Adjuvant Pembrolizumab After Nephrectomy for Renal Cell Carcinoma

In the era of immunotherapy, it is unfortunate that patients with higher risk renal cell carcinoma (RCC) have limited adjuvant therapeutic options. According to a recent seminal report published in The New England Journal of Medicine, immunotherapy is becoming an important tool in the treatment armamentarium and has the potential to improve cancer-specific survival when used as an adjuvant to surgery for specific patients with RCC.¹

This report is important because, until this point, the large studies that evaluated adjuvant therapy after surgical resection held conflicting evidence. The S-TRAC study evaluating sunitinib showed an improvement in disease-free survival (DFS), whereas the ASSURE trial evaluating sunitinib or sorafenib did not indicate similar DFS improvement. Although the findings of the S-TRAC study led to the approval of sunitinib use in the adjuvant setting for patients with RCC, sunitinib has not been globally accepted in this setting because of conflicting results seen in the ASSURE trial and the significant adverse events (AEs) associated with this chemotherapeutic agent. The KEYNOTE-564 randomized controlled clinical trial looked at the immunotherapeutic agent pembrolizumab (PEMBRO), a programmed death-1 inhibitor that has been evaluated in several other metastatic cancers.

Adjuvant Pembrolizumab in Keynote-564 Clinical Trial

Surgical resection is the standard of care for the treatment of patients with renal cell carcinoma.² Approximately 50% of patients who undergo surgical resection will have recurrence. There are specific risk factors that put an individual at high risk for recurrence and development of metastatic disease, including:

• tumor stage 2 with nuclear grade 4 or sarcomatoid differentiation
• tumor stage 3 or higher
• regional lymph-node metastasis
• oligometastatic disease that was completely resected at the time of partial or radical nephrectomy (M1 no evidence of disease [NED]).³

This patient population with intermediate-to-high or high risk for disease recurrence was the target population in the KEYNOTE-564 study. Criteria for participation included having undergone either partial or radical surgery (and, in the case of M1 NED patients, complete metastatectomy) with negative surgical margins. The study considered patients’ level of functionality as determined by the Eastern Cooperative Oncology Group (ECOG) performance status score.

Patients either received PEMBRO 200 mg or saline placebo intravenously every 3 weeks for a maximum of 17 cycles, which corresponded to ~1 year of treatments. Reasons for stopping treatments early included evidence of disease recurrence, medication-specific toxicity that was unacceptable, intercurrent illness preventing administration of the drug, decision by the investigator, development of a new cancer requiring treatment, pregnancy, or nonadherence to the protocol.

The primary study endpoint was DFS from the time of randomization to the time of documented local or distant recurrence or death due to any cause. Secondary endpoints included overall survival (OS) from time of randomization, safety, and patient-reported outcomes, which were measures using the Functional Assessment of Cancer Therapy Kidney Symptom Index–Disease-Related Symptoms (FKSI-DRS) tool and the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30).

The study enrolled patients from June 2017 to September 2019. Approximately 1400 patients were screened, and 412 were excluded for not meeting study criteria. A total of 994 patients were randomized to either the PEMBRO arm (n=496) or the placebo arm (n=498). Patient characteristics were similar between the 2 arms. There were 5.8% of patients with M1 NED in each of the trial arms.

In the PEMBRO arm, 61.1% of patients completed the full 17 cycles of treatment; for the 40% who did not, the most common reasons were AEs (21.3%) or disease recurrence (10.5%). This was in contrast to the placebo arm, where more patients completed the treatment regimen (73.6%); of the 26.2% who did not finish, the most common reason was disease recurrence (20.4%). Patients in the PEMBRO arm who discontinued completed a median of 7 treatment cycles for a median exposure time of nearly 4.5 months.

Results on Adjuvant Pembrolizumab for Renal Cell Carcinoma

The study boasted significant efficacy when compared to the placebo, with a 32% lower risk of disease recurrence or death in the PEMBRO arm. The estimated percentage of patients alive and recurrence free at the 2-year timepoint was 77.3% with PEMBRO compared with 68.1% in the placebo arm. Local recurrence was seen in 3.4% of patients in the PEMBRO arm versus 6.4% in the placebo arm. The trend was similar for distant recurrence rates (17.3% for PEMBRO vs 23.5% for placebo). A total of 51 deaths occurred during the study time period, with 18 in the PEMBRO arm and 33 in the placebo arm. The OS endpoints were not reached.

The safety report indicated that AEs of any degree were similar in both arms (96.3% for PEMBRO vs 91.1% for placebo). However, when comparing results for grade 3–5 AEs, the rate in the PEMBRO arm was twice that in the placebo arm (32.4% vs 17.7%). Additionally, 80% of patients in the treatment arm had an AE attributed to PEMBRO, compared with 53.4% in the placebo arm, and 18.9% of these patients in the PEMBRO had a grade 3 or 4 AE, compared with 1.2% in the placebo arm. Certain AEs, such as fatigue, diarrhea, and arthralgia, were seen in both groups, but patients receiving PEMBRO were more likely to experience thyroid dysfunction (both hypo- and hyperthyroidism), pruritus, and rash. In all, 20% of patients discontinued PEMBRO because of AEs, compared with 2% in the placebo arm; additionally, ~25% of patients in the PEMBRO arm had a dosage change owing to an AE. No deaths were attributed to either the treatment or placebo used in the study, although there were 2 deaths in the PEMBRO arm and 1 death in the placebo arm. Immune-mediated AEs were seen in 34.6% of patients receiving PEMBRO, 8.6% of which were of grade 3 or 4 severity. Glucocorticoid therapy was administered to 7.4% of patients.

The investigators concluded that the initial analysis of KEYNOTE-564 offers significant evidence that the use of adjuvant immunotherapy, specifically PEMBRO, portends improved DFS results, compared with placebo, in patients after surgery for intermediate- to high-risk RCC or M1 NED, although the M1 NED group was a small sample size. The safety profile for PEMBRO was similar to those previously seen with the use of immunotherapy; results were therefore expected and, for the most part, manageable.

Additionally, patient quality of life and symptom scores were not meaningfully different with PEMBRO compared to placebo. The authors concluded, “The results of this phase 3 trial support the use of [PEMBRO] as adjuvant immunotherapy in patients with [RCC] and an intermediate-to-high or high risk of disease recurrence.” Longer follow-up is needed to continue evaluating the benefit of adjuvant therapy in this patient population.

In the comments following publication of the report, some correspondents questioned the 1-year length of adjuvant therapy⁴ and noted that there are several studies looking at other immunotherapy agents, such as nivolumab⁵ or nivolumab plus ipilimumab,⁶ with shorter treatment durations. One correspondent cautioned about the rate of AEs, and specifically serious AEs, that can occur with immunotherapy.⁷ In an expert opinion piece published in European Urology, Magee and Kutikov questioned whether the AE profile of immunotherapy—including events seen and not seen in KEYNOTE-564—coupled with the significant economic cost of PEMBRO is “worth the squeeze,” and contended that the data should be considered premature until further studies evaluating OS are conducted.⁸

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology. 

References

1. Choueiri TK, Tomczak P, Park SH, et al; for the KEYNOTE-564 Investigators. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391
2. National Comprehensive Cancer Networkâ. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelinesâ). Version 4.2022. Published December 21, 2021. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf
3. Correa AF, Jegede O, Haas NB, et al. Predicting renal cancer recurrence: defining limitations of existing prognostic models with prospective trial-based validation. J Clin Oncol. 2019;37(23):2062-2071. doi:10.1200/JCO.19.00107
4. Sharma A, Sahoo RK, Batra A. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(20):1919. doi:10.1056/NEJMc2115204
5. Harshman LC, Pullgandla M, Haas NB, et al; for the PROSPER RCC PROSPER: a phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients with localized renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN 8143). J Clin Oncol. 2019;37(7 suppl); abstract TPS684. doi:10.1200/JCO.2019.37.7_suppl.TPS684
6. Bex A, Russo P, Tomita Y, et al. A phase III, randomized, placebo-controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (CheckMate 914). J Clin Oncol. 2020;38(15 suppl); abstract TPS5009. doi:10.1200/JCO.2020.38.15_suppl.TPS5099
7. Bleyer A. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(20):1919-1920. doi:10.1056/NEJMc2115204
8. Magee DE, Kutikov A. Re: Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. Eur Urol. 2022;81(3):317-318. doi:10.1016/j.eururo.2021.11.026