First-line systemic therapy following adjuvant immunotherapy in renal cell carcinoma (RCC): An international multi-center study.
Authors: El Zarif Talal , Semaan Karl , Xie Wanling , Nguyen Charles B , Fahey Catherine , Zarba Martin , Zemankova Anezka , Ebrahimi Hedyeh , Procopio Giuseppe , Stellato Marco , Buti Sebastiano , Melichar Bohuslav , Venugopal Balaji , Karam Jose A. , Campbell Matthew T , Beckermann Katy , Alva Ajjai Shivaram , Pal Sumanta Kumar , Heng Daniel Yick Chin , CHOUEIRI Toni K. 
Published: June 2024

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Background: Adjuvant pembrolizumab significantly improved overall survival (OS) and is FDA-approved for adjuvant RCC treatment. However, there is a paucity of data on sequential treatment following recurrence after pembrolizumab or other immune-oncology (IO)-based therapies (PD-1 or PD-L1 inhibitors) administered in the adjuvant setting. Methods: This study included consecutive patients (pts) from 27 international centers who received adjuvant IO-based systemic RCC therapies. Safety and efficacy of subsequent systemic therapy regimens that included vascular endothelial growth factor-targeted therapies (VEGF-TT) or alternative IO-based therapies were evaluated. Progression-free survival (PFS) and OS from the time of systemic therapy initiation following adjuvant IO were estimated using the Kaplan-Meier method. Objective response rates (ORRs) were determined per RECIST 1.1 criteria. Treatment-related adverse events (trAEs) leading to treatment discontinuation, dose reduction, or steroid use were collected. Results: Among 144 pts who received adjuvant IO, median (Q1-Q3) age was 56 (50-64) years, and 105 (73%) were males. Most pts had clear cell RCC (n=130, 90%), underwent radical nephrectomy (n=136, 94%), and had high or intermediate-high risk disease (n=129, 90%) per KEYNOTE-564 risk groups. Tumors of 15 (10%) pts had sarcomatoid features. Most pts received adjuvant pembrolizumab (n=74, 51%), atezolizumab (n=40, 28%), or nivolumab plus ipilimumab combination therapy (n=16, 11%). Most common reasons for adjuvant IO cessation were treatment completion (n=65, 45%), recurrence (n=36, 25%), or toxicity (n=34, 24%). RCC did not recur in 52 (36%) pts who remained under observation, whereas 92 (64%) had recurrent disease. Following tumor recurrence, 69/92 (75%) pts received systemic therapy; the remaining 25% underwent surgery or radiotherapy. Median follow-up from systemic therapy initiation was 16.7 months. Median PFS was 16 months (95% CI = 10.4 – 41.7), and 18-month OS was 86% (95%CI: 76.4 – 97.3%). ORR was 36% (n = 25/69). Most pts received VEGF-TT (n=32, 46%), IO/VEGF-TT combinations (n=21, 30%), or single/combination IO (n=12, 17%). ORRs were comparable (35% in VEGF-TT monotherapy, 45% in IO/VEGF-TT combination, 42% in single/combination IO cohort). In 23 pts who received adjuvant pembrolizumab monotherapy and subsequent systemic therapy, ORR was 44% (4/9) vs. 29% (4/14) for those recurring after vs. prior to discontinuation of pembrolizumab, respectively. Two out of 8 pts who discontinued adjuvant IO due to toxicity were rechallenged with subsequent IO and had stable disease, and one of them developed an immune-related AE. TrAEs occurred in 28/69 (41%) pts treated with subsequent systemic therapy. Conclusions: Patients with RCC who recur on or after adjuvant IO treatment benefit from subsequent systemic therapies across different regimens.