Of 1096 patients randomized in CheckMate 214, 139 patients with sRCC and IMDC I/P-risk disease (NIVO+IPI, n=74; SUN, n=65) and six with favorable-risk disease (NIVO+IPI, n=3; SUN, n=3) were identified via independent central pathology review of archival tumor tissue or histological classification per local pathology report. Patients received NIVO+IPI (3 mg/kg of NIVO and 1 mg/kg of IPI) every 3 weeks for four doses, followed by NIVO monotherapy (3 mg/kg) every 2 weeks. SUN (50 mg) was administered orally once daily for 4 weeks on and 2 weeks off in each 6-week cycle.8 As in the overall study, endpoints in patients with sRCC and IMDC I/P-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, objective response rate (ORR) per RECIST v1.1, and safety.8
With 42 months minimum follow-up, NIVO+IPI was associated with long-term survival benefits and notable antitumor activity versus SUN in patients with sRCC and I/P risk. Median OS (95% CI) was not reached (25.2 months to not estimable) with NIVO+IPI versus 14.2 months (9.3-22.9) with SUN; hazard ratio (HR) for death was 0.45 (95% confidence interval [CI]: 0.3-0.7). Median PFS (95% CI) was also longer with NIVO+IPI versus SUN: 26.5 months (8.4 to not estimable) versus 5.1 months (4.0-6.9), with a HR for disease progression or death of 0.54 (95% CI: 0.3-0.9).
Responses were durable and ORR (95% CI) favored NIVO+IPI versus SUN (60.8% [48.8-72.0] vs 23.1% [13.5-35.2]), with complete response rates of 18.9% and 3.1%, respectively. With NIVO+IPI, most patients experienced either no increase or a reduction in target lesion size over time. The median duration of response (95% CI) was not reached (22.5 months to not estimable) with NIVO+IPI versus 20.7 months (7.2-38.7) with SUN.
Efficacy outcomes were also better with NIVO+IPI versus SUN, regardless of programmed death-ligand 1 (PD-L1) expression; yet, the magnitude of efficacy outcomes with NIVO+IPI observed in this patient subgroup was generally greater for patients with tumor PD-L1 expression ≥1% versus those with tumor PD-L1 expression <1%. Notably, 22% of patients with sRCC and tumor PD-L1 expression ≥1% achieved a complete response with NIVO+IPI versus 3.0% with SUN. Caution is warranted in interpreting these results as the analyses were not powered to detect differences by baseline PD-L1 expression, and thus the findings should be considered hypothesis-generating.
Safety with NIVO+IPI versus SUN in patients with sRCC was consistent with the overall trial population, with treatment-related adverse events (TRAEs) of any grade reported in 97% of treated patients in either arm (NIVO+IPI, n=73; SUN, n=65). Grade 3 or 4 TRAEs occurred in 49% and 45% of patients, respectively. Most commonly reported grade 3-4 events included increased lipase (11% and 5%), increased alanine aminotransferase (10% and 2%), and fatigue (8% and 6%) for NIVO+IPI versus SUN. One treatment-related death reported previously, occurred in a patient with sRCC and I/P-risk disease treated with NIVO+IPI and no deaths were reported in patients treated with SUN. Of the 73 patients with sRCC treated with NIVO+IPI, 21% received corticosteroids (≥40 mg prednisone daily or equivalent) to manage TRAEs that were potentially immune-mediated.
Limitations of the current analysis include its non-prespecified, exploratory post hoc nature, although the distribution of patients with sRCC was balanced between treatment arms. Additionally, this analysis identified patients with sRCC and sarcomatoid histology via two distinct methodologies: central pathology review and local pathology reports. Despite the differing methodologies, sensitivity analyses showed similar efficacy outcomes with the exception of complete response rates, which reflects only a small number of patients. In conclusion, there is a high unmet medical need in patients with sRCC, and currently, very few compelling data. However, the data presented in this post hoc exploratory analysis of CheckMate 214 with an extended minimum follow-up of 42 months show that NIVO+IPI offers the potential to achieve durable responses and improved survival benefits over SUN, supporting this combination as a standard of care for first-line treatment in patients with clear cell sRCC and I/P-risk disease.
Written by: Nizar M. Tannir, MD, FACP, Professor, Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
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