ASCO 2022: Are We Improving Outcomes Comprehensively in Renal Cell Carcinoma? - Discussion

(UroToday.com) Following four abstract presentations in the oral abstract session focused on Kidney and Bladder cancers at the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, Dr. Leonard J. Appleman provided a discussion of how these data can help us understand to what extent we are improving outcomes for patients with renal cell carcinoma (RCC).

Dr. Appleman first discussed the presentation of the EVEREST trial from Dr. Ryan examining adjuvant everolimus in patients with resected RCC. He noted that this trial included 16.5% of patients with non-clear cell histology.

Further, he noted that the authors used a risk stratification in terms of the patients likelihood of recurrence following surgical resection. Notably, the trial was relatively enriched (55%) in patients at very high risk of recurrence.

Examining the primary endpoint of recurrence-free survival, Dr. Appleman noted a “strong trend” towards benefit for patients receiving everolimus. However, the trial was statistically non-significant.

While overall negative, he noted a “striking” benefit of adjuvant everolimus among patients at very high risk of recurrence. Examining the Kaplan Meier curve below, he noted the value of the recurrence stratification schema used in this trial as a prognosticator: among patients who received placebo, recurrence free survival was clearly much superior in patients in the intermediate/high risk group as compared to the very high risk group.

Moving forward, he suggested that one approach is to employ molecular patient selection of patients who are most likely to benefit for adjuvant everolimus. Given that there is a relatively high rate of primary progression among patients with advanced RCC treated with anti-PD-1 monotherapy, he noted that there is likely to be relatively large subset of patients who will not benefit from adjuvant pembrolizumab (as supported by the KEYNOTE-564 trial and now approved). Thus, he proposed a biomarker driven trial focused on the very high risk subset to examine these two adjuvant treatment approaches.

He further noted the potential for “valuable” translational science to come from this study cohort.

Dr. Appleman then moved to discuss the presentation from Dr. Suarez examining the correlation between the degree of response and long-term outcomes among patients receiving first-line therapy for metastatic RCC in the CheckMate 9ER trial. While the degree of response was associated with long term outcomes for patients in both arms of this trial, he noted a more pronounced effect among those receiving nivolumab and cabozantinib. However, he further highlighted data based on 18-month overall survival demonstrating that, in both treatment arms, patients with PR1 responses achieved essentially equivalent outcomes as those who achieved a complete response. He noted the need for longer follow-up to see if PR1 remains equivalent to CR.

In terms of applying these data, he suggested that we may be able to use the combination CR or PR1 as an endpoint for early signal-finding phase II trials. Further, these outcomes may allow for adaptive treatment with early intensification or de-intensification. Indeed, such an approach is currently being tested in the PDIGREE trial examining treatment intensification based on a 3-month response assessment among patients receiving nivolumab and ipilimumab.

However, there is a question as to what the best tool is for early response assessment. Currently (and in this work by Dr. Suarez), conventional imaging with interpretation using RECIST has benefits, there are potential benefits to mechanism-based imaging/assays. He suggested that there may be role for each of these approaches moving forward.

Dr. Appleman then moved to a discussion of the presentation from Drs. Motzer and Cella regarding the association between patient-reported health-related quality of life (HRQoL) and survival outcomes, among patients receiving first-line therapy for advanced RCC. He noted that examining both progression-free and overall survival, both baseline and longitudinal assessments of HRQoL were prognostic.

However, longitudinal data appeared to have significantly more prognostic value. Dr. Appleman highlighted that these are “fascinating” data due to differing patient experiences: all of these analyses rely on mean HRQoL data. While toxicity outcomes are often very predictable and dose-dependent in patients receiving tyrosine kinase inhibitors, for patients who are receiving immunotherapy, outliers may be particularly important. In particular, we need to consider the rare but devastating and permanent toxicity of these therapies.

In ongoing dialogue including patient groups, Dr. Appleman emphasized the need for new instruments to capture the effects of immunotherapy on the lives of patients and caregivers.

Finally, Dr. Appleman moved to a discussion of the presentation from Dr. Powles describing the results of the CALYPSO trial. He first noted the ambition of the trial investigators to demonstrate a 50% response rate. Unfortunately, each of the treatment arms fell well short of this. In particular, Dr. Appleman noted the additive effect of combining durvalumab and savolitinib, rather than any combinatorial benefit.

He further noted the interesting observation that activity of savolitinib was relatively limited in patients with both MET and non-MET driven RCC in this study. This is notable given that both mechanistically, in vitro, and in clinical studies of other MET-driven tumors, savolitinib is a potent and efficacious inhibitor of MET. He hypothesized that, in RCC, escape pathways may mediate this lack of effect. There are clues to this effect in studies of savolitinib in papillary RCC. Examining data from the PAPMET and SAVIOR trials, we see that savolitinib responses are much higher among the biomarker selected patients in SAVIOR. In contrast, the multi-kinase inhibitor cabozantinib had better response rates in the histologically selected cohort in PAPMET.