Half of the patients with metastatic melanoma treated with nivolumab-ipilimumab are still alive after 5 years
The phase III CheckMate 067 trial previously established a significant improvement in overall (OS) and progression-free survival (PFS) for patients with metastatic melanoma who were treated with a combination of nivolumab and ipilimumab (NIVO+IPI), or with NIVO alone compared to IPI alone. In addition, the NIVO+IPI combination resulted in a significantly better PFS compared to NIVO alone. The 5-year update of this trial, presented at ESMO 2019, confirmed these earlier findings and showed that 52% of patients in the NIVO+IPI arm were still alive after 5 years (vs. 44% and 26% with NIVO and IPI, respectively). The median OS with NIVO+IPI was still not reached in this updated analysis. In addition, three-quarters of patients treated with NIVO+IPI were alive and free of subsequent therapy. Importantly, quality of life was preserved in both NIVO arms.
Historically, the survival prospects for patients with metastatic melanoma were very poor, with a median OS of 9 months and a 5-year OS rate of approximately 5%. This dire situation changed with the introduction of the checkpoint inhibitor IPI, which was associated with a 3-year OS rate of 26%. This prognosis was even further improved with the introduction of the PD-1 inhibitor NIVO, initially as monotherapy, but later on also in combination with IPI. As mentioned above, the phase III CheckMate 067 trial demonstrated a significant improvement in OS, PFS, and objective response rate with NIVO+IPI or NIVO alone compared to IPI alone.
In CheckMate 067, 945 previously untreated patients with stage III or IV melanoma were randomly assigned (1:1:1) to NIVO+ IPI, NIVO or IPI. Patients were stratified by PD-L1 expression status, BRAF mutation status, and metastasis stage. Patients either received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W (N= 314), NIVO 3 mg/kg Q2W + placebo (N= 316), or IPI 3 mg/kg Q3W for 4 doses + placebo (N= 315) until progression or unacceptable toxicity. The two co-primary endpoints of the trial were OS and PFS. Of note, the study was not powered to compare the two NIVO-containing groups.
With a minimum follow-up of 60 months, the NIVO-containing arms continued to show improved OS and PFS, and higher response rates compared to IPI. At the 5-year landmark, 52% of patients in the NIVO+IPI arm were still alive compared to 44% and 26% with NIVO and IPI, respectively. The median OS was not yet reached with NIVO+IPI, while this was reported at 36.9 months with NIVO alone and 19.9 months with IPI alone (HR [95% CI] for NIVO+IPI vs IPI: 0.52 [0.42-0.64]; NIVO vs IPI: 0.63 [0.52-0.76]; NIVO+IPI vs NIVO: 0.83 [0.67-1.03]). Of note, the difference in OS rates between the 2 NIVO arms steadily increased with each year of follow-up, from 5% at 2 years to 8% in this 5-year update. Interestingly, the OS benefit of NIVO+IPI and NIVO vs IPI alone was seen irrespective of the BRAF mutation status and the baseline lactate dehydrogenase (LDH) level and was observed regardless of the baseline PD-L1 expression (similar results in patients with PD-L1 expression < and ≥5%). For example, in the large subgroup of patients with a BRAF mutation the 5-year OS rates were 30%, 46% and 60% with IPI, NIVO and NIVO+IPI, respectively.
Also the PFS remained to be significantly better with NIVO+IPI and NIVO compared to IPI alone (median PFS: 11.5, 6.9 and 2.9 months; respectively. HR [95% CI] NIVO+IPI vs IPI: 0.42 [0.35-0.51]; NIVO vs IPI: 0.53 [0.44-0.64]; NIVO+IPI vs NIVO: 0.79 [0.64-0.96]). The two NIVO-containing regimens were also associated with a higher ORR compared to IPI (58% with NIVO+IPI and 45% with NIVO vs 19% with IPI). The responses to NIVO+IPI and NIVO also proved to be very durable (median duration of response not yet reached vs 14.4 months with IPI).
Only 46% of patients in the NIVO+IPI arm received any form of subsequent therapy as compared to 59% and 75% with NIVO and IPI alone. Importantly, the time from randomization to the start of the first subsequent therapy was not yet reached in the NIVO+IPI arm as compared to 25.2 and 8.0 months with NIVO or IPI alone. Among patients who discontinued therapy, the median time of the treatment-free interval was 18.1 months with NIVO+IPI as compared to 1.8 and 1.9 months with NIVO and IPI. Finally, there was no sustained deterioration of health-related quality of life (EQ-5D-3L utility index) during treatment or following treatment discontinuation with NIVO or NIVO+IPI.
This 5-year analysis represents the longest phase III follow-up for checkpoint inhibitor combination therapy and demonstrates long-term survival with both NIVO-containing arms vs IPI. In descriptive analyses, NIVO+IPI was associated with improved survival and a higher likelihood of being alive and treatment-free compared with NIVO alone, both without loss of QoL.
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. 5-year survival outcomes of the CheckMate 067 phase III trial of nivolumab plus ipilimumab (NIVO+IPI) combination therapy in advanced melanoma. Presented at ESMO 2019; Abstract LBA68_PR