Current evidence for second-line treatment in metastatic renal cell carcinoma after progression to immune-based combinations

by Selleckchem | Jan 05 2024

The recent approval of immune checkpoint inhibitor (ICI)-based combinations has redefined the first-line standard of care of metastatic renal cell carcinoma (mRCC) patients. Although the undisputed advantage of these combinations, most patients progressed, requiring subsequent therapies. The change of first-line therapy inevitably led to modification of the all mRCC treatment algorithm; to date, the most appropriate second-line options remain still unclear. The aim of our review was to provide a useful summary of the available evidence in order to overcome the doubts about treatment sequences. Retrospectively, the efficacy of second-line VEGFR-TKIs seems to be greater after failure of a dual ICIs combination rather than after ICIs plus VEGFR-TKIs, nevertheless prospective data of second-line TKIs are limited. Moreover, ICI re-challenge could be an option but, again, most data derived from retrospective series emphasizing the identification of predictive factors of response to select mRCC patients that could benefit from this strategy. Novel molecules and different ICI-based combinations are under evaluation with the aim of implementing the second-line setting. In particular, belzutifan, ciforadenant (CPI-444), and talazoparib achieved encouraging objective response rates (ORR) in phase I/II trials. Phase III trials comparing these new molecules with the standard of care are currently ongoing. The first-line regimen, and the type and duration of response emerged as crucial factors that could influence the efficacy of second-line therapy. Prognostic models that integrate clinical features and molecular biomarkers with a predictive value are warranted to guide clinicians in the decision-making process with the ultimate goal of offering to the patients the most effective therapy in a personalized, precision medicine-based, therapeutic strategy.

Comments:

It seems like you're discussing the evolving landscape of treatment for metastatic renal cell carcinoma (mRCC), particularly regarding the shifting standards of care and the uncertainties surrounding second-line therapies. The emergence of immune checkpoint inhibitor (ICI)-based combinations has significantly impacted first-line treatment, but subsequent therapies after progression remain a challenge.

The review aims to summarize available evidence, highlighting the complexities in choosing second-line options. Interestingly, retrospective data suggest varying efficacy of second-line VEGFR-TKIs based on prior treatment sequences. However, prospective data on second-line TKIs are limited, prompting the exploration of other strategies like ICI re-challenge. While retrospective studies offer insights, they emphasize the need for identifying predictive factors to better select patients benefiting from such approaches.

The ongoing evaluation of novel molecules like belzutifan, ciforadenant (CPI-444), and talazoparib, showing promising objective response rates in phase I/II trials, brings hope for refining second-line treatments. Phase III trials comparing these molecules against standard care will provide further clarity.

Crucial factors influencing second-line therapy efficacy include the initial treatment regimen, response type, and duration. Developing prognostic models integrating clinical features and molecular biomarkers could aid clinicians in personalized decision-making, aligning with precision medicine principles for more effective patient-specific therapies.

The evolving landscape underscores the need for continued research to establish optimal treatment sequences, improve patient outcomes, and advance precision medicine in managing mRCC.