Southern CA GU Cancer Research Forum 2024: Key Updates in Kidney Cancer

(UroToday.com) The 2024 Southern California Genitourinary Cancer Research Forum featured a kidney cancer session and a presentation by Dr. Rana McKay discussing key updates in kidney cancer. Based on 2023 statistics, kidney and renal pelvis cancer is the 6^th most common malignancy among males (52,360 estimated new cases) and 9^th most common (29,440 estimated new cases) in females. However, the global incidence of renal cell carcinoma has increased over the past two decades by 2% per year. While 75% of all renal cell carcinomas comprise clear cell histology, which is driven by alterations in the VHL gene, approximately 25% of cases represent variant histologies with variable incidence and unique molecular alterations, driving disease pathogenesis and informing survival outcomes. The most common variant histology includes papillary RCC followed by chromophobe and collecting duct carcinoma:

Most recently in 2022, the WHO classification of renal tumors was updated with key distinct changes. For one, the updated WHO classification removed the distinction between papillary type 1 and 2 tumors, given frequent co-occurring features of these subtypes. Additionally, several entities were newly defined, including an expanding list of molecularly defined entities driven by distinct genomic alterations:

Dr. McKay then discussed sarcomatoid dedifferentiation, which can occur in any RCC histology and is typically present in approximately 20% of individuals with stage IV disease. Sarcomatoid differentiation occurs as a result of epithelial to mesenchymal transition and is associated with distinct molecular features, including enrichment in BAP1 alterations, NF2 alteration, EZH2 amplifications, CDKN2A/B deletions, and MYC transcriptional programs. Additionally, these tumors are associated with an immune inflamed phenotype, with activation of immune pathways, increased expression of antigen presentation machinery genes, increased cytotoxic immune infiltration, and high PDL1 protein expression on tumor cells.

Dr. McKay emphasized that since the mid-2000s, we have had a renaissance of treatment options approved for renal cell carcinoma:

As follows is a list of phase 3 trials of VEGF targeted therapies in RCC:

Landmark work by Dr. Choueiri and Dr. Heng in 2009 led to the development of the IMDC prognostic model in the TKI era.¹ Four of the five adverse prognostic factors according to the MSKCC risk factors were independent predictors of short survival: hemoglobin less than the lower limit of normal (p < 0.0001), corrected calcium greater than the upper limit of normal (p = 0.0006), Karnofsky performance status less than 80% (p < 0.0001), and time from diagnosis to treatment of less than 1 year (p = 0.01). Additionally, neutrophils greater than the upper limit of normal (p < 0.0001) and platelets greater than the upper limit of normal (p = 0.01) were independent adverse prognostic factors. For this study, patients were also aggregated into three risk categories: the favorable-risk group (no prognostic factors - median OS was not reached and 2-year OS was 75%), intermediate-risk group (1 or 2 prognostic factors – median OS of 27 months and 2-year OS was 53%), and poor-risk group (3 - 6 prognostic factors – median OS was 8.8 months and 2-year OS was 7%):

Since then, we have had several landmark combination frontline studies in RCC including CheckMate 214,² KEYNOTE-426,³ CheckMate-9ER,⁴ and the CLEAR trial.⁵ Baseline characteristics from these trials are as follows:

Outcomes from these trials in the ITT population, specifically highlighting a 90-month landmark PFS rate of 21% in CheckMate 214 and exceptional objective response rates of 71% in the CLEAR trial, are as follows:

Several of these trials now have extended follow-up. At ASCO GU 2024, Dr. Tannir presented long-term follow-up (median 8 years) of the CheckMate 214 trial. Overall survival with nivolumab + ipilimumab vs sunitinib remained superior in the ITT population (HR 0.72, 95% CI 0.62-0.83), and median progression-free survival was consistent with previous reports, including by independent radiology review committee (HR 0.88, 95% CI 0.75-1.03):

In 2020, Powles and colleagues published long-term follow-up of the KEYNOTE-426 trial (minimum of 42 months follow-up), noting a persistent benefit of pembrolizumab + axitinib versus sunitinib for both overall survival and PFS in the ITT population⁶:

Dr. McKay notes it is important to continue to define new endpoints that are clinically relevant for kidney cancer patients, including several new time to event endpoints: time to subsequent therapy initiation or death, time to cessation of both protocol therapy and toxicity, time to protocol therapy cessation, and time to cessation of protocol therapy without toxicity:

Time to treatment free survival has been assessed in the CheckMate 214 trial of nivolumab + ipilimumab versus sunitinib:

Dr. McKay highlighted that among these four trials, there is benefit across all regimens for patients with intermediate and poor risk disease, with median overall survival outcomes in all trials > 42 months:

There are many options for patients with favorable risk disease, but specifically, with longer follow-up, the CheckMate 214 combination of nivolumab + ipilimumab appears to have notable benefits for the combination therapy:

Specific to nivolumab and ipilimumab for sarcomatoid RCC, Dr. McKay notes that in a post hoc analysis of the CheckMate 214 trial, objective response rate was 61% in patients with sarcomatoid RCC with a complete response rate of 19% in this cohort.⁷ Additionally, the benefit of nivolumab + ipilimumab resulted in a statistically significant improvement in overall survival and PFS. Specific to the PFS curve, there is a plateau emerging around 12 months which is sustained with a minimum 42 months follow up. Moreover, it is striking how poor this population does with VEGF monotherapy (median PFS 5.1 months):

Additional post hoc analyses from phase 2-3 studies of IO-VEGF combination therapy demonstrated the activity of such regimens in patients with sarcomatoid differentiation with objective response rates ranging from 50-60%:

Dr. McKay then discussed triplet therapy notably the COSMIC 313 trial that tested first line cabozantinib + nivolumab + ipilimumab versus placebo + nivolumab + ipilimumab among patients with intermediate and poor risk clear cell metastatic RCC:

In this trial, there were 855 patients randomized of whom 428 received cabozantinib + nivolumab + ipilimumab and 427 received placebo + nivolumab + ipilimumab. In the overall cohort, IMDC risk was intermediate for 75% and poor for 25%. Among the first 550 patients randomized, the median follow-up is 20.2 months (16.1-31.3) and in the ITT population it was 17.7 months (10.2-31.3). The study met the primary endpoint with a significantly improved PFS (HR 0.73, 95% CI, 0.57–0.94; p=0.013): median PFS was not reached (NR; 95% CI, 14.0–not estimable) among those receiving cabozantinib + nivolumab + ipilimumab as compared to 11.3 months (95% CI, 7.7–18.2) for placebo + nivolumab + ipilimumab:

The objective response rate was 43% (95% CI, 37.2–49.2) for those receiving cabozantinib + nivolumab + ipilimumab as compared to 36% (95% CI, 30.1–41.8) for placebo + nivolumab + ipilimumab, though the median duration of response was not reached in either group in either treatment group:

Grade 3/4 treatment related adverse events are somewhat more common in those receiving cabozantinib + nivolumab + ipilimumab (73%) than those receiving placebo + nivolumab + ipilimumab (41%). In each arm, three patients had grade 5 events.

Dr. McKay notes that on the horizon there are additional triplet therapy combination trials for patients in the first line setting, notably MK6482-012, which is testing belzutifan + pembrolizumab + lenvatinib versus quavonlimab + lenvatinib versus pembrolizumab + lenvatinib:

Another study upcoming is the PDIGREE (Alliance A031704) trial that is testing maintenance IO-VEGF, specifically nivolumab + ipilimumab followed by nivolumab or nivolumab + cabozantinib:

With regards to treatment options for non-clear cell RCC, there are several studies showing benefit, namely the PapMet trial assessing cabozantinib for papillary RCC (objective response rate 23%) and the Savior trial assessing savolitinib for met-driven RCC (objective response rate 27%):

In the era of doublet and now potentially triplet therapy, it is important to balance the goals of selection of therapy:

• Benefits: improve overall survival, improved progression free survival, improved response rate, limited progressive disease rate, durability of response, depth of response, complete response, treatment-free survival, and improved quality of life
• Risks: immune-mediate adverse events, chronic TKI toxicity, limited durability of response, primary progressive disease rate, and no benefit in quality of life

In 2024, Dr. McKay’s practical approach to front-line treatment of metastatic RCC is as follows:

In the refractory setting, there are several VEGF therapies available based on data from AXIS,⁸ METEOR,⁹ lenvatinib + everolimus, TIVO-3,¹⁰ and CANTATA, with objective response rates ranging from 17% to 43%:

Notably, based on work presented at ESMO 2023, the LITESPARK-005 trial of belzutifan in refractory clear cell RCC led to FDA approval in December 2023. This trial randomized patients 1:1 to belzutifan versus everolimus among patients that had received 1-3 previous lines of therapy. This trial met its co-primary endpoint of PFS assessed by BICR, with a landmark 18 month analysis showing 22.5% of patients remained free of progression with belzutifan, compared to 9% with everolimus (HR 0.74, 95% CI 0.63-0.88):

To date, no overall survival benefit has been observed for belzutifan, although there is perhaps a signal for benefit (HR 0.88, 95% CI 0.73-1.07), with an 18 month OS rate of 55.2% for belzutifan and 50.6% for everolimus:

An objective response rate was observed in 22.7% of belzutifan patients compared to 3.5% for everolimus, with 3.5% of belzutifan patients having a complete response versus no patients with everolimus having a complete response.

To conclude, Dr. McKay discussed localized RCC and selecting high risk patients for treatment based on risk stratification tools, as highlighted below:

For high risk patients after surgery, Dr. McKay emphasized that adjuvant cytokine therapy did not improve survival and adjuvant targeted therapy had mixed results, with only a DFS benefit for sunitinib in the S-TRAC trial (HR 0.76, 95% CI 0.59-0.98).¹¹ Based on data from ASCO GU 2024 presented by Dr. Toni Choueiri, KEYNOTE-564¹² is the first adjuvant IO therapy trial to improve overall survival (as well as previously shown improved DFS) in any malignancy (HR 0.62, 95% CI 0.44-0.87, p = 0.002):

The decision for adjuvant therapy involves weighing the risks and benefits of the following:

• Disease-free survival
• Overall survival
• Risk of over treatment
• Side effects of therapy
• Quality of life

Indeed, there have been decades of progress in first-line metastatic RCC therapy, from an overall survival benefit of 10 months in 1992 for cytokine therapy to 56 months in 2018 for combination immune checkpoint blockade and targeted therapy:

Dr. McKay concluded her presentation by discussing key updates in kidney cancer with the following summary statements:

• Significant advances in our understanding of cancer and RCC tumor biology have resulted in improved therapeutic options for patients in the clinic
• Survival has dramatically improved for patients with RCC over the past decade and approaches 5 years in the modern era
• Additional studies designed to test novel treatments, radiation therapy, surgery, and biomarker based strategies are underway and will certainly impact the future landscape of RCC 

Presented by: Rana R. McKay, MD, University of California San Diego, San Diego, CA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Southern California Genitourinary Cancer Research Forum, Costa Mesa, CA, Fri, Mar 1, 2024.

References:

1. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. J Clin Oncol. 2009 Dec 1;27(34):5794-5799.
2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carinoma. N Engl J Med 2018;378(14):1277-1290.
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7. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res. 2021 Jan 1;27(1);78-86.
8. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 2011;378(9807):1931-1939.
9. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373(19):1814-1823.
10. Rini RI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): A phase 3, multicentre, randomized, controlled, open-label study. Lancet Oncol 2020 Jan;21(1):95-104.
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