Editor’s Note: The ASCO-GU, a premier academic conference in urologic oncology, at the beginning of the year sparked academic enthusiasm in 2024, receiving over 140 abstracts related to renal cell carcinoma (RCC). Professor Xiongjun Ye from the Chinese Academy of Medical Sciences Cancer Hospital presented a report on the significant progress in RCC treatment from the ASCO-GU at the 4th Yanqi Lake Conference of the Chinese Medical Association Urology Surgery Branch, summarizing the essence for all to appreciate.
LBA359 Pembrolizumab vs. Placebo as Adjuvant Therapy in ccRCC Patients — Analysis of Overall Survival Results from Phase III Study KEYNOTE-564
The KEYNOTE-564 study investigating the adjuvant treatment of high-risk recurrent RCC patients with pembrolizumab has previously confirmed a significant improvement in disease-free survival (DFS), making pembrolizumab the only successful drug in adjuvant treatment after kidney cancer surgery. This conference further updated the efficacy and safety results with a median follow-up of 57 months.
It is worth mentioning that all patients included in this study had intermediate to high risk of recurrence after surgery: pT2, grade 4 or sarcomatoid, N0M0; pT3-pT4, any grade, N0M0; any pT, any grade, N+M0; or post-nephrectomy + complete resection of metastases (M1 NED); and had not previously received systemic treatment for RCC. A total of 994 patients were enrolled in the study and randomly assigned in a 1:1 ratio to receive intravenous infusion of 200 mg pembrolizumab or placebo every 3 weeks for ≥17 cycles (approximately 1 year) or until disease recurrence, intolerable toxicity, or withdrawal of consent. DFS assessed by investigators was the primary study endpoint.
After a median follow-up of 57.2 months, although overall survival (OS) data are still immature, adjuvant treatment with pembrolizumab after surgery for high-risk recurrent RCC showed an OS benefit trend compared to the placebo group, mOS NR vs. NR, 95% CI 0.44-0.87, HR=0.62, P=0.002; further tracking of previously reported DFS data showed continued stability in DFS data, mPFS NR vs. NR, 95% CI 0.59-0.87, HR=0.72.
However, subgroup analysis revealed differences between different subgroups. From the subgroup analysis, we can see that patients without sarcomatoid differentiation (HR 0.57, 95% CI 0.39−0.84) or PD-L1 positive patients (HR 0.62, 95% CI 0.42−0.91) had a greater trend of benefit from adjuvant treatment.
In terms of safety, treatment-related adverse events (AEs) of any grade were 79.1% and 53.0% respectively, and grade 3-4 treatment-related AEs were 18.6% and 1.2% respectively. In the nivolumab monotherapy group and the placebo group, 18.2% and 0.8% of patients respectively discontinued treatment due to any-grade treatment-related AEs. Adjuvant treatment with pembrolizumab continued to be stable, with no new safety signals identified.
Commentary:
The latest research results presented at this conference have once again made pembrolizumab the first product to benefit in terms of OS after being the first to show DFS benefit in RCC adjuvant therapy, solidifying its position in adjuvant treatment after kidney cancer surgery.
LBA358 CheckMate914 Study: Limitations of Adjuvant Nivolumab plus Ipilimumab versus Placebo in High-Risk Renal Cell Carcinoma (RCC) Post-Nephrectomy
CheckMate 914 (NCT03138512) is a randomized, double-blind, placebo-controlled Phase III trial aimed at evaluating the efficacy and safety of nivolumab ± ipilimumab compared to placebo as adjuvant therapy in patients with localized RCC who underwent radical or partial nephrectomy and are at high risk of recurrence. The study consists of two parts, with part A comparing nivolumab plus ipilimumab to placebo and part B comparing nivolumab plus ipilimumab to nivolumab alone versus placebo. Results of part A at a median follow-up of 37 months showed no disease-free survival (DFS) benefit with NIVO+IPI compared to placebo. The findings of part B were reported at the ASCO-GU meeting.
The study enrolled M0 patients with pathologic stage T2a (3/4 grade) N0M0, T2bT4N0M0, or any TN1M0. The primary endpoint was DFS evaluated by independent central review (BICR). Secondary endpoints included overall survival (OS) and safety. A total of 619 patients were randomized to the nivolumab monotherapy group (n=411) or the placebo group (n=208). At a median follow-up of 27.0 months, there was no significant difference in DFS between nivolumab monotherapy and placebo (HR, 0.87; 95% CI, 0.621.21; P=0.3962). Median DFS was not reached; DFS rates at 12 months were 83.3% vs 78.2%, and at 18 months were 78.4% vs 75.4%.
In terms of safety, treatment-related adverse events (AEs) of any grade occurred in 72.5% and 51.7% of patients, respectively, and grade 3~4 treatment-related AEs occurred in 8.8% and 1.9%, respectively. Discontinuation due to any-grade treatment-related AEs was observed in 9.6% and 1.0% of patients in the nivolumab monotherapy and placebo groups, respectively.
Commentary:
Unfortunately, adjuvant therapy with nivolumab did not replicate the promising results of the KEYNOTE-564 study. Several factors may account for this discrepancy: Firstly, there were differences in the patient populations between the two studies. Subgroup analyses showed a trend towards benefit in high-risk populations treated with adjuvant PD-1 blockade in both studies, but the KEYNOTE-564 study may have benefited more from its inclusion of a higher proportion of extremely high-risk patients. Patients who are M1 NED or PD-L1 positive may derive more benefit from postoperative immunotherapy.
Furthermore, there was a difference in treatment duration. In CheckMate914, the treatment regimen of nivolumab plus ipilimumab was planned for 6 months, with an actual median duration of 5.1 months; whereas in KEYNOTE-564, the pembrolizumab treatment regimen was approximately 1 year, with a median actual duration of 11.1 months. Discrepancies between planned and actual treatment durations can also affect the outcomes of each trial.
Moreover, different studies utilized different methods for assessing endpoint events. KEYNOTE-564 used investigator assessment, while CheckMate 914 used investigator assessment confirmed by BICR. Additionally, the failure of nivolumab plus ipilimumab in part A of the CheckMate 914 study may be attributed to the adverse events associated with dual immunotherapy, especially grade 3~4 adverse events, which affected the final treatment outcomes, resulting in disease-free survival (DFS) not reaching the primary endpoint.
LBA360
CheckMate-67T Study: Pharmacokinetics, Efficacy, and Safety Evaluation of Subcutaneous versus Intravenous Administration of Nivolumab in Advanced or Metastatic Clear Cell Renal Cell Carcinoma (ccRCC)
The CheckMate 67T study evaluated the non-inferiority of pharmacokinetic (PK) data and objective response rate (ORR) between subcutaneous (SC) and intravenous (IV) administration of nivolumab (NIVO) in patients with locally advanced or metastatic ccRCC. Eligible patients had measurable disease progression after 1-2 systemic treatments, had not received prior immune-oncology therapy, and had a Karnofsky Performance Status (KPS) score of ≥70. Patients were randomized 1:1 to receive NIVO SC 1200 mg + recombinant human hyaluronidase PH20 Q4W or NIVO IV 3 mg/kg Q2W until disease progression, unacceptable toxicity, withdrawal of consent, completion of 2 years of treatment, or death. The co-primary PK endpoints were the mean serum concentration (Cavgd28) at Day 28 and the steady-state trough serum concentration (Cminss) determined by population PK analysis. The key secondary endpoint, assessed by blinded independent central review (BICR), was ORR. Additional secondary objectives included additional PK exposure measurements, safety, efficacy, and immunogenicity.
A total of 495 patients were randomized to the NIVO SC group (n=248) or the NIVO IV group (n=247). The median ages in the SC and IV groups were 64 and 66 years, respectively, with the majority being male. The average injection time for NIVO SC was 5 minutes. Results showed no significant differences between SC and IV administration in the primary PK endpoints. The ORR was 24.2% vs. 18.2% for SC vs. IV, respectively, with complete response (CR) rates of 2.0% vs. 1.6% and partial response (PR) rates of 22.2% vs. 16.6%. Disease control rates (DCR) were 62.9% vs. 62.7% for SC vs. IV, with no significant difference between the two groups, meeting both primary and key secondary non-inferiority endpoints.
The incidence of local injection site reactions with NIVO SC was 8.1%, with low-grade reactions of short duration (mean duration 3.02 days). The study achieved its primary PK endpoints and key secondary ORR endpoint, supporting the use of NIVO SC as a new option to enhance healthcare efficiency.
Commentary:
In recent years, evolving treatment modalities have generated a demand for dosage form selections that address treatment burden and improve healthcare system efficacy. Subcutaneous formulations not only greatly save medical resources, effectively reduce patients’ treatment time costs, and enhance treatment experience but also psychologically empower patients to return to normal life. The CheckMate-67T study demonstrates that subcutaneous administration of nivolumab yields comparable pharmacokinetics and safety to intravenous infusion, with no new adverse events observed. We look forward to the potential benefits that the new formulation of nivolumab may bring to patients in the future.
A361
LITESPARK-005 Study: Outcomes of Cabozantinib versus Everolimus in Previously Treated Advanced ccRCC
LITESPARK-005 is a multicenter, randomized, open-label, Phase III trial designed to evaluate the safety and efficacy of cabozantinib compared to everolimus in patients with advanced renal clear cell carcinoma (ccRCC) who progressed after 1-3 lines of IO or TKI therapy. Previous study results have reported a benefit in the primary endpoint of PFS (HR 0.75, 95% CI 0.63~0.90, P=0.01) and the key secondary endpoint of ORR (21.9% vs. 3.5%). The US FDA approved cabozantinib for the treatment of advanced ccRCC in December 2023. This conference primarily updated the patient-reported outcomes of cabozantinib versus everolimus in the advanced renal cell carcinoma patient population at a median follow-up of 25.7 months.
The LITESPARK-005 study reported quality of life scores from baseline to Week 17, with deterioration in quality of life defined as a decrease of ≥3 points in FKSI-DRS or ≥10 points in EORTC QLQ-C30. As of June 13, 2023 (the data cut-off date for the second pre-specified interim analysis), the median follow-up time was 25.7 months. The median treatment duration was 7.6 months for cabozantinib and 3.9 months for everolimus, with 84 (22.6%) and 18 (5.0%) patients, respectively, still on treatment. 366 of 374 subjects in the cabozantinib group and 354 of 372 subjects in the everolimus group were included in the PRO analysis population. Completion rates for FKSI-DRS and QLQ-C30 were >90% at baseline and >55% at Week 17 (~4 months).
Compared to everolimus, cabozantinib showed a significant improvement in patients’ progression-free survival prognosis (5.6 months vs. 5.6 months, HR=0.74), although there was no observed overall survival benefit for cabozantinib (21.4 months vs. 18.1 months; HR: 0.88, 95% CI: 0.73 – 1.07, P=0.099). The ORR for cabozantinib patients was 22.7%, compared to 3.5% for everolimus patients. Complete response was observed in 3.5% of patients in the cabozantinib group, while none was observed in the everolimus group.
FKSI-DRS and QLQ-C30 GHS/QoL score TTD showed significant prolongation for cabozantinib compared to everolimus, with NR vs. 11.99 months and 19.35 months vs. 10.19 months, respectively. The least squares mean change in FKSI-DRS and QLQ-C30 GHS/QoL scores demonstrated stability for the cabozantinib group from baseline to Week 17 and a trend of deterioration for the everolimus group, with a potentially greater decline trend in physical functioning (PF) scores compared to the cabozantinib group.
Commentary:
The results show that cabozantinib improves ORR and PFS while prolonging the time to disease deterioration. Compared to everolimus, cabozantinib offers a better quality of life experience for patients.
Currently, research on drugs for advanced renal cell carcinoma is progressing rapidly, and the renal cancer drug research presented at this ASCO-GU conference is particularly exciting. In addition to the continued exploration of IO-TKI drugs in the perioperative and first-line settings, research on new targeted therapy drugs for advanced-line treatment has also made breakthroughs. It is believed that there will be more explorations of combinations and deployments in the future, and the treatment decisions for advanced renal cell carcinoma will become increasingly refined, leading to new changes in treatment patterns.
Xiongjun Ye, Professor
Director and Chief Physician of Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Member of CUA Robotics Group
Member of CUDA Repair and Reconstruction Group
Member of CSCO Kidney Cancer/Urinary Tract Carcinoma Committee
Expert of CUA Prostate Cancer Guidelines Writing Group
Expert of CSCO Urinary Tract Carcinoma Guidelines Writing Group
Vice Chairman of Chinese Sexology Association Urology Branch
Deputy Director of Chinese Research Hospital Urology Youth Committee
Member of Chinese Association of Automation Medical Robotics Professional Committee
Member of Chinese Urological Laparoscopic Association
Executive Director of Beijing Anti-Cancer Association Urological Oncology Youth Committee
Deputy Director of Beijing Health Promotion Association Urology Youth Committee
Member of Beijing Physician Association Urology Specialist Committee
Member of Beijing Medical Association Urology Branch Digital Urology Group
Member of Beijing Oncology Association Urological Oncology Special Committee
Communicating Editor of Chinese Journal of Urology
Editorial Board Member of Journal of Urology (Chinese Edition)
Editorial Board Member of BJU International (Chinese Edition)
Editorial Board Member of Current Opinion in Urology (Chinese Edition)Top of Form
