to tivozanib versus sorafenib. Tivozanib demonstrated significantly greater PFS (HR 0.73, 95% CI 0.56-0.94) and ORR (15.2% versus 7.5%, p=0.003) versus sorafenib in the intention to treat population, in the subset of patients treated with two prior VEGFR-TKIs, and in patients treated with a prior VEGFR-TKI and an anti-PD-1 antibody.1 On March 10, 2021, this led to the FDA approval of tivozanib for relapsed or refractory advanced renal cell carcinoma.
There is also data suggesting the feasibility of an IO rechallenge in the second-line setting following IO in the first line. Retrospective data from Ravi et al.2 looked at patients from nine institutions who received at least two separate lines of immune checkpoint inhibitor therapy, assessing best overall response and immune-related adverse events. Among 69 patients included, the most common therapies received in the first-line setting were single-agent immune checkpoint inhibitor (n = 27, 39%) or immune checkpoint inhibitor in combination with targeted therapy (n = 29, 42%), while in the second-line setting, the most common therapies were single-agent immune checkpoint inhibitor (n = 26, 38%) or dual immune checkpoint inhibitor (n = 22, 32%). Most patients discontinued first-line therapy secondary to disease progression (n = 50, 72%) or toxic effects (n = 16, 23%). The overall response rate in the first-line setting was 37% and in the second-line setting was 23%. The likelihood of a response in the second-line setting was greatest among patients who had previously responded in the first-line setting (7 of 24, 29%), although responses in the second-line setting were seen in those who had progressive disease as their best response following first-line treatment (3 of 14, 21%), as well as in those who received single-agent immune checkpoint inhibitor in the second-line (7 of 23, 30%). Grade 3 or higher immune-related adverse events were seen in 18 patients (26%) and 11 patients (16%) in the first- and second-line settings, respectively.
The following table summarizes the data for IO + IO post-IO in relapsed RCC:
The Fast Real-Time Assessment of Combination Therapies in Immuno-Oncology (FRACTION-RCC) study was first presented at the 2020 ASCO virtual annual meeting. This randomized phase II trial is utilizing an adaptive design to test a variety of immune-oncology combination therapies rapidly, including nivolumab and ipilimumab; nivolumab and relatlimab; nivolumab and BMS-986205; and, nivolumab and BMS-813160. The preliminary results of patients receiving nivolumab and ipilimumab in patients with advanced renal cell carcinoma who had progressed on checkpoint inhibitor therapy were presented at last year’s meeting. Among the 46 patients included in the analysis, the median PFS was 16.1 weeks, objective response rate was 15.2%, the disease control rate was 52.2%, however, there were no complete responses.
A summary of adaptive IO therapy trials in the relapsed setting is as follows:
Finally, there are additional combination regimens (IO + TKI) that are feasible in the second-line setting following first-line IO therapy:
First presented by Lee et al at the ASCO 2020 annual meeting was combination pembrolizumab + lenvatinib among patients that had disease progression following PD-1/PD-L1 therapy. Among 104 patients, the objective response rate by irRECIST was 55%, with a median PFS of 11.7 months and median duration of response of 12 months. Only 5% of patients had progressive disease, however, there were no complete responses. There is also early data (first presented at GU ASCO 2021) suggesting activity of belzutifan following first-line IO therapy. Among 55 patients (62% with >= 3 lines of prior therapy), 64% had a reduction in target lesions size, the objective response rate was 25%, disease control rate was 80%, median PFS was 14.5 months, and again there were no complete responses.
There are several ongoing phase 3 studies in this disease space:
- Belzutifan versus everolimus (n=736): primary endpoint of OS
- CONTACT-3 à cabozantinib +/- atezolizumab (n=500): primary endpoint of OS
- TiNivo-2 à tivozanib +/- nivolumab (n=326): primary endpoint of PFS
As follows is a summary of the current level of evidence for second-line treatment after IO first-line therapy:
Dr. McKay concluded her presentation of systemic therapy after frontline immunotherapy combinations with the following take-home messages:
- Treatment options for relapsed RCC are evolving given the shift in the frontline treatment landscape for advanced RCC
- There is data to support VEGF blockade and IO combinations post-IO in the refractory setting
- Currently, prospective studies will help inform treatment options for relapsed RCC
- Novel targets with activity post-IO are warranted to improve outcomes for patients
Presented by: Rana R. McKay, MD, University of California San Diego, Moores Cancer Center, San Diego, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021
References:
- Rini RI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): A phase 3, multicentre, randomized, controlled, open-lable study. Lancet Oncol 2020 Jan;21(1):95-104.
- Ravi P, Mantia C, Su C, et al. Evaluation of the safety and efficacy of immunotherapy rechallenge in patients with renal cell carcinoma. JAMA Oncol. 2020 Oct 1;6(10):1606-1610.