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ESMO21: Highlights from clinical trial results

By Dr. Umberto Capitanio and Dr. Idir Ouzaid

During the ESMO Congress 2021, exciting and important results from many clinical trials were reported. We rounded up some research highlights from the Congress.

Following the NEJM publication of KEYNOTE-564 trial, Dr. Toni Choueiri discussed patient-reported outcomes (PROs) among patients included in the trial and receiving pembrolizumab versus placebo as adjuvant therapy for renal cell carcinoma (RCC). The study met its primary endpoint of disease-free survival with adjuvant pembrolizumab vs placebo (HR 0.68, 95% CI 0.53-0.87) following surgery in patients with RCC. At ESMO 2021, PROs results were reported, providing an understanding of participant experiences that can complement traditional clinical metrics of efficacy and safety. PROs were evaluated in all randomized patients with ≥1 dose study treatment and ≥1 completed assessment for the specific outcome. FKSI-DRS and EORTC QLQ-C30 were administered at cycles 1, 5, 9, 13, and 17, treatment discontinuation, 30 days after last dose, and annually thereafter until recurrence or salvage therapy. No clinically meaningful changes from baseline in health-related QoL or symptom scores were observed with adjuvant pembrolizumab or placebo. These scores remained stable over time. Moreover, PRO findings suggested that adjuvant pembrolizumab was tolerable from a patient perspective, as well.

There were also amazing focuses of other key aspects in RCC setting: Dr. Schmidinger – for instance – presented in a dedicated session the “Current Status of Personalized Therapy in Metastatic RCC”. She confirmed that tumour mutational burden, immune cell composition and genetic alterations are currently not mature to be able to guide therapy and that other easily available biomarkers (PD-L1, sarcomatoid features, NLR) are prognostic rather than predictive. mRNA signatures have probably the highest potential to become relevant for treatment selection in the future and may identify candidates for targeted therapy and IO (ie. ccrcc2, ccrcc3, ccrcc4, BIONIKK etc).

Dr. Cristina Suarez discussed “The Future Targets And Combinations For Metastatic RCC”. These unique combinations include alternative proangiogenic pathways, immune checkpoint inhibitors, metabolic pathways and PARP inhibitors. Dr. Suarez started by discussing the HIF-2alpha inhibitors. Particularly, she evoked the phase 2 study of MK-6482 for VHL disease-associated RCC which led to the FDA approval of belzutifan for cancers associated with VHL disease on August 13, 2021. She also recalled the results of a phase 2 trial of MK-6482 in combination with cabozantinib in patients with advanced clear cell RCC, presented this year at ESMO21 (see below). Disease control rate, as defined as CR+PR+SD, was up to 92.7% in patients previously received immunotherapy and/or TKIs. Finally, she reported the recent findings regarding the potential role of other HIF-2alpha inhibitors (PT2385 and PT2399) that have shown greater activity than VEGFR inhibitors in xenograft models and have shown tolerable safety results in a Phase I clinical trial.

Dr. Choueiri addressed the key question “Is There an Optimal First-Line Combination Approach for Metastatic mRCC?” Finally, he concluded that different combinations for the first-line treatment – including CheckMate 214, CLEAR, JAVELIN Renal 101, KEYNOTE-426 and CheckMate 9ER – are available, with all trials showing improvement in the combination therapy compared to sunitinib. Even more importantly, he remarked that real-life patients do not always reflect the trial population and therefore many factors can influence the clinical choice including availability, efficacy, safety, QoL, prior treatment, comorbidities, and costs. For patients with sarcomatoid features is now well defined that nivolumab + ipilimumab should be the standard of care.

Dr. Gafanov summarized “Subsequent Therapy Following Pembrolizumab + Axitinib or Sunitinib Treatment for Advanced RCC in the Phase 3 KEYNOTE-426 Study”. Although the baseline characteristics of the patients that received subsequent therapy were similar to those in the overall population, subsequent IO therapy was less common after pembrolizumab + axitinib (P+A), and subsequent VEGF/VEGFR therapy was more frequent after P+A therapy. Moreover, in the ITT population, longer OS with P+A compared with sunitinib was observed, reinforcing the role of the combination in the first-line setting.

Very interestingly from a urological point of view, Dr. Grimm analyzed the impact of prior nephrectomy on outcomes in the JAVELIN Renal 101 trial. This is a very hot topic following the recent publication of CARMENA and SURTIME trials – which however were recently questioned by the advent of IO therapy in the first line setting. Interestingly, in the avelumab + axitinib arm, PFS and OS and ORR were numerically longer in patients with a prior nephrectomy versus those without a prior nephrectomy. No differences were observed between groups in the sunitinib arm. This reinforced again the discussion regarding the current role of cytoreductive nephrectomy in mRCC.

Finally, several phase II studies which will probably affect clinical decision in the next future have been reported at ESMO 2021:

See you in Paris at ESMO22!