With NIVO + IPI, Advanced RCC Survival Approaches 5 years

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 of the CheckMate 214 trial presented by Nizar Tannir, MD, FACP, at the 2021 International Kidney Cancer Symposium: North American.

The combination of nivolumab and ipilimumab (NIVO + IPI) replaced sunitinib (Sutent) as the standard of care for advanced RCC after data from the CheckMate 214 trial (NCT02231749) found that the combination demonstrated superior long-term survival benefits.

During the phase 3 CheckMate 214 trial, patients with previously untreated clear cell advanced RCC were randomized 1:1 to receive either the experimental combination or the monotherapy. Patients were stratified by geographic region and international Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk status. End points included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).

In the experimental cohort’s intent to treat population (n=550), the median age was 62 (range, 26-85) and 75% were male. Prognostic scores included favorable (23%), intermediate (61%), and poor (17%). Eleven percent received prior radiotherapy and 82% received prior nephrectomy. Seventy-eight percent 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 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.

In the intent-to-treat sunitinib cohort (n = 546), the median age was 62 (range, 38-81) and 73% were male. IMDC scores included favorable (23%), intermediate (61%), and poor (16%). Prior radiotherapy was seen in 13% of patients with prior nephrectomy in 80% of patients. Seventy-eight percent 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 lung (68%), lymph node (49%), bone (22%), and liver (20%). Quantifiable tumor PD-L1 expression of 1% or more was observed in 25% of patients.

In the patients with long-term survival treated with the experimental combination (n = 236), the median age was 61 (range, 34-81) and 73% were male. IMDC scores included favorable (29%), intermediate (61%), and poor (11%). Prior radiotherapy was seen in 8% of patients and prior nephrectomy in 85% of patients. Seventy percent 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 long-term survival treated with sunitinib (n = 171), the median age was 61 (range, 32-85), with 74% being male. IMDC scores included favorable (31%), intermediate (63%), and poor (5%). Prior radiotherapy was seen in 9% of patients and prior nephrectomy in 91% of patients. Sixty-nine percent 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.

In long-term survival patients who had intermediate or poor IMDC scores, 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 NIVO- IPI required subsequent systemic therapy compared with 78% of patients in the sunitinib arm.

The confirmed objective response rate (ORR) of patients treated with the combination was 61%. A complete response was seen in 24% of patients and a partial response in 38% of patients. Stable disease was seen in 33% of patients and progressive disease in 5% of patients. The median time to response 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%, with a complete response of 9%, and a partial response of 47%. Stable disease was seen in 32% of patients and progressive disease in 9%. The median time to response was 4 months and 59% were experiencing an ongoing response. Ninety-two percent of patients saw a reduction in tumor size with 42% seeing a reduction of 50% or more.

In patients with intermediate- or poor-risk scores, the ORR was 71% in the experimental cohort and 50% in the monotherapy cohort. Twenty-five percent of patients in the NIVO- IPI arm saw a complete response compared with 6% of patients in the sunitinib arm. Partial response rates were 46% and 44%, respectively. Stable disease was seen in 25% of patients and progressive disease was seen in 4% of patients in the combination arm. In the monotherapy arm, the stable disease rate was 34% and the progressive disease rate was 13%. In the combination arm, the median time to response was 2.8 months compared with 4 months in the monotherapy arm. In the NIVO- IPI 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% compared with 66% in the monotherapy arm. A complete response was seen in 22% of patients in the experimental arm and 14% of patients in the sunitinib arm. Partial responses were seen in 19% and 53% of patients respectively. Stable disease was observed in 52% of patients in the combination arm and 27% of patients in the monotherapy arm, with progressive disease in 7% of patients in the experimental arm and 3% of patients in the control arm. The median time to response was 2.8 months with NIVO- IPI 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% of patients experiencing a reduction of 50% or more.

In terms of safety, more long-term responders in the NIVO- IPI arm experienced a treatment disruption than with sunitinib. Fifty-four percent of patients with an intermediate- or poor-risk scores experienced a disruption in the experimental arm compared with 14% of patients in 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 the monotherapy in patients with an intermediate- or poor-risk score. For patients with a favorable-risk score, the median disruption was 59 months (range, 7-68) with the combination versus 47 months (range, 4-62), with the monotherapy.

Patients with long-term survival received an average of 41 doses (range, 1-154) of nivolumab and 4 doses of ipilimumab (range, 1-4). Patients in the overall study population received an average of 14 doses (range, 1-154) of nivolumab and 4 doses of ipilimumab (range, 1-4). Seventy-nine percent 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 NIVO- IPI include skin (61%), endocrine (39%), gastrointestinal (36%), hepatic (22%), renal (12%), and pulmonary (10%). Eleven percent 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%). Fifteen percent 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 combination arm versus 13% of patients in the monotherapy arm. For patients with long-term survival, a treatment-related AE lead to discontinuation in 28% and 16% of patients, respectively.

_REFERENCE:

_{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 the International Kidney Cancer Symposium: North America. November 5-6, 2021; Austin, TX.}