Pembrolizumab outperforms tyrosine kinase inhibitors in the adjuvant therapy of patients with high-risk renal cell carcinoma

Despite radical nephrectomy for non-metastatic renal cell carcinoma (RCC), up to 40% of patients experience disease relapse.¹ Adjuvant systemic therapy, however, has been not widely used to reduce this risk.^2,3 Despite the benefit of tyrosine kinase inhibitors (TKIs) as systemic therapy for metastatic RCC, the data on their efficacy in the adjuvant setting for non-metastatic RCC remains controversial, atbest.^4-10 The lack of significant survival benefits along with the significant side effect profile of TKIs poses a challenge to their use inthe adjuvant setting (i.e., overtreatment risk and limited tolerability).^5,11

Recently, immune checkpoint inhibitor (ICI) therapies have been tested and approved in the metastatic RCC setting.^12,13 Given their favorable adverse event (AEs) profile, they have been tested in the adjuvant setting in patients of increased risk for relapse after nephrectomy in the first phase III randomized clinical trial KEYNOTE-564 (pembrolizumab).¹⁴ Given the lack of data on risk/benefit comparison of ICIs and TKIs in adjuvant RCC setting, we performed a systematic review and network meta-analysis (NMA) of phase III RCTs to compare the oncologic and toxicity outcomes of adjuvant ICIs and TKIs in post-nephrectomy patients with localized and locally advanced RCC.¹⁵ Six trials (KEYNOTE-564, S-TRAC, ASSURE, PROTECT, ATLAS, and SORCE) were included in our analysis (Tab. 1).

Tab. 1:Characteristics of included phase III randomized control trials of adjuvant therapies in patients with localized and locally advanced renal cell carcinoma after nephrectomy.

Results and interpretation

We found that in surgically treated RCC patients with a curative intent adjuvant pembrolizumab was the most effective treatment with regards to both disease-free survival (DFS) and overall survival (OS) compared with adjuvant TKIs and placebo. Pembrolizumab was also scored the best tolerated drug and the drug with the least serious adverse events (AEs grade ≥3; Fig.1).

Fig. 1:Pembrolizumab was the best tolerated drug and the drug with the least serious adverse events

Despite the superior outcomes achieved with adjuvant pembrolizumab, these results should be interpreted with caution due to several factors. In contrast to TKIs studies, the KEYNOTE-564 trial included along with intermediate- and high-risk patients also those who developed metastasis within a year after radical nephrectomy and those who underwent metastasectomy. Hence, the KEYNOTE-564 trial patient population is highly heterogeneous with an enrichment for patients of highest risk for recurrence (i.e., ranging from 20% to 80%).¹⁶ Nevertheless, the efficacy of pembrolizumab was observed across all subgroups of patients independently from any clinicopathologic features including performance status, PD-L1 status, and metastatic status. Further, it should be highlighted that ASSURE and SORCE trials enrolled patients with any histologic subtype of RCC versus the KEYNOTE-564, PROTECT, S-TRAC, and ATLAS trials only enrolled patients with clear cell RCC. However, the updated results of the ASSURE trial, that were used in our analysis, included patients with only clear cell histology. To reduce potential bias, we performed a subgroup analysis in the clear cell histology RCC patients only; the results did not differ from the main analysis due to the limited number of non-clear cell RCC patients in the SORCE trial.

Another challenging point in the interpretation of the results is the immature follow-up of the KEYNOTE-564 trial with a median of 2 years. Additional follow-up is awaited for its key secondary endpoint of OS. Nevertheless, DFS prolongation already represents as a significant clinical benefit for pembrolizumab in the adjuvant setting. Moreover, the benefit seems to outweigh the toxicity of the treatment. Given the toxicity profile of TKIs, updated analyses with longer follow-up are unlikely to significantly change the results. In most studies included in this analysis, the duration of adjuvant treatment was one year. The most efficacious therapy duration in the adjuvant setting remains unknown. Investigations of the best optimal therapy schedule are necessary to improve decision-making regarding adjuvant therapy. Standardized criteria for patients with localized and locally advanced RCC should be established to help identify those who benefit most from adjuvant therapy.

Discussion

The differences in the mechanisms of action of TKIs versus ICIs may explain the better benefit/risk outcome ratio of the latter. The lack of clear benefit of TKIs in the adjuvant setting is difficult to understand as TKIs are effective in the metastatic setting.¹⁰ That emphasizes the importance of a better understanding of tumor biology underlying the mechanisms of recurrence. Biomarker-based trials might help in guiding the appropriate selection of individual RCC patients who are the best candidates for adjuvant therapy.^17,18 Potentially, a combination of ICIs and TKIs could be considered in selected patients with expected very poor prognoses in a shared decision-making process with the patients based on their profile and comorbidities. Further studies on adjuvant ICIs including nivolumab (PROSPER; NCT03055013), atezolizumab (IMmotion010; NCT03024996), nivolumab plus ipilimumab (CheckMate 914; NCT03138512), and durvalumab (RAMPART; NCT03288532) have been already launched, and their results awaited.

Among limitations, the included ICI study suffers from immature follow-up and OS data; with further follow-up the data may change. Second, the discrepancy across the included studies in the definition of the risk of disease relapse might lead to bias. For example, the KEYNOTE-564 and SORCE trials used the Leibovich scoring system,¹⁶ while most of the other studies reported a population with T3/T4 tumors, higher Fuhrman grades,¹⁹ and/or lymph nodes involvement. This heterogeneity highlights the need for a standardized prediction tool to assess the risk of disease relapse.

Conclusion

In summary, Pembrolizumab is a new standard of care in the adjuvant setting for post-nephrectomy patients with RCC who are at a very high risk of relapse. Postoperative systemic therapy with Pembrolizumab seems to offer a satisfactory risk/benefit balance for RCC patients with high risk of recurrence after nephrectomy. Identification of patients most likely to benefit from adjuvant ICI therapy and the optimal length of therapy need to be further investigated.