Determining the Optimal Use of Adjuvant Immunotherapy in Renal Cell Carcinoma

Benjamin Garmezy, MD

Kidney and renal pelvis cancers are one of the 10 most common new malignant diagnoses in both men and women in the United States, with an estimated 52,360 new cases in men and 29,440 new cases in women per year.¹ Renal cell carcinoma (RCC) is the most common malignancy of the kidney and globally accounts for approximately 2% of cancer diagnoses and deaths.²

Five-year survival is dependent on stage at diagnosis: 93% for stage I, 72.5% for stage II/III, and 12% for stage IV metastatic disease.³ Approximately two-thirds of patients are diagnosed with localized disease, and an additional third will progress after curative-intent surgery, including up to half of patients with high-risk disease.⁴ Seventy-five percent of patients have clear cell histology (ccRCC), 10% to 15% have papillary, 5% have chromophobe histology, and the additional patients have even more rare subtypes such as translocation or renal medullary carcinoma.³

For patients with localized disease, partial or radical nephrectomy is the standard of care for most, and surveillance or ablation can be considered in a subset of patients with stage I disease.^5,6 Given the high recurrence rate after curative-intent therapy, perioperative therapy has been studied to improve upon patient outcomes.

The 2 major classes of therapeutics used in RCC included immune checkpoint inhibitors and vascular endothelial growth factor (VEGF)-targeting tyrosine kinase inhibitors (TKIs). In 2017, the FDA approved sunitinib (Sutent), a multitargeted TKI, as the first adjuvant therapy based upon data from the S-TRAC trial (NCT00375674). This phase 3 trial randomized patients to post-nephrectomy to 1 year of treatment with sunitinib vs placebo. Median duration of disease-free survival (DFS) was 6.8 years vs 5.6 years (HR 0.76; P = .03).⁷ However, updated data indicated no significant difference in median overall survival (OS, not reached (NR) vs NR; HR, 0.92; 95% CI, 0.66-1.28; P = .6) and therefore this treatment option has not been widely adopted due to significant increase in toxicity with sunitinib relative to placebo.⁸ Other TKIs have been studied in this setting and none have shown a clinically significant benefit, including a trial comparing sunitinib and sorafenib (ASSURE; NCT00326898)⁹, an additional trial with sorafenib (SORCE)¹⁰, pazopanib (Votrient; PROTECT [NCT01235962])¹¹, and axitinib (Inlyta; ATLAS [NCT01599754]).¹²

Following the failure of TKIs in the adjuvant setting, pembrolizumab (Keytruda) was studied in the phase 3 KEYNOTE-564 trial (NCT03142334), randomizing 994 patients 1:1 to 1 year of adjuvant immunotherapy vs placebo.¹³ Inclusion criteria comprised patients with a clear-cell component and met criteria for a high risk of recurrence (pT2 with nuclear grade 4 or sarcomatoid differentiation, pT3+, pTanyN+, or M1 NED post completely resected metastatic disease within 1 year of nephrectomy). Patients in the investigational arm received pembrolizumab 200 mg every 3 weeks for up to 17 cycles.

Results showed that disease-free survival (DFS) was significantly longer in patients who received pembrolizumab, with 24-month DFS rates at 77.3% with pembrolizumab vs 68.1% with placebo (HR, 0.68, P = .002). Unsurprisingly, DFS benefit was greatest in patients with M1 NED status at study enrollment (HR, 0.29; 95% CI, 0.12-0.69) and otherwise was generally consistent across subgroups.

Important to note, approximately 90% of the patients enrolled in the trial had pT3 disease, 10% had sarcomatoid features, 6% had node-positive disease, and 6% had M1 no evidence of disease.

Safety was consistent with the known profile of pembrolizumab and grade 3 or higher adverse events were seen in 32.4% of patients who received pembrolizumab compared with 17.7% in the control arm. At the first interim analysis, with a median follow up of 30.1 months, the updated median DFS remained not reached (NR) vs NR, but the hazard ratio (HR) decreased to 0.63 (95% CI, 0.50-0.80),¹⁴ similar in patients regardless of PD-L1 status. OS data remain immature but there is a trend toward benefit with pembrolizumab compared with placebo (HR, 0.52; 95% CI 0.31-0.86). At 30 months, an estimated 95.7% of patients who received pembrolizumab were alive compared with 91.4% in the group that received placebo.

While the KEYNOTE-564 data were impressive, additional recent perioperative immunotherapy trials presented at the 2022 ESMO Congress have complicated the treatment landscape. The phase 3 IMotion010 study (NCT03024996) enrolled a similar patient population and randomized them 1:1 to receive atezolizumab (Tecentriq) vs placebo for 1-year post nephrectomy with or without metastasectomy.¹⁵ The median investigator-assessed DFS was 57.2 vs 49.5 months (HR, 0.93; 95% CI, 0.75-1.15; P = .50). There were no clear subgroups of patients who benefited from therapy and, of note, the HR for M1 NED patients was 0.93 (95% CI, 0.58-1.49). OS remains immature but there is no current signal of benefit, with a HR of 0.97 for reduced risk of death and 3-year OS rate of 90.3% vs 89.8% with placebo.

The CheckMate 914 trial (NCT03138512) randomized patients with localized RCC to nivolumab/ipilimumab vs placebo (part A) and nivolumab monotherapy vs placebo (part B).¹⁶ The median DFS was not statistically significant at NR vs 50.7 months (HR, 0.93; 95% CI 0.72-1.20; P = .57). One subgroup that appeared to have more benefit were patients with sarcomatoid features, though this only represented a small fraction of the patients enrolled on the study (HR, 0.29; 95% CI, 0.09-0.91). Of note, treatment-related adverse events led to the discontinuation of nivolumab/ipilimumab in 29% of patients.

PROSPER (NCT03055013) enrolled patients in a different phase 3 trial design, where 819 patients were randomized to perioperative nivolumab vs surgery alone. However, 1 dose of nivolumab was given prior to surgery followed by 9 adjuvant doses (480 mg intravenously every 4 weeks).¹⁶ Enrolled patients included 53% of those with cT2 disease, 47% disease had cT3/4, 17% N+, and 4% cM1; 83% of patients had clear cell histology. The trial was stopped early by the Data Safety and Monitoring Board due to futility for recurrence-free survival (RFS; HR, 0.97; P = .43). OS data remain immature but there was no indication of benefit (HR, 1.48; 95% CI, 0.89-2.48; P = .93). 

With 1 positive study and 3 negative studies, clinical decision making has become more complicated. There are concerns that PD-1/PD-L1 inhibitors have different activity in RCC, potentially explaining the negative IMmotion010 data. PD-1 and PD-L1 have differential expression in cells in the tumor microenvironment and PD-1 inhibitors also inhibit PD-L2 with potential for different immunomodulation.^17,18

Nevertheless, pembrolizumab and nivolumab are both PD-1 inhibitors and therefore theoretically have similar activity. It is possible that discontinuation in CheckMate 914 due to increased toxicity from an immunotherapy doublet may have influenced the results. Patients had a median duration of treatment of 5.1 months and were only scheduled for 6 months due to potential toxicity concerns, whereas in KEYNOTE-564 with pembrolizumab patients had a median duration of treatment of 11.1 months.¹⁴

In addition, M1 NED patients were not included. PROSPER, in the perioperative RCC setting, was a different trial design. There was an unfortunate amount of dropout, patients lost to follow-up, and approximately 20% of patients had no clear cell histology. While data from all of these trials can be “explained” relative to the KEYNOTE-564 trial with adjuvant pembrolizumab, there are a concerning number of negative trials relative to 1 positive trial in the perioperative RCC setting.

Group B of CheckMate 914 with single-agent nivolumab vs placebo has completed enrollment. These pending data will be important as well, though patients were only treated for a planned 6 months of therapy instead of 1 year.

In conclusion, patients with RCC with a clear cell component on histology at high-risk of recurrence should be considered for 1 year of adjuvant pembrolizumab after discussion of risks and benefits with each individual patient. More data are needed to clarify which subgroups derive the most benefit, and additional trials are warranted to study the non-clear cell patient population before adjuvant therapy is deployed for variant disease.

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