Post-Hoc Analysis Supports Adjuvant Pembrolizumab in ccRCC at Increased Risk of Recurrence

Adjuvant pembrolizumab prolonged disease-free survival (DFS) and distant metastasis–free survival (DMFS) vs placebo in patients with clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence after nephrectomy, irrespective of UCLA Integrated Staging System (UISS) risk category and disease stage, according to data from a post-hoc analysis of the phase 3 KEYNOTE-564 trial (NCT03142334).¹

Data presented at the 2023 Genitourinary Cancers Symposium showed that patients with UISS intermediate-risk disease who received pembrolizumab (n = 359) experienced a 24-month DFS rate of 81.5% compared with 72.4% for those given placebo (n = 373). The median DFS was not yet reached (NR) in both groups (HR for pembrolizumab vs placebo, 0.65; 95% CI, 0.48-0.88).

In the UISS high-risk group, the 24-month DFS rate was 65.0% in patients treated with pembrolizumab (n = 100) and 55.9% in those who received placebo (n = 95). The median DFS was NR (95% CI, 25.8-NR) in the pembrolizumab group vs 40.5 months (95% CI, 19.4-NR) in the placebo group (HR, 0.77; 95% CI, 0.49-1.20). For patients who were M1 with no evidence of disease (NED), the 24-month DFS rate was 78.4% for those given pembrolizumab (n = 29), compared with 37.9% for those given placebo (n = 29). The median DFS was NR (95% CI, 25.7-NR) with pembrolizumab vs 11.6 months (95% CI, 5.6-NR) with placebo (HR, 0.28; 95% CI, 0.12-0.66).

DFS benefit with pembrolizumab over placebo was observed in subgroups of patients with American Joint Committee on Cancer (AJCC) stage 2 disease (HR, 0.74; 95% CI, 0.30-1.83), stage 3 disease (HR, 0.67; 95% CI, 0.52-0.88), and stage 4 disease (HR, 0.37; 95% CI, 0.19-0.74).

Moreover, DMFS favored pembrolizumab vs placebo in the intent-to-treat population (HR, 0.63; 95% CI, 0.49-0.82), and that benefit was observed across subgroups, including those with UISS intermediate-risk disease (HR, 0.65; 95% CI, 0.47-0.88), high-risk disease (HR, 0.79; 95% CI, 0.49-1.26), and M1 NED (HR, 0.28; 95% CI, 0.11-0.73). This was also observed in those with AJCC stage 2 disease (HR, 0.67; 95% CI, 0.26-1.69), stage 3 disease (HR, 0.68; 95% CI, 0.51-0.89), and stage 4 disease (HR, 0.42; 95% CI, 0.20-0.87).

“Results of this exploratory analysis further support the use of adjuvant pembrolizumab after nephrectomy as standard of care for patients with RCC at increased risk of recurrence,” lead study author Toni Choueiri, MD, and colleagues, wrote in a poster presentation of the data. Choueiri is the director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and a senior physician at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

In November 2021, the FDA approved pembrolizumab for the adjuvant treatment of patients with RCC who are at intermediate-high or high risk of recurrence following nephrectomy, or after nephrectomy and resection of metastatic lesions.² The regulatory decision was based on previously reported data from an interim analysis of KEYNOTE-564, which showed that pembrolizumab provided a statistically significant improvement in DFS vs placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .0010).

Updated data from the study showed that at a median follow-up of 30.1 months, pembrolizumab maintained a DFS benefit vs placebo (HR, 0.63; 95% CI, 0.50-0.80).³

The phase 3 study enrolled patients with histologically confirmed ccRCC who received no prior systemic therapy for their disease and had an ECOG performance status of 0 or 1. Moreover, following nephrectomy, patients needed to be intermediate-high risk or high risk for recurrence, or be M1 NED after nephrectomy and complete resection of metastasis.

Patients were randomly assigned in a 1:1 fashion to receive intravenous (IV) pembrolizumab at 200 mg once every 3 weeks (n = 496) or IV placebo once every 3 weeks (n = 498) for up to 17 cycles.

M1 NED vs M0 served as a key stratification factor. Within those who were M0, patients were further stratified by ECOG performance status (0 vs 1) and whether they resided in the United States (yes vs no).

UISS risk groups were derived retrospectively from Fuhrman nuclear grade, ECOG performance status, and TNM status which comprises the size of the tumor (T), involvement of the lymph nodes (N), and presence of metastases (M). Other subgroups were evaluated based on AJCC disease stage, which classifies cancers by TNM status and Fuhrman nuclear grade.

The exploratory end points of the post-hoc analysis included DFS and DMFS in subgroups defined by UISS and TNM disease stage. DFS and DMFS were estimated utilizing the Kaplan-Meier method, and hazard ratios and confidence intervals were estimated by leveraging a Cox proportional hazards model with the Efron method of handling ties. Treatment group served as a covariate.

The analysis had a data cutoff date of June 14, 2021 and a median follow-up of 30.1 months (range, 20.8-47.5).

In evaluable patients treated with pembrolizumab (n = 488), 73.6% were UISS intermediate risk, 20.5% were high risk, and 5.9% were M1 NED. Among evaluable patients treated with placebo (n = 497), 75.1% were UISS intermediate risk, 19.1% were high risk, and 5.8% were M1 NED.

In patients evaluable for AJCC disease stage in the pembrolizumab arm (n = 495), 4.4% were AJCC stage 2, 87.3% were stage 3, and 8.3% were stage 4. Among evaluable patients given placebo (n = 498), the rates of those with AJCC stage 2, stage 3, and stage 4 disease were 3.8%, 88.0%, and 8.2%, respectively.

Regarding population distribution of TNM status and Fuhrman nuclear grade for evaluable patients in the pembrolizumab arm (n = 488), 33.0% were T2, G4, N0, M0 and T3, G1-2, N0, M0; 52.9% were T3, G3-4, N0, M0; 2.3% were T4, N0, M0; 5.9% were N1, M0; and 5.9% were M1 NED. In evaluable patients from the placebo arm (n = 497), these rates were 33.6%, 53.3%, 2.2%, 5.0%, and 5.8%, respectively.

In the pembrolizumab-treated patients who were UISS intermediate risk, high risk, and M1 NED, the median ages were 58 years (27-81), 64 years (range, 29-81), and 61 years (range, 45-79), respectively. Most patients evaluated in each subset were male. An ECOG performance status of 0 was observed in 99.4%, 34.0%, and 79.3% of patients, respectively; 91.6%, 96%, and 93.1% of patients, respectively, had a radical nephrectomy.

The primary tumor site in the pembrolizumab-treated patients with UISS intermediate-risk disease was T2 (4.5%) and T3 (95.5%). Those in the high-risk subgroup had primary tumor sites of T1 (4.0%), T2 (4.0%), T3 (80.0%), and T4 (12.0%); in the M1 NED subgroup, these rates were 20.7%, 3.4%, 69.0%, and 6.9%, respectively. Across the UISS intermediate-risk, the high-risk, and M1 NED subgroups, tumor grades included grade 1 (5.0%; 0%; 3.4%, respectively), grade 2 (30.1%; 32.0%; 37.9%), grade 3 (44.3%; 45.0%; 37.9%), and grade 4 (20.6%; 23.0%; 17.2%). Notably, tumor grade information was missing for 1 patient in the M1 NED group. Lymph node stages were N0 (100.0%; 71.0%; 93.1%) and N1 (0%, 29.0%; 6.9%).

In patients treated with placebo who were UISS intermediate risk, high risk, and M1 NED, the median ages were 59 years (range, 25-81), 64 years (range, 30-84), and 57 years (range, 30-77), respectively. Again, the majority of patients in all subgroups were male. An ECOG performance status of 0 was reported in 99.2%, 32.6%, and 82.8% of patients, respectively, and 91.2%, 96.8%, and 93.1% had a radical nephrectomy.

The primary tumor sites in the placebo-treated UISS intermediate-risk subgroup were T2 (4.8%) and T3 (95.2%). In the high-risk subgroup, primary tumor sites included T1 (5.3%), T2 (3.2%), T3 (78.9%), and T4 (12.6%); and T1 (34.5%), T2, (37.9%), T3 (24.1%), and T4 (3.4%) in the M1 NED subgroup. In the UISS intermediate-risk, high-risk, and M1 NED groups, primary tumor grades included grade 1 (4.3%; 0%; 0%, respectively), grade 2 (29.8%; 29.5%; 37.9%), grade 3 (42.1%; 42.1%; 51.7%), and grade 4 (23.9%; 28.4%; 10.3%). Lymph node stages were N0 (100.0%; 73.7%; 79.3%) and N1 (0%, 26.3%; 20.7%).

Additional data showed that DFS and DMFS benefits with the immunotherapy over placebo were observed across TNM and Fuhrman nuclear grade subgroups.

“No formal statistical testing was conducted for this post-hoc analysis, and results should be interpreted with caution due to the small sample size of some subgroups,” Choueiri and colleagues concluded.

References

1. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab (pembro) for renal cell carcinoma (RCC) across UCLA Integrated Staging System (UISS) risk groups and disease stage: Subgroup analyses from the KEYNOTE-564. J Clin Oncol. 2023;41(suppl 6):604. doi:10.1200/JCO.2023.41.6_suppl.679.
2. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed April 13, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma
3. Powles T, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23(9):1133-1144. doi:10.1016/S1470-2045(22)00487-9