With Nivolumab/Ipilimumab, Advanced RCC Survival Approaches 5 Years

Supplement, Meeting Spolight: 2021 International Kidney Cancer Symposium,
Pages: 3

First-line nivolumab (Opdivo) plus ipilimumab (Yervoy) produced a long-term survival of 5 years in some patients with advanced renal cell carcinoma (RCC), according to a poster on long-term data from the phase 3 CheckMate 214 trial (NCT02231749) presented by Nizar Tannir, MD, FACP, at the 2021 International Kidney Cancer Symposium.1 The combination replaced sunitinib (Sutent) as the standard of care for advanced RCC after the combination demonstrated superior long-term survival benefits in the trial.

During CheckMate 214, patients with previously untreated, advanced clear cell RCC were randomized 1:1 to receive either the experimental combination or the monotherapy. Patients were stratified by geographic region and International Metastatic RCC Database Consortium (IMDC) risk status. End points included overall survival, progression-free survival, and objective response rate (ORR).2

In the experimental cohort’s intention-to-treat population (ITT; n = 550), the median age was 62 (range, 26-85) and 75% of patients were male. Prognostic scores were favorable for 23% of patients, intermediate for 61%, and poor for 17%. There were 11% of patients who had received prior radiotherapy and 82% who had undergone prior nephrectomy. Moreover, 78% of patients had 2 or more target or nontarget lesions with the median sum of reference diameters for target lesions being 65.5 mm (range, 10-357). Sites of metastasis included the lung (69%), lymph node (45%), bone (20%), and liver (18%). Less than 1% of quantifiable tumor PD-L1 expression was seen in 77% of patients.1

In the ITT sunitinib group (n = 546), the median age was 62 (range, 38-81) and 73% were male. IMDC scores were favorable in 23% of patients, intermediate in 61%, and poor in 16%. Prior radiotherapy was seen in 13% of patients, with prior nephrectomy in 80% of patients. Additionally, 78% of patients had 2 or more target or nontarget lesions with the median sum of reference diameter being 63 mm (range, 10-359). Sites of metastases included the lung (68%), lymph node (49%), bone (22%), and liver (20%). Quantifiable tumor PD-L1 expression of 1% or less was observed in 75% of patients.

In the patients with long-term survival who were treated with the experimental combination (n = 236), the median age was 61 (range, 34-81) and 73% were male. IMDC scores were favorable in 29% of patients, intermediate in 61%, and poor in 11%. Prior radiotherapy was seen in 8% of patients and prior nephrectomy in 85% of patients. Additionally, 70% of patients had 2 or more target or nontarget lesions with the median sum of reference diameter being 50.5 mm (range, 10-276). Sites of metastasis included lung (69%), lymph node (41%), bone (11%), and liver (13%). Quantifiable tumor PD-L1 expression of 1% or more was seen in 24% of patients.

In patients treated with sunitinib who achieved long-term survival (n = 171), the median age was 61 (range, 32-85), with 74% being male. IMDC scores were favorable in 31% of patients, intermediate in 63%, and poor in 5%. Prior radiotherapy was reported in 9% of patients and prior nephrectomy in 91%. Additionally, 69% of patients had 2 or more target or nontarget lesions with the median sum of reference diameter being 48 mm (range, 10-283). Sites of metastases included lung (62%), lymph node (45%), bone (11%), and liver (16%). Quantifiable tumor PD-L1 expression of 1% or more was seen in 22% of patients.

At the 5-year follow-up, 14% of patients in the combination arm and 5% of patients in the monotherapy arm remained on treatment. Baseline characteristics of patients with long-term survival did not set them apart from the general patients, with the exception that these patients had lower target lesion burden at baseline and a smaller proportion of them had 2 or more target lesions.

Efficacy

In patients who had intermediate or poor IMDC scores who achieved long-term survival, 39% of patients in the combination arm required further systemic therapy compared with 75% of patients in the monotherapy arm. For patients who had a favorable-risk score, further systemic therapy was needed for 68% of patients in the experimental arm and 83% of patients in the sunitinib arm. In the overall long-term survival population, 48% of patients in the nivolumab/ipilimumab arm required subsequent systemic therapy compared with 78% of patients in the sunitinib arm.

The confirmed ORR of patients treated with the combination was 61% (95% CI, 55%-68%). A complete response (CR) was seen in 24% of patients and a partial response (PR) in 38%. Stable disease (SD) was seen in 33% of patients and progressive disease (PD) in 5% of patients. The median time to response (TTR) was 2.8 months and 77% were experiencing an ongoing response. Any tumor size reduction was seen in 86% of patients, with 61% of patients experiencing a reduction of 50% or more.

The confirmed ORR of patients in the sunitinib arm was 56% (95% CI, 48%-63%), with a CR rate of 9% and a PR of 47%. SD was seen in 32% of patients and PD in 9%. The median TTR was 4.0 months and 59% were experiencing an ongoing response. Additionally, 92% of patients saw a reduction in tumor size with 42% seeing a reduction of 50% or more.

In patients with intermediate-risk or poor-risk scores, the ORR was 71% (95% CI, 63%-77%) in the experimental cohort and 50% (95% CI, 40%-60%) in the monotherapy cohort. Additionally, 25% of patients in the nivolumab/ipilimumab arm had a CR compared with 6% of patients in the sunitinib arm. PRs were 46% and 44%, respectively. SD was seen in 25% of patients and PD was seen in 4% of patients in the combination arm. In the monotherapy arm, the SD rate was 34% and the PD rate was 13%. In the combination arm, the median TTR was 2.8 months compared with 4 months in the monotherapy arm. In the nivolumab/ipilimumab arm, an ongoing response was seen in 80% of patients compared with 55% of patients in the sunitinib arm. A reduction in tumor size of 50% or more was seen in 71% of patients in the combination arm and 37% of patients in the monotherapy arm. Any tumor reduction was seen in 87% of patients in the combination arm and 89% of patients in the monotherapy arm.

In patients with a favorable-risk score, the confirmed ORR of the combination arm was 41% (95% CI, 30%-53%) compared with 66% (95% CI, 53%-78%) in the monotherapy arm. A CR was seen in 22% of patients in the experimental arm and 14% in the sunitinib arm. PRs were seen in 19% and 53% of patients, respectively. SD was observed in 52% of patients in the combination arm and 27% in the monotherapy arm, with PD in 7% of patients in the experimental arm and 3% in the control arm. The median TTR was 2.8 months with nivolumab/ipilimumab and 4.2 months with sunitinib. An ongoing response was observed in 67% and 64% of patients, respectively. In the experimental arm, any reduction in tumor size was seen in 82% of patients, with a reduction of 50% or more in 40% of patients. In the control arm, any reduction was seen in 98% of patients, with 52% experiencing a reduction of 50% or more.

Across all patients with long-term survival and in all risk groups, the median duration of response was not reached with nivolumab and ipilimumab treatment vs 38.7 months (95% CI, 26.3-60.4) with sunitinib for all patients, 23.5 months (95% CI, 18.2-60.4) in those with intermediate-risk or poor-risk RCC, and 51.4 months (95% CI, 33.2–not evaluable) in those with favorable-risk disease.

Safety

More long-term responders in the nivolumab/ipilimumab arm experienced a treatment disruption than with sunitinib. A total of 54% of patients with intermediate- or poor-risk scores experienced a disruption in the experimental arm compared with 14% of patients in the control arm. In patients with a favorable score, disruptions were seen in 43% and 19% of patients, respectively. The median treatment-free interval was 42 months (range, 4-68) with the combination and 43 months (range, 16-60) with sunitinib in patients with intermediate/ poor risk. For patients with a favorable-risk score, the median disruption was 59 months (range, 7-68) with the combination vs 47 months (range, 4-62) with sunitinib.

Patients with long-term survival received an average of 41 doses (range, 1-154) of nivolumab and 4 doses (range, 1-4) of ipilimumab. Patients in the overall study population received an average of 14 doses (range, 1-154) of nivolumab and 4 doses (range, 1-4) of ipilimumab. Additionally, 79% of patients in the overall population and 88% of patients in the long-term survival cohort received 4 doses of ipilimumab.

Any-grade adverse events (AEs) seen in the long-term survival population treated with nivolumab plus ipilimumab included skin (61%), endocrine (39%), gastrointestinal (36%), hepatic (22%), renal (12%), and pulmonary (10%). Also, 11% of patients in this cohort experienced a grade 3/4 hepatic AE.

In patients treated with sunitinib, any-grade AEs included skin (74%), endocrine (39%), gastrointestinal (64%), hepatic (18%), renal (9%), and pulmonary (1%). Also, 15% of patients experienced a grade 3/4 skin-related AE.

In the overall study population, a treatment-related AE led to a discontinuation of 23% of patients in the combination arm vs 13% of patients in the monotherapy arm. For patients with long-term survival, a treatment-related AE led to discontinuation in 28% and 16% of patients, respectively.

REFERENCES:


1. Tannir N, Motzer R, McDermott D, et al. First-line nivolumab plus ipilimumab versus sunitinib in patients with long-term survival of ≥ 5 years in the CheckMate 214 trial. Presented at: 2021 International Kidney Cancer Symposium: North America; November 5-6, 2021; Austin, TX. Abstract CTR11.

2. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126