The combination of nivolumab plus cabozantinib achieved a continued survival benefit compared with sunitinib in patients with untreated clear cell metastatic or advanced renal cell carcinoma, according to a final overall survival analysis of the phase III CheckMate 9ER trial.1 Additionally, nivolumab plus cabozantinib led to sustained progression-free survival and objective response rate benefit after a minimum follow-up of 2 years. Tumor shrinkage was greater in those treated with nivolumab plus cabozantinib as well.
“With this extended median follow-up of 33 months, nivolumab/cabozantinib provided improved survival vs sunitinib in the final overall survival analysis. With nivolumab/cabozantinib vs sunitinib, median progression-free survival, objective response rate, and complete response rates were approximately double,” said lead author Thomas Powles, MD, PhD, Professor of Genitourinary Oncology and Director of Barts Cancer Centre at St. Bartholomew’s Hospital, London.
Thomas Powles, MD, PhD
The previously published results of the open-label, randomized phase III CheckMate 9ER trial demonstrated that first-line nivolumab/cabozantinib was superior to sunitinib, with 10.6 months of minimum follow-up.2 A total of 651 patients with treatment-naive, clear cell renal cell carcinoma were assigned 1:1 to receive nivolumab/cabozantinib (nivolumab at 240 mg every 2 weeks and cabozantinib at 40 mg once daily) vs sunitinib (50 mg once daily for 4 weeks of each 6-week cycle).
The primary endpoint was progression-free survival according to blinded independent central review in the intent-to-treat population. Secondary endpoints included overall survival, objective response rate, and safety. A final overall survival analysis was planned after 254 events were observed. Post hoc exploratory analyses included maximal reduction of target lung, lymph node, kidney, and liver lesions evaluated per blinded independent central review.
At a median follow-up of 32.9 months, nivolumab/cabozantinib improved overall survival by 30% compared with sunitinib. Median overall survival was 37.7 months with the combination compared with 34.3 months with sunitinib. The median progression-free survival was improved with nivolumab/cabozantinib vs sunitinib: 16.6 months vs 8.3 months, respectively.
Objective response rate, complete response rate, median time to response, and median duration of response were all improved with nivolumab/cabozantinib vs sunitinib:
In an exploratory post hoc analysis, more patients experienced reductions in target lesions with nivolumab/cabozantinib vs sunitinib: bone, 55.6% vs 20.0%; lymph nodes, 74.4% vs 47.8%; lungs, 75.9% vs 46.4%; liver, 47.7% vs 33.3; and kidneys, 45.2% vs 29.7%.
No new safety signals were observed with longer follow-up. Grade 3 or higher treatment-related adverse events were reported in 65% of those on the nivolumab/cabozantinib arm and 54% on the sunitinib arm.
“These results continue to support the use of nivolumab/cabozantinib as a first-line treatment option for patients with advanced renal cell carcinoma,” Dr. Powles concluded.
Second-Line Cabozantinib After Immunotherapy
Second-line treatment with cabozantinib achieved similar outcomes in advanced renal cell carcinoma regardless of first-line immuno-oncology combinations, according to a data set from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).3 Investigators also evaluated outcomes for patients who received approved third-line treatment after second-line cabozantinib.
Overall, the median time to treatment failure was 7.6 months, the median overall survival was 18.1 months, the 1-year treatment failure free–rate was 34.3%, the 1-year overall survival was 63.5%, and the overall response rate was 26.2%, according to lead author Visha Navani, MA, MBBS, MRCP, a medical oncology fellow at the University of Calgary, Tom Baker Cancer Centre, Alberta, Canada.
Visha Navani, MA, MBBS, MRCP
In addition to overall outcomes, the study authors wanted to evaluate the activity of second-line cabozantinib after the first-line standard-of-care immunotherapy: ipilimumab plus nivolumab or immuno-oncology/vascular endothelial growth factor (VEGF) inhibitor combinations.
A total of 346 patients who had been treated with second-line cabozantinib for metastatic or advanced renal cell carcinoma were identified retrospectively. In the first-line setting, 78 patients had received ipilimumab plus nivolumab, 46 patients received the immune-oncology/VEGF inhibitor combination, and 222 patients received other first-line treatment.
According to stratification for first-line therapy, patients who received ipilimumab plus nivolumab had a median time to treatment failure of 6.9 months and a median overall survival of 21.4 months. The 1-year treatment failure–free rate was 34.3%, the 1-year overall survival was 66.6%, and the overall response rate was 26.4%.
Outcomes with second-line cabozantinib for patients who received front-line immuno-oncology/VEGF inhibitor combinations follow: median time to treatment failure, 5.7 months; median overall survival, 15.7 months. The 1-year treatment failure–free rate was 26.8%, the 1-year overall survival was 54.3%, and the overall response rate was 32.5%.
For patients treated with a first-line therapy other than combination immunotherapy, the median time to treatment failure was 8.0 months, the median overall survival was 18.4 months, the 1-year treatment failure–free rate was 35.7%, the 1-year overall survival was 63.5%, and the overall response rate was 23.9%. After adjusting for IMDC risk groups, the hazard ratios for second-line cabozantinib overall survival and time to treatment failure for immuno-oncology/VEGF vs ipilimumab plus nivolumab were 1.73 (95% confidence interval [CI] = 0.83–3.62, P = .14) and 1.62 (95% CI = 0.89–2.95, P = .11), respectively.
When patients who received third-line therapy (n = 125) post second-line cabozantinib were examined, investigators found that the median time to treatment failure was 3.2 months, the median overall survival was 10.9 months, the 1-year treatment failure–free rate was 19.9%, the 1-year overall survival rate was 48.4%, and the overall response rate was 13.3%.
Overall, the endpoints of time to events and response rates were similar regardless of which first-line immunotherapy was administered. The investigators were unable to identify a meaningful or statistical difference in overall survival or time to treatment failure based on type of preceeding first-line therapy. In the third-line setting, single-agent VEGF inhibitors after cabozantinib treatment also had activity, but as expected, response rates were lower than with earlier lines of therapy.
Tivozanib in Resistant Kidney Cancer
Patients with pretreated relapsed or refractory renal cell carcinoma who received third-line or later tivozanib, a multikinase inhibitor that inhibits VEGFR1, VEGFR2, and VEGFR3, were five times more likely to experience long-term progression-free survival compared with sorafenib, according to longer follow-up of the TIVO-3 trial.4 “A clinically relevant proportion of patients were alive and progression-free at 3 and 4 years after initiating [tivozanib] therapy compared with sorafenib, and this difference was consistent across all clinical and demographic subgroups evaluated,” wrote the authors of the poster presentation.
TIVO-3 enrolled 350 patients with relapsed or refractory renal cell carcinoma who received two or more prior lines of systemic therapy. Patients were randomly assigned 1:1 to receive tivozanib or sorafenib. Results of the study led to the approval of tivozanib in March 2021. Longer-term follow-up with a data cutoff of May 24, 2021, continued to demonstrate the superior efficacy of tivozanib vs sorafenib in the third-line or later setting.
At the 3-year mark, long-term investigator-assessed progression-free survival was 12.3% and 2.4% (in the tivozanib and sorafenib arms, respectively). At 4 years, progression-free survival rates were 7.6% and 0%, respectively.
At baseline, both treatment arms were well balanced for risk status. Most patients in each group received no prior immunotherapy, and 79 patients in the tivozanib group had treatment with two tyrosine kinase inhibitor therapies, compared with 80 patients in the sorafenib group.
Factors associated with 15% long-term progression-free survival at 3 years were favorable risk, female gender, and an Eastern Cooperative Oncology Group performance score of 0.
Comparing Tivozanib With Other Tyrosine Kinase Inhibitors
Tivozanib was noninferior to other tyrosine kinase inhibitors as first-line treatment of metastatic renal cell carcinoma, according to a real-world, retrospective study.5 Tivozanib’s relatively less toxic safety profile may make it an attractive option for some patients.
“We set out to evaluate the real-world use of tivozanib because we had some signals that this might be the preferred drug [for first-line treatment] because of the toxicity profile. So, we gathered data across our three separate regional cancer centers from March 2017 to 2019 and looked at these outcomes,” said lead study author Jonathan Heseltine, MBChB, of the Clatterbridge Cancer Centre, UK.
Jonathan Heseltine, MBChB
The retrospective study included 113 patients with metastatic renal cell carcinoma; 82% (n = 93) had confirmed clear cell histology and 18% (n = 20) had an undefined histology. About half of the patients (52%) were classified as intermediate risk according to the IMDC standards. A total of 22% (n = 25) were favorable risk and 26% (n = 29) were poor risk. A total of 66% (n = 75) had undergone a previous nephrectomy.
At a median follow-up of 25.9 months, overall response rate was 29%. There were no complete responses, and 29% of patients experienced a partial response, 39% achieved stable disease, 26% had progressive disease, and 6% were not evaluable.
Median progression-free survival was 9 months (P < .0001) but differed according to IMDC risk group. The IMDC favorable-risk group had a median progression-free survival of 23 months; the IMDC intermediate-risk group had a median progression-free survival of 10 months; the IMDC poor-risk group had a median progression-free survival of 3 months.
A total of 77% of patients experienced an adverse event of any grade, and 14% had grade 3 adverse events. Notable grade 3 events included abnormal liver function (3%), vascular events (2%), and seizure (< 1%). There were no treatment-related deaths, but 18% of patients discontinued treatment due to toxicity.
“The real-world data demonstrate similar progression-free and overall survival to the pivotal clinical trial, and that’s even with our population having a high proportion of poor-risk patients,” Dr. Heseltine commented.
DISCLOSURE: Dr. Powles has received honoraria, served as a consultant or advisor to, and received research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Ipsen, Merck, Pfizer, and Roche. Dr. Navani has served on speakers bureaus for Ekas, Ipsos, and Kyowa Kirin. Dr. Heseltine has received honoriaria and compensation from EUSA Pharma.
1. Thomas P, Choueiri TC, Mauricio B, et al: Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. 2022 ASCO Genitourinary Cancers Symposium. Abstract 350. Presented February 19, 2022.
2. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators: Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 384:829-841, 2021.
3. Navani V, Wells C, Boyne DJ, et al: CABOSEQ: The efficacy of cabozantinib post up-front immuno-oncology combinations in patients with advanced renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). 2022 ASCO Genitourinary Cancers Symposium. Abstract 318. Presented February 19, 2022.
4. Atkins MB, Verzoni E, Escudier B, et al: Long-term PFS from TIVO-3: Tivozanib versus sorafenib in relapsed/refractory advanced RCC. 2022 ASCO Genitourinary Cancers Symposium. Abstract 362. Presented February 19, 2022.
5. Heseltine J, Allison J, Wong S, et al: Tivozanib as first-line treatment of metastatic renal cell carcinoma: A real-world outcome review in North-West of England, UK. 2022 ASCO Genitourinary Cancers Symposium. Abstract 335. Presented February 19, 2022.