The RCC highlights of this year's conference included the ZIRCON study which evaluated radiolabeled 89Zr-DFO-girentuximab (a monoclonal antibody targeting CA IX) for detection of clear cell RCC in patients with indeterminate renal masses. This phase III trial included patients with renal masses (≤7 cm, cT1) who were scheduled to undergo a nephrectomy in 90 days and all patients received a single dose of Radiolabeled 89Zr-DFO-girentuximab (37 MBq ± 10%; 10 mg girentuximab) on Day 0 and underwent PET/CT imaging on Day 5 (± 2 days) prior to surgery. The study met its co-primary end points exceeding the sensitivity and specificity thresholds and confirmed a favorable toxicity profile (Shuch, Pantuck et al. 2023). This study lays the foundation and provides a convenient non-invasive platform for pre-treatment risk stratification of clear cell RCC akin to PSMA in prostate cancer.

Dr. Choueiri presented an exploratory post hoc subgroup analysis of KEYNOTE 564 across the UISS (University of California Los Angeles Integrated Staging System) risk groups and disease stage. The Keynote 564 trial showed an improvement in disease free survival in patients with clear cell RCC with a high risk of recurrence leading to the FDA approval of pembrolizumab in the adjuvant setting. The UISS is a commonly used prognostic model that predicts the 5-year survival rates following a nephrectomy. In this trial, most patients in both the arms were categorized in the UISS intermediate group (75%) with 5.9% of patients having M1NED disease. Up to 88% of patients had AJCC Stage 3 disease. The results showed that adjuvant pembrolizumab prolonged disease-free survival across subgroups by AJCC Stage, TNM staging, Fuhrman grading and UISS risk compared to placebo. The extent of benefit was most pronounced in patients with M1NED disease (HR: 0.28, 95% CI: 0.11 – 0.73), AJCC stage 3 (HR: 0.68, 95% CI: 0.51 – 0.89) and Stage 4 disease (HR: 0.42, 95% CI: 0.20 – 0.87). This exploratory analysis further supports the use of pembrolizumab in patients with a high risk of recurrence in the adjuvant setting (Choueiri, Tomczak et al. 2023).

Dr. Powles presented an updated analysis of the COSMIC 313 trial which was the first phase 3 trial exploring the triplet combination of cabozantinib along with ipilimumab and nivolumab versus ipilimumab and nivolumab, a contemporary control arm in patients with advanced RCC with intermediate or poor IMDC risk. With an additional follow up of 5 months, the progression free survival (PFS) benefit with the triplet combination was maintained in the overall population with a HR of 0.74 (95% CI 0.61-0.90) and HR of 0.68 (95% CI 0.54-0.86) in the intermediate risk population. Similarly, the objective response rate was also higher with the triplet combination in the intermediate risk group compared to the poor risk group. There were no major differences in the treatment exposure between both the triplet arms that could explain the enhanced efficacy in the intermediate risk group (11.3 months in the intermediate risk population and 10.4 months in the poor risk population). The daily dose of cabozantinib received was also similar in both the groups. Adverse events leading to treatment discontinuation was more common in the intermediate risk population compared to the poor risk group. It is important to note that patients in the poor risk group had significantly fewer nephrectomies compared to the intermediate risk group (40% and 50% in the triplet arm and comparator poor risk group compared to 73% and 69% in the triplet and comparator intermediate risk group respectively) and this could be one of the reasons behind the lower response rates in this patient population. Another likely explanation is that the poor risk group is biologically more immune driven than angiogenesis driven compared to the favorable risk population (Rini, Huseni et al. 2018, Tannir, Signoretti et al. 2021). Overall survival follow up in ongoing (Powles, Motzer et al. 2023) and will be important to consider for regulatory approval of this combination in intermediate and poor risk IMDC risk groups.

Treatment free survival is a meaningful clinical end point that has not been traditionally evaluated as a predefined end point in clinical trials. Dr. Atkins presented the updated analysis of treatment free survival of HCRN GU16-260-Cohort A (Atkins, Jegede et al. 2023). In this study, 128 patients with advanced clear cell RCC received treatment with nivolumab and based on their response they received additional treatment with nivolumab for up to 96 weeks if they had a partial response or a complete response or salvage ipilimumab was added if they had progressive disease or stable disease at 48 weeks. Treatment free survival was defined as the area between the Kaplan Meier curves for time from registration to stopping protocol therapy and time from registration to starting subsequent therapy or death estimated at a mean of 36 months. The response rate in the favorable risk group was 57.9% with the overall response rates being 35.9% at 3 years, 65.6% of patients with favorable risk were alive and treatment free compared to 27.1% of patients with intermediate/ poor risk disease. The overall PFS was 14.6%. The 36 month mean treatment free survival was 36% in the favorable risk group which included 4% of patients with TRAE >3 and the treatment free survival was 22% in the intermediate/poor risk group which included 3% of patients with TRAE >3. Based on this study, salvage ipi/ nivo in is a viable option in patients who do not respond to nivolumab monotherapy in the front line setting and has a robust treatment free survival with limited toxicity. The maximum benefit was obtained by the favorable risk group like the DFS benefit in favorable risk group in the Checkmate 214 trial supporting the use of this regimen in favorable risk patients (45% vs 36%)

Dr. Albiges presented to interim results of CaboPoint which is a phase II study of cabozantinib in adults with advanced clear cell RCC with progressive disease after front line checkpoint inhibitor therapy. The study consisted of two cohorts: Cohort A including patients with progressive disease after ipilimumab and nivolumab and cohort B including patients with progressive disease on immunotherapy and a VEGFR TKI. Most patients had intermediate risk disease with upfront metastatic disease and did not have a nephrectomy. The ORR in cohort A was 31.7% (95% CI, 20.3-45) and Cohort B was 25% (95% CI, 10.7-44.9). Cabozantinib was effective as a second line treatment option irrespective of the front-line regimen used, with patients with intermediate risk disease having failed ipilimumab and nivolumab seemed to benefit the most with a RR of 40%. The duration of front line therapy also had an impact with patients benefitting more if they received cabozantinib in the primary refractory setting having had progressive disease within 6 months of front line therapy (Albiges, Powles et al. 2023).

The updated results of the BIONIKK trials were also presented (Vano, Phan et al. 2023). This was a randomized phase II trial that prospectively selected patients to receive either nivolumab, nivolumab￾ipilimumab or a VEGRF TKI based on the tumor molecular group. They had previously reported high efficacy of VEGFR TKI in CCRCC2 tumors (51%) and high efficacy of nivolumab with ipilimumab in CCRC4 (50%) compared to CCRC1 (39%) tumors. After a follow up of 46.5 months, the median overall survival was not reached for ipilimumab /nivolumab and was 35 months for nivolumab (HR compared to nivo/ipi: 1.56, 95% CI: 0.99 to 2.46) and 45 months for VEGFR TKI (HR compared to nivo/ipi: 1.29, 95% CI: 0.76 to 2.19). When the overall survival was characterized by molecular group, superior survival was observed with the ipilimumab/nivolumab combination compared to nivolumab alone in CCRC1 (HR: 1.44) and CCRC4 (HR: 1.64) groups. There was no difference in survival with treatment with either VEGFR TKI or ipilimumab/ nivolumab in the CCRC2 (HR: 1.15) group. About 80% of patients went on to receive second line treatment and most of them received a VEGFR TKI (79%). After a median follow up of 34 months, there was a higher response rate after ipilimumab and nivolumab (33%) than after single agent nivolumab (11%) in the CCRC4 group and the CCRC2 group has the highest response rate of 62% post ipilimumab and nivolumab and 57% post VEGRF TKI. The updated results confirmed the feasibility of biomarker driven trials in RCC and the efficacy of ipililumab/nivolumab in CCRC4 and VEGFR TKI in CCRC2 molecular groups.

Dr. Siva reviewed the use of radiation in oligometastatic kidney cancer. The ASCO guidelines include radiotherapy for management of patients with low volume metastatic disease (Rathmell, Rumble et al. 2022) . In a meta-analysis of 28 studies including 1600 patients with almost 4000 treated lesions, the local control rate for both intra cranial and extracranial lesions was 90%. Prospective trials of radiation in oligometastatic RCC have shown that SABR (stereotactic ablative radiation) can be effectively delivered in lieu of systemic therapy. In a single center study of 30 patients with low burden of disease (having 1 median number of metastases) with a median follow up of 17.5 months, the one-year progression free survival was 64%, the median progression free survival was 23 months and importantly, at one year, 82% of patients did not receive any systemic therapy (Tang, Msaouel et al. 2021) . Radiation can also be used in the oligoprogressive setting to prolong the efficacy of systemic therapy.

In a multicenter trial of 37 patients with oligoprogressive disease, SABR to the oligoprogressive sites resulted in a 93% one-year disease control rate and a progression free survival of 9.3 months. SABR can also be safely delivered with immunotherapy. In the RAPPORT trial, patients received a combination of six months of pembrolizumab with SABR taking advantage of the synergy between radiotherapy and immunotherapy inducing tumor antigen and cytokine release by radiotherapy which can prime the tumor microenvironment and likely transform a cold to hot microenvironment. The median progression free survival was 15 months, and the two-year local control rate was 92% (Siva, Bressel et al. 2022) . SABR therefore, provides a safe, non-invasive option of prolonging the efficacy of systemic therapy and has synergy with immunotherapy

* Arpita Desai, MD

University of California San Francisco, San Francisco CA