Non–clear cell renal cell carcinoma (RCC) presents unique treatment challenges due to its rarity and histological diversity. During a virtual event with oncologists from California, Nataliya Mar, MD, associate clinical professor in the Division of Hematology/Oncology, Medicine at UC Irvine Chao Comprehensive Cancer Center, discussed cabozantinib (Cabometyx) plus nivolumab (Opdivo) for this patient population. Mar compared the efficacy and safety data from this combination with pembrolizumab (Keytruda) plus lenvatinib (Lenvima).
Register today to join a Case-Based Roundtable near you.
This article is part 2 of a 2-part series from a Case-Based Roundtable event.
Targeted Oncology: Can you discuss the design of the CA209-9KU trial (NCT03635892) looking at combination therapy in non–clear cell RCC?
Nataliya Mar, MD: The nivolumab/cabozantinib study was an older study.1 It preceded KEYNOTE-B61 [NCT04704219] and it had less patients. B61 had 158 patients,2 and this trial had 47 patients. The patient population was similar to B61. Patients needed to have advanced or metastatic non–clear cell RCC.1 They allowed both untreated patients as well as patients with 1 prior line of systemic therapy, so that was one distinction.
Patients were divided into 2 cohorts. Cohort 1 had papillary, unclassified, and translocation-associated RCC, which was 40 patients in total. Cohort 2 had chromophobe patients, which were 7 patients in total. This cohort was closed early because there was a 0% objective response rate [ORR] at 13 months of follow up; it was closed for futility. I am just going to focus on Cohort 1 when I talk about the results.
This was also a single-arm phase 2 study. Patients received a combination of nivolumab at standard doses plus cabozantinib at 40 mg daily. The primary end point was the same as in the B61 study, ORR and secondary end points were also similar to the B61 study.1,2
What responses were observed among different subtypes of RCC included on the trial?
For previously untreated patients of any histology, first-line therapy or histologies combined together, which came out to 26 patients in total, the ORR was 54%. Complete responses [CRs] were seen in 4%, partial responses [PRs] in 50%, and stable disease [SD] in 46%.3
In the second-line patients, with all histologies grouped together, the ORR dropped to 36%. There were no CRs, less PRs, more SD, and more primary progressive disease. To focus more on the different subtypes of RCC regardless of which line of therapy it was, just based on histology, in papillary RCC, or 32 patients on the study, the ORR was 47%. When you look at unclassified RCC, the ORR was 50%. In translocation RCC, the ORR was 50%. A majority of patients had papillary disease. All of the histologies’ [results were] similar to the overall study population, and patients who were previously treated did worse than untreated patients.
What were the survival outcomes and toxicity profile for these patients?
The median progression-free survival [PFS] was 13 months on this study. The median overall survival [OS] was 28 months.1 If you look at the same type of breakdown in terms of median PFS in previously untreated patients of any histology, median PFS was 11 months. Patients in the second-line setting had a median PFS of 13 months. If you break it down by histology, papillary vs unclassified vs translocation, unclassified had a lower median PFS, but papillary and translocation did similarly to the overall study population.
Grade 3 and 4 toxicities, meaning severe or very severe, were much less frequent than all-grade toxicities.3 The rate of hypertension was lower than [with lenvatinib and pembrolizumab] in the B61 study,1 but the rest of them were fairly low, although diarrhea and hand-foot syndrome come in at 7.5% and 5%, respectively, in terms of severe and very severe adverse events [AEs].3
How else did the KEYNOTE-B61 trial and the CA209-9KU trial differ?
We’re not supposed to do cross-trial comparisons because populations are heterogeneous, so take this with a grain of salt. KEYNOTE-B61 was a larger study compared to the cabozantinib/nivolumab trial.1,2 It had almost 4 times as many patients. In terms of subtypes of RCC, papillary seemed to dominate both studies, although there was a solid representation for chromophobe RCC in B61. In terms of International mRCC Database Consortium risk groups, B61 had twice as many favorable-risk patients, less intermediate-risk and less poor-risk patients. Prior nephrectomy was lower in the B61 study. The ORR were comparable. Rates of CRs were somewhat higher in B61, and rate of PRs a little bit higher in B61. The B61 data is less mature, so we don’t have median OS yet for that, and median PFS was higher with B61 vs cabozantinib/nivolumab.
Virtually all patients on both trials had some sort of treatment-related AE. In terms of severe or very severe treatment-related AEs, they were pretty similar between the 2 trials. For AEs leading to discontinuation of either study drug, there was a difference with pembrolizumab/lenvatinib at 22% and with cabozantinib/nivolumab at 50%. Treatment-related toxicities leading to discontinuation of both study drugs was also very different, pembrolizumab/lenvatinib at 4%, cabozantinib/nivolumab at 33%.
Register today to join a Case-Based Roundtable near you.
DISCLOSURES: Mar previously reported a consulting or advisory role with Exelixis, EMD Serono, Pfizer, Aveo, a part of the speakers’ bureau with Eisai and Merck, and research funding from Gilead Sciences.
References:
1. Lee C-H, Fitzgerald KN, Voss MH, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Updated results from a phase 2 trial. J Clin Oncol. 2023;41(suppl 16):4537. doi:10.1200/JCO.2023.41.16_suppl.4537
2. Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): extended follow-up of the phase 2 KEYNOTE-B61 study. J Clin Oncol. 2024;42(suppl; abstr 2). doi:10.1200/JCO.2024.42.4_suppl.2
3. Fitzgerald KN, Lee CH, Voss MH, et al. Cabozantinib plus nivolumab in patients with non-clear cell renal cell carcinoma: Updated results from a phase 2 trial. Eur Urol. 2024;86(2):90-94. doi:10.1016/j.eururo.2024.04.025