A multi-institution analysis of outcomes with first-line ipilimumab and nivolumab for 514 patients with metastatic clear cell renal cell carcinoma by number of doses.

441 Background: Ipilimumab (IPI) and nivolumab (NIVO) are a standard first line systemic therapy option for patients with metastatic ccRCC. The regimen is administered in combination for 4 doses, followed by NIVO maintenance. Patients are often unable to receive all 4 doses of IPI due to toxicity. Whether this affects clinical outcomes is unknown. We assessed outcomes with IPI/NIVO by number of doses given in patients with metastatic ccRCC. Methods: We conducted a retrospective study of patients with metastatic ccRCC at Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center treated with first line IPI/NIVO. We evaluated clinical outcomes starting at 12 weeks after initiation of therapy, including patients who were alive and being followed at that time point. We calculated time to second line treatment (TT2) and overall survival (OS) by the Kaplan-Meier method from the 12-week landmark for patients who received all 4 doses versus those who received < 4 doses for toxicity, excluding early progressors. Results: 514 patients initiated IPI/NIVO. 320 patients (62%) received all 4 doses, 193 (38%) received < 4 doses (73 - 3 doses, 71 - 2, 49 - 1), whereas 1 patient received 10 doses and was excluded. Most patients received < 4 doses for toxicity (106, 55%) or progression (47, 24%). In the TT2 and OS analyses, all 320 patients who received 4 doses and 106 patients who received < 4 due to toxicity were included. The two groups had comparable distributions of sarcomatoid and/or rhabdoid features (37% and 35%, respectively) and IMDC risk groups. NIVO maintenance was initiated in 251 (78%) of those who completed 4 doses and 25 (24%) in those who received < 4 doses. Median TT2 in 4 and < 4 dose group was 12.5 and 11.7 months, respectively. One-year TT2 rates are 51% and 49% with a 1-year difference of 2.6% (95% CI: -9.3, 14.6). Median OS in the 4 and < 4 dose group was 5.0 and 4.7 years, respectively. Two-year survival probabilities are 78% and 74% with a 2-year survival difference of 3.3% (95% CI: -6.8, 13.5). Median follow-up for survivors is 3.9 years. In a landmark Cox proportional-hazards model for survival adjusted for IMDC risk, sarcomatoid and rhabdoid features, the HR for 4 doses vs < 4 due to toxicity is 0.80 (95% CI: 0.56, 1.13). Conclusions: In this observational analysis, we found comparable TT2 and OS in patients who received 4 doses of IPI/NIVO compared to those who received < 4 doses due to toxicity. A prospective trial would help inform whether there is need for all 4 doses of IPI/NIVO in all patients. Four Doses of IPI + NIVO (N=320) Fewer Than Four Doses of IPI + NIVO for Toxicity (N=106) One-year TT2 rates 51% (95% CI: 46, 57) 49% (95% CI: 38, 59) Median TT2, months (95% CI) 12.5 months (95% CI: 9.5, 16.8) 11.7 months (95% CI: 6.8, 19.6) Two-year OS probabilities 78% (95% CI: 72, 82) 74% (95% CI: 64, 82) Median OS, years(95% CI) 5.0 years (95% CI: 3.9, 6.7) 4.7 years (95% CI: 3.0, 7.4)