With Nivolumab/Ipilimumab, Advanced RCC Survival Approaches 5 Years

Nizar Tannir, MD, FACP

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}