Combination therapies in non-clear-cell renal cell carcinoma

We read the Article by Laurence Albiges and colleagues1Albiges L Gurney H Atduev V et al.Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial.Lancet Oncol. 2023; 24: 881-891Summary Full Text Full Text PDF Google Scholar with great interest. This study provides valuable insights into the treatment of non-clear-cell renal cell carcinoma with a combination of pembrolizumab and lenvatinib. However, the absence of a subgroup analysis focusing on cytoreductive nephrectomy substantially reduces the applicability of the findings, considering the potential effects of cytoreductive nephrectomy in this patient population. The study acknowledges that approximately 60% of patients had undergone previous nephrectomy, but it remains unclear whether these surgeries were performed for cytoreductive reasons. Cytoreductive nephrectomy has shown survival benefits in patients with clear-cell renal cell carcinoma during the interferon-kinase and tyrosine-kinase inhibitor eras; nonetheless, non-clear-cell histological samples were often excluded from these trials.2Mejean A Escudier B Thezenas S et al.CARMENA: cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—results of a phase III noninferiority trial.Proc Am Soc Clin Oncol. 2018; 36 (abstr).LBA3Google Scholar Therefore, the insufficient information on cytoreductive nephrectomy in the context of non-clear-cell renal cell carcinoma is a crucial gap that merits further exploration. Retrospective studies, such as the database analysis by Marchioni and colleagues,3Marchioni M Bandini M Preisser F et al.Survival after cytoreductive nephrectomy in metastatic non-clear cell renal cell carcinoma patients: a population-based study.Eur Urol Focus. 2019; 5: 488-496Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar have indicated a survival benefit of cytoreductive nephrectomy in patients with non-clear-cell renal cell carcinoma. Similarly, other retrospective studies and case series have supported the advantageous role of cytoreductive nephrectomy in this subgroup of patients.4Aizer AA Urun Y McKay RR Kibel AS Nguyen PL Choueiri TK Cytoreductive nephrectomy in patients with metastatic non-clear-cell renal cell carcinoma (RCC).BJU Int. 2014; 113: E67-E74Crossref PubMed Scopus (52) Google Scholar, 5Heng DY Wells JC Rini BI et al.Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium.Eur Urol. 2014; 66: 704-710Summary Full Text Full Text PDF PubMed Scopus (342) Google Scholar Given these existing data, the omission of a dedicated analysis for cytoreductive nephrectomy in the KEYNOTE-B61 trial is a limitation, hindering comprehensive understanding of the therapeutic benefits for patients with non-clear-cell renal cell carcinoma who have undergone cytoreductive nephrectomy. Incorporating a subgroup analysis focused on patients with prior cytoreductive nephrectomy in the KEYNOTE-B61 trial could offer valuable insights into the effect of this surgical intervention in the context of pembrolizumab plus lenvatinib therapy. Understanding the interplay between cytoreductive nephrectomy and immunotherapy plus tyrosine-kinase inhibitor combination therapies could have substantial clinical implications for the management of non-clear-cell renal cell carcinoma. To further strengthen the study's conclusions and provide more comprehensive evidence for clinical decision making, the authors should consider discussing the potential implications of cytoreductive nephrectomy within the current trial setting. Moreover, the limitations associated with scarce cytoreductive nephrectomy-specific data should be addressed transparently, acknowledging the need for future research on this topic. In conclusion, the study contributes valuable findings to the treatment landscape of non-clear-cell renal cell carcinoma. However, the absence of a subgroup analysis focusing on cytoreductive nephrectomy reduces the study's applicability, and hinders complete understanding of the potential benefits of pembrolizumab plus lenvatinib therapy in patients with previous cytoreductive nephrectomy. Addressing this limitation and recognising the significance of cytoreductive nephrectomy in the treatment of non-clear-cell renal cell carcinoma would render the study more informative and relevant for the broader urological oncology community. We declare no competing interests.