Kidney Cancer Research Highlights from ASCO-GU 2024 Meeting

Abstract

The 2024 American Society of Clinical Oncology (GU ASCO 2024) Genitourinary Cancers Symposium brought together leading cancer specialists from around the world to discuss the latest breakthroughs in treating genitourinary cancers, especially kidney cancer. The focus was on immunotherapy and combination treatments, offering promising new options for patients with advanced and high-risk tumors. The symposium also highlighted advancements in patient care, including a new tool to assess quality of life in people with metastatic kidney cancer.

INTRODUCTION

The 2024 ASCO-GU 2024 was held on January 25 to 27, 2024, in San Francisco, California. This event brought together worldwide experts in genitourinary cancers across multiple specialties. This meeting summary focuses on key kidney cancer research updates presented at the meeting. Access to presentation slides from the event is available on the ASCO meeting library website.

Adjuvant Therapy Updates

Locally advanced kidney cancer is primarily managed with surgical resection with nephrectomy performed in a curative intent¹. However, approximately 30% of patients develop recurrent metastatic disease after surgical resection, prompting an exploration into the potential role of adjuvant therapy aimed at diminishing the risk of recurrence post-nephrectomy².

Over the past few decades, numerous studies were conducted to investigate the effectiveness of neoadjuvant, perioperative, and adjuvant targeted therapies and immunotherapies in kidney cancer³. Thus far, the U.S. Food and Drug Administration (FDA) has approved two adjuvant therapies in renal cell carcinoma, including, sunitinib in 2017 followed in 2021 by pembrolizumab^4,5. Pembrolizumab approval was based on the phase 3 double-blind, multicenter, randomized KEYNOTE-564 study which investigated adjuvant pembrolizumab for 12 months versus placebo in patients with intermediate-high or high risk of recurrence after nephrectomy which met its primary endpoint at first interim analysis with significant improvement in disease free survival (HR 0.68, 95% CI, 0.53–0.87, P=0)⁵.

An updated analysis from KEYNOTE-564 study was presented at the meeting of the overall survival (OS) analysis which is a key secondary endpoint⁶. The study led to a statistically significant improvement in OS in patients treated with pembrolizumab compared to placebo in the adjuvant setting (medians not reached, HR 0.62, 95% CI 0.44–0.87; P=.0024). The OS benefit was observed across key subgroups, including in patients with M0 disease (HR 0.63, 95% CI 0.44–0.90) or M1 NED (HR 0.51, 95% CI 0.15–1.75), with PD-L1 CPS <1 (HR 0.65, 95% CI 0.31–1.38) or CPS ≥1 (HR 0.62, 95% CI 0.42–0.91), and with presence (HR 0.69, 95% CI 0.28–1.70) or absence (HR 0.57, 95% CI 0.39–0.84) of sarcomatoid features. This is the first study to report a significant improvement in OS with any adjuvant therapy in kidney cancer marking an important landmark in the treatment landscape of kidney cancer.

The CheckMate 914 trial was a randomized phase 3 trial of adjuvant nivolumab plus ipilimumab (Arm A) for 6 months and adjuvant nivolumab (Arm B) for 6 months versus placebo in patients with localized clear cell RCC who were at high risk of relapse after radical or partial nephrectomy⁷. The primary endpoint of Arm A of the study with nivolumab plus ipilimumab was previously reported and it failed to meet the primary endpoint of improving the median disease-free survival in comparison to placebo (HR 0. 92, 95% CI 0•71–1•19; P=0•53)⁷. The results of Arm B of the study with 6 months of adjuvant nivolumab were reported at the meeting⁸. A total of 619 patients were randomized to receive nivolumab (n=411) or placebo (n=208). After a median follow-up time of 27.0 months (range, 18.0–42.4), the primary efficacy endpoint of disease-free survival nivolumab monotherapy versus placebo was not met (HR, 0.87; 95% CI, 0.62–1.21; P = 0.3962). Grade 3–4 treatment-related adverse events were reported in 8.8% vs 1.9%, in the nivolumab and placebo arms, respectively. Discontinuation of treatment due to any-grade treatment-related adverse events were reported in 9.6% and 1.0% of patients in the nivolumab monotherapy and placebo arms, respectively.

Updates on Systemic Therapy for Metastatic Kidney Cancer

The treatment landscape of metastatic RCC has rapidly evolved in recent years with the advent and approvals of multiple immune-checkpoint inhibitors (ICIs) that block the PD1 and CTLA⁴ in addition multiple vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-TKIs)². Several updates were presented at the meeting on the frontline and refractory treatment settings.

All ICI treatments for kidney cancer are currently approved to be administered intravenously, including nivolumab which is currently indicated for patients with metastatic kidney cancer in combination with ipilimumab and cabozantinib in the frontline setting and as a monotherapy agent in the second line and beyond setting. To facilitate the ease of administration and improve healthcare resource utilization, multiple studies were conducted or ongoing to investigate the subcutaneous administration of ICIs^9,10. Subcutaneous nivolumab was developed in co-formulation with recombinant human hyaluronidase PH20 and various doses were assessed in the dose finding phase 1/2 Checkmate 8KX leading to determining a flat dose of nivolumab 1200 mg subcutaneously for further investigation¹⁰.

At the meeting, the results of CheckMate 67T trial were reported which is a multicenter, randomized, open-label, phase 3 study that evaluated the pharmacokinetics and objective response rate noninferiority of subcutaneous versus intravenous nivolumab in patients with locally advanced or metastatic clear cell kidney cancer¹¹. A total of 495 patients were randomized to subcutaneous nivolumab 1200 mg every 4 weeks (n = 248) or intravenous nivolumab at 3 mg/kg every 2 weeks (n = 247). The study co-primary endpoints were pharmacokinetics endpoints for non-inferiority, including Cavgd28 which was defined as time-average serum concentration of nivolumab over the first 28 days of treatment, and Cminss which was defined as the minimum serum concentration of nivolumab at serum state. The objective response rate was a powered key secondary endpoint. The co-primary pharmacokinetics endpoints and the key powered secondary objective response rate endpoints were met demonstrating non-inferiority of subcutaneous nivolumab to intravenous administration. The incidence of subcutaneous nivolumab local injection-site reactions were low (8.1%) and there were no safety signals of worsening immune-related toxicities. This data may support the future approval of subcutaneous nivolumab.

Belzutifan is a first-in-class, oral hypoxia-inducible factor (HIF)-2α inhibitor targeting HIF-2α which is a key oncogenic driver in clear cell kidney cancer¹². It was approved by the FDA in 2021 for treatment of patients with von Hippel–Lindau disease who require therapy for associated RCC or other malignancies based on the LITESPARK-004 trial and approved for the treatment of patients with advanced clear cell RCC following the progression on a PD1/PDL1 inhibitor and a VEGF-TKI in 2023 based on the LITESPARK-005 trial^13,14. At the meeting, updates on patient-reported outcomes (PROs) from the LITESPARK-005 trial were reported¹⁵. PROs in the study were evaluated by the FKSI-DRS and EORTC QLQ-C30 questionnaires in all randomized patients who were enrolled in both study arms (belzutifan or everolimus) and administered electronically at multiple timepoints starting from day 1 of week 1. Completion rates for FKSI-DRS and QLQ-C30 were >90% at baseline and >55% at week 17 in each arm. Belzutifan was associated with prolonged time to deterioration in FKSI-DRS and EORTC QLQ-C30 compared to everolimus indicating better disease-specific symptoms and quality of life among patients treated with belzutifan.

The Checkmate 214 trial was a randomized phase 3 trial of ipilimumab plus nivolumab versus sunitinib as a first line therapy in metastatic clear cell RCC patients and based on this study, nivolumab plus ipilimumab was FDA approved as a first line treatment in patients with IMDC intermediate/poor risk clear cell RCC¹⁶. At the meeting, updated analysis from the Checkmate 214 trial with a median follow-up of 8 years was presented¹⁷. The OS with nivolumab plus ipilimumab remained superior in the intention to treat population (HR 0.72) and the intermediate/poor risk population (HR 0.68) and continued to improve over time in the favorable risk population (HR 0.82). The median duration of response (DOR) was longer with nivolumab plus ipilimumab in patients with intermediate/poor risk disease (82.8 months, 95% CI 54.1-NE versus 19.8 months, 95% CI 16.4–26.4) and in the favorable risk patients (61.5 months, 95% CI 27.8-NE versus 33.2 months, 95% CI 24.8–51.4). These results further support the long-term durable outcomes of nivolumab plus ipilimumab as first line treatment in metastatic clear cell RCC.

Trials in Progress Update

In addition to the latest findings, the meeting showcased trials in progress exploring innovative treatment approaches for kidney cancer. Here, we will delve into some of these trials presented.

In recent years, stereotactic ablative radiation (SAbR) has emerged as a promising treatment option for patients with oligometastatic RCC potentially delaying the time to systemic therapy and leading to synergy in combination with ICIs^18,19. The ECOG-ACRIN trial (EA8211-SOAR) is a phase 3 randomized non-inferiority trial of SAbR in comparison to systemic therapy in patients with metastatic RCC which is being conducted through the NCTN and led by ECOG co-operative in the US randomizing patients to frontline systemic therapy (at the discretion of the treating investigator) or SAbR followed by systemic therapy (NCT05863351)²⁰. Eligible patients are those with RCC (any histology), ECOG performance status of 0 to 2, favorable or intermediate risk IMDC score, no prior systemic therapy for metastatic RCC, and presence or 2 to 5 extracranial metastases. The co-primary endpoints of the study are OS and toxicity with a target accrual of 472 patients.

Papillary RCC is the second most common type of kidney cancer with limited treatment options in the metastatic setting². Molecular analyses of these tumors demonstrated prevalence of MET activating alterations which led to investigating MET inhibition in papillary RCC². The PAPMET (S1500) was a phase 3 study which established single agent cabozantinib as the standard of care in metastaic papillary RCC with a median progression free survival of 9.0 months compared to 5.6 months with sunitinib²¹. Recent small single arm phase 2 trials demonstrated the efficacy of ICI plus VEGF-TKI combinations in metastatic papillary RCC, however, there are no randomized trials comparing VEGF-TKIs to ICI plus VEGF-TKIs combination in papillary RCC^22,23. The PAPMET2 (S2200) is a prospective randomized phase 2 clinical trial conducted through the NCTN and led by SWOG randomizing patients with metastatic papillary RCC to cabozantinib 60mg/day versus cabozantinib 60mg/day plus atezolizumab 1200 mg q3 weeks²⁴. The key eligibility criteria of the study are patients with pathologic confirmation of papillary RCC, 0 to 1 prior systemic therapy lines for metastatic disease, and presence of measurable disease. The primary endpoint of the study is the progression free survival between cabozantinib and cabozantinib plus atezolizumab with a target enrollment of 200 patients. Secondary endpoints include comparison of objective response rate, OS, and safety.

SUMMARY

In summary, the meeting was rich in novel results and concepts to expand the field of kidney cancer research. The data on subcutaneous nivolumab is potentially practice change pending regulatory approvals of its use and the OS benefit of adjuvant pembrolizumab is the first ever OS advantage in the adjuvant setting to be reported with any type of kidney cancer therapy. We highlighted some of the interesting presentations at the meeting, however, there were multiple exciting abstract and poster presentations which are available for review in the meeting’s website.

FIGURE 1.

At the general session of GU ASCO 2024

FIGURE 2.

The latest outcomes of KEYNOTE-564 study delivered by Dr. Toni Choueiri.