The final readout of the phase 2 TITAN-RCC trial highlighted an improvement in responses following an individualized regimen of nivolumab and ipilimumab boost after single-agent nivolumab in patients with advanced renal cell carcinoma.
Patients with advanced renal cell carcinoma (RCC) in their first- and second-line of treatment experienced improved responses following an individualized treatment strategy with nivolumab (Opdivo) and ipilimumab (Yervoy) boost following single-agent nivolumab, according to the final update of the phase 2 TITAN-RCC trial (NCT02917772).
Data presented at the 2022 European Society for Medical Oncology Congress showed that nivolumab followed by nivolumab/ipilimumab resulted in an overall response rate (ORR) of 34%, which included a complete response (CR) rate of 7%, a partial response (PR) rate of 27%, and a stable disease (SD) rate of 26%; 39% of patients had progressive disease (PD). Patients who received only single-agent nivolumab experienced a ORR of 24%, which included a CR rate of 1%, a PR rate of 23%, a SD rate of 25%, and a PD rate of 15%. Additionally, 24% of patients who received nivolumab alone had early PD and received a nivolumab/ipilimumab boost at week 8. Of 207 enrolled patients, 139 received at least 1 nivolumab/ipilimumab boost cycle.
For patients treated in the first-line setting, the ORR with nivolumab monotherapy followed by nivolumab/ipilimumab boosting was 36%, which included a CR rate of 7%, a PR rate of 28%, a SD rate of 28%, and a PD rate of 35%. Those administered nivolumab alone experienced an ORR of 28%, which was comprised of a CR rate of 2%, a PR rate of 27%, a SD rate of 27%, and a PD rate of 12%. Twenty percent of patients who received nivolumab alone had early PD and required a boosting cycle at week 8.
In the second-line setting, nivolumab monotherapy followed by nivolumab/ipilimumab boosting resulted in an ORR of 32%, which included a CR rate of 6%, a PR rate of 26%, a SD rate of 23%, and a PD rate of 43%. Nivolumab alone produced an ORR of 18%, which comprised a PR rate of 18%, a SD rate of 23%, and a PD rate of 18%. Twenty-eight percent of patients who received nivolumab alone required a boosting cycle at week 8 following early PD.
“TITAN-RCC provides further evidence to the added value of ipilimumab in combination with nivolumab in advanced RCC,” lead study author Marc-Oliver Grimm, MD, of Jena University Hospital, said in a presentation of the data. “In the first-line [setting], boosting significantly—based on our assumptions—improved ORR, and activity parameters are, however, inferior in the TITAN-RCC regimen if we compare that with a direct start with nivolumab/ipilimumab, as it is approved. In the second-line [setting], boosting numerically improved ORR, and activity parameters suggest superiority to have the adaptive approach of TITAN-RCC compared with nivolumab monotherapy, as it is approved and used today.”
TITAN-RCC enrolled patients with histologically confirmed locally advanced or metastatic RCC with a clear cell component who were intermediate/high risk by International mRCC Database Consortium criteria. Patients were permitted to be treatment naïve or have received 1 prior therapy with a TKI. Other inclusion criteria included having measurable disease per RECIST v1.1 criteria, a Karnofsky performance status of at least 70, and an evaluable tumor sample to test PD-L1 expression.
Once enrolled, all patients received induction treatment with 240 mg of intravenous nivolumab given every 2 weeks for 8 cycles. Patients who achieved a CR or PR continued nivolumab maintenance at 240 mg every 2 weeks or 480 mg every 4 weeks.
Patients who had early PD at week 8 or SD/PD after nivolumab induction received 2 boosting cycles of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks. Patients who achieved a CR or PR following the 2 boosting cycles shifted to nivolumab maintenance, and patients who still had SD or PD received 2 more nivolumab/ipilimumab boosting cycles. Patients with a CR, PR, or SD following the third and fourth boosting cycles moved to nivolumab maintenance, and patients with PD were deemed to have immunotherapy resistance.
The primary end point of the trial was ORR, and secondary end points were comprised of progression-free survival (PFS), overall survival (OS), remission rates after boosting cycles, safety, and quality of life.
Among all patients treated, the median age was 65 years (range, 20-87), and 71% were male. Additionally, 18% of patients had a Karnofsky performance status of less than 80%, 66% had their initial RCC diagnosis within 12 months, 53% had hemoglobin below the lower limit of normal, 19% had a platelet count above the upper limit of normal (ULN), 13% had an absolute neutrophil count above ULN, and 13% had calcium above ULN. Thirty percent of patients had a PD-L1 expression of at least 1%.
Four percent of patients had favorable-risk disease, 71% had intermediate-risk disease, and 25% had high-risk disease. Among those who received prior first-line therapy, 72% received sunitinib (Sutent), 22% received pazopanib (Votrient), and 5% received another agent.
Among patients in the first-line setting who received boosting with nivolumab/ipilimumab in week 8 (n = 49), the best response rate was 33%, which included a CR rate of 2%, a PR rate of 14%, and a SD rate of 16%. The median duration of response (DOR) for those who achieved a CR, PR, or SD was not estimated (NE; 27.8 months), 8.3 months (range, 5.3-30.5), and 6.2 months range, 2.8-8.5), respectively. Among patients in the first-line setting who were boosted beyond week 16 (n = 17), the best response rate was 53%, which included a PR rate of 18% and a SD rate of 35%; the DOR for patients who had a PR or SD was NE (95% CI, 4.2-22.1) and 15.7 (95% CI, 2.6-28.4), respectively.
For patients who were boosted in the second-line setting in week 8 (n = 59), the best response rate was 37%, which comprised a CR rate of 5%, a PR rate of 12%, and a SD rate of 20%. The DOR following the boost in patients who achieved a CR, PR, or SD was NE (range, 4.9-40.4), 18.2 months (range, 2.8-20.0), and 5.2 (range, 1.6-27.7), respectively. In patients in the second-line setting who were boosted beyond week 16 (n = 11), the best response rate was 55%, which comprised a PR rate of 18% and a SD rate of 36%; the DOR in those who had a PR or SD was NE (95% CI, 4.1-11.1) and NE (95% CI, 2.7-73), respectively.
The median PFS was 6.0 months (95% CI, 3.7-10.1) for patients in the first-line setting and 3.7 months (95% CI, 1.8-4.5) for patients in the second-line setting. The median OS for those 2 groups was 36.1 months (95% CI, 27.2-46.7) and 33.7 months (95% CI, 21.6–not calculable), respectively.
“Please note, however, that due to the study design, [the PFS data] mainly reflect nivolumab monotherapy,” Grimm explained.
Although Grimm did not present full safety data, he noted that no new safety signals were identified.
Grimm M-O, Esteban E, Barthelemy P, et al. Efficacy of a tailored approach with nivolumab and nivolumab/ipilimumab as immune-therapeutic boost in metastatic renal cell carcinoma – final results of TITAN-RCC. Ann Oncol. 2022;33(suppl 7):S660-S680. doi:10.1016/annonc/annonc1072