Over the past year, the COVID-19 pandemic has continued to affect the dissemination of critical clinical study findings. Congresses and meetings that were previously held live, including those hosted by the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology, have shifted to virtual meetings. These virtual formats may make it more challenging to reach intended audiences. Nonetheless, cutting-edge research and advances in unresectable renal-cell carcinoma (RCC) treatment and management have continued at an unprecedented pace. This Year in Review series attempts to ameliorate the effects of COVID-19–related shifts in attendance at meetings by presenting effective and timely information on therapeutic advances in oncology to clinicians engaged in cancer care delivery and research.
This edition of Year in Review is focused on advanced RCC, with an emphasis on updates in the management of relapsed/refractory disease. Over the past 3 years, the US Food and Drug Administration has approved a host of novel treatment combinations in the frontline setting: nivolumab plus ipilimumab (2018), pembrolizumab plus axitinib (2019), nivolumab plus cabozantinib (January 2021), and pembrolizumab plus lenvatinib (August 2021). With these approvals comes considerable excitement for improving survival in patients with advanced RCC, but they also introduce new clinical challenges, including selection and sequencing of treatments in second and subsequent lines of therapy. This clinical process is made even more complex by the March 2021 approval of the novel tyrosine kinase inhibitor (TKI) tivozanib for adults with relapsed or refractory RCC following ≥2 previous systemic therapies, introducing an additional agent for clinicians to consider.
The 2021 US Food and Drug Administration approvals of first-line TKI/immuno-oncology combinations were based on the results of large phase 3 clinical trials. The CheckMate-9ER clinical trial results found that nivolumab in combination with cabozantinib significantly improved progression-free survival (PFS) and overall survival versus treatment with the TKI sunitinib. Similarly, the CLEAR clinical trial compared pembrolizumab plus lenvatinib with sunitinib and showed significant PFS and overall survival advantages with the combination therapy.
With these approvals, there has been considerable interest in the positioning of subsequent lines of therapy. Most recently, the TIVO-3 clinical trial showed that tivozanib improved PFS and overall response rate versus sorafenib in 2020. Subgroup and post-hoc analyses of TIVO-3 provide additional information regarding the appropriate use of tivozanib, and initial real-world data have begun to emerge. In presentations at ASCO this year, additional follow-up of TIVO-3 revealed that tivozanib was associated with continued PFS benefits along with a higher response rate and more durable responses than sorafenib. In addition, tivozanib was associated with fewer all-grade and grade 3 adverse events despite longer durations of drug exposure. In a subgroup analysis, tivozanib showed better tolerability than sorafenib regardless of patient age or previous exposure to immuno-oncology therapy.
Reducing the risk for recurrence for patients postnephrectomy is an unmet need. The KEYNOTE-564 trial established the role that pembrolizumab has as an effective therapeutic option to improve disease-free survival compared with placebo.
This year in RCC, there has also been considerable interest in the impact of treatments on patient quality of life. In a novel analysis of the TIVO-3 trial, the impact of tivozanib on quality of life was evaluated using quality-adjusted time without symptoms of disease and toxicity methods, which quantify the overall health benefits of tivozanib in the presence of similar overall survival results. Tivozanib was shown to significantly extend time without symptoms of disease or toxicity compared with sorafenib, which may be considered an alternative benefit of tivozanib in the third-line and beyond settings.
Other questions that clinical research presentations have attempted to answer this year include the effectiveness of novel treatments and combinations in relapsed or refractory advanced RCC, including the use of the hypoxia-inducible factor-2α belzutifan, which was recently approved for use in patients with tumors related to von Hippel-Lindau disease. Other combinations of interest for later-line treatment include TKI/immuno-oncology and TKI/mammalian target of rapamycin therapies. Finally, there has also been some interest in the use of stereotactic radiotherapy for patients with oligometastatic progression during TKI treatment.
It is our pleasure to present the highlights of these clinical findings and more in this RCC issue of Year in Review.
Brian I. Rini, MD, FASCO
Chief of Clinical Trials
Vanderbilt-Ingram Cancer Center
Ingram Professor of Medicine
Division of Hematology/Oncology
Vanderbilt University Medical Center