(UroToday.com) The 2023 ASCO annual meeting included a kidney cancer session, featuring a presentation by Dr. Toni Choueiri discussing the primary progression free survival analysis from the phase 3, randomized, open-label CONTACT-03 study assessing the efficacy and safety of atezolizumab + cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor treatment in metastatic RCC.
Immune checkpoint inhibitor-based regimens are the standard of care for first-line treatment of metastatic clear cell RCC. The introduction of immune checkpoint inhibitors as first-line treatment has led to questions around optimal second line therapy. Treatment options following disease progression during or after immune checkpoint inhibitor therapy are limited but can include single-agent TKIs, such as cabozantinib. However, an emerging practice in the treatment of metastatic RCC and other cancers is the rechallenge of PD-L1 or PD-1 inhibitors after initial progression. CONTACT-03 evaluated anti–PD-L1 atezolizumab + cabozantinib vs cabozantinib alone in patients with metastatic RCC that progressed during or after prior immune checkpoint inhibitor treatment and is the first phase 3 randomized trial to test the benefit of immune checkpoint inhibitor rechallenge by direct addition to a control arm.
CONTACT-03 enrolled patients with histologically confirmed, inoperable, locally advanced or metastatic clear cell or non-clear cell RCC, regardless of PD-L1 status, that progressed on or after immune checkpoint inhibitor treatment. Randomization was 1:1 to atezolizumab (1200 mg IV q3w) + cabozantinib (60 mg oral QD) or cabozantinib alone. The trial design for CONTACT-03 is as follows:
Stratification factors were IMDC risk factors (0 vs 1-2 vs ≥3), most recent line of prior immune checkpoint inhibitor therapy (adjuvant vs first-line vs second-line), and histology (dominant clear cell without sarcomatoid vs dominant non-clear cell [papillary or unclassified] without sarcomatoid vs clear cell or non-clear cell with any sarcomatoid component). The primary efficacy endpoints were centrally reviewed RECIST 1.1 progression free survival and overall survival. Key secondary endpoints were investigator-assessed progression free survival, centrally reviewed RECIST 1.1 objective response rate and duration of response and safety.
Among 522 patients randomized to atezolizumab + cabozantinib (n=263) or cabozantinib (n=259), the median age was early 60’s, the majority of patients were male, and the majority were white. Of note, 55% and 51% had most recent immune checkpoint inhibitor in the first-line setting and 10% and 11% had sarcomatoid RCC, respectively. The complete baseline demographics and characteristics are as follows:
The most common prior systemic cancer treatment, by line of therapy is highlighted in the following table:
At the data cutoff (January 3, 2023), median follow-up was 15.2 months. No progression free survival or overall survival benefit was observed with atezolizumab + cabozantinib vs cabozantinib. The median progression free survival for atezolizumab + cabozantinib was 10.6 months versus 10.8 months for cabozantinib (HR 1.03, 95% CI 0.83-1.28):
Centrally reviewed progression free survival by subgroup did not demonstrate a signal favoring atezolizumab + cabozantinib. The median overall survival for atezolizumab + cabozantinib was 25.7 months versus not reached for cabozantinib (HR 0.94, 95% CI 0.70-1.27):
The objective response rate was 41% in both arms, and duration of response was 12.7 (95% CI 10.5, 17.4) months with atezolizumab + cabozantinib and 14.8 (95% CI 11.3, 20.0) months with cabozantinib. The most common subsequent therapy for atezolizumab + cabozantinib was TKI/VEGF inhibitor (23.2%; most commonly axitinib) and for cabozantinib was also TKI/VEGF inhibitor (24.7%, most commonly lenvatinib):
All-cause Grade 3/4 adverse events occurred in 68% (177/262) and 62% (158/256) of safety-evaluable patients receiving atezolizumab + cabozantinib or cabozantinib, respectively, whereas all-cause Grade 5 adverse events occurred in 6% and 4%, respectively. The most common all grade adverse event for atezolizumab + cabozantinib was diarrhea (65.3%) and for cabozantinib was also diarrhea (70.7%). Adverse events leading to treatment withdrawal occurred in 16% of patients on atezolizumab + cabozantinib and 4% on cabozantinib.
Dr. Choueiri concluded his presentation discussing the primary progression free survival analysis from the phase 3, randomized, open-label CONTACT-03 study with the following take-home points:
- CONTACT-03 was the first randomized, phase III trial to examine the efficacy and safety of a PD-L1 inhibitor following progression on or after prior treatment with PD-L1/PD-1 therapy
- The addition of atezolizumab to cabozantinib did not improve clinical outcomes in patients with metastatic RCC who progressed on or after prior immune checkpoint inhibitor treatment. Subgroup analyses did not identify a subset of patients who may benefit from atezolizumab + cabozantinib
- Increased toxicity was observed with the combination, although no specific safety signal was identified
- These data highlight the importance of randomized, prospective assessment of re-challenge with checkpoint inhibitors in RCC and other tumor types
Following Dr. Choueiri’s presentation, this trial was concomitantly published in The Lancet.1
Presented by: Toni K. Choueiri, MD, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.
Reference:
- Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): A multicenter, randomized, open-labl, phase 3 trial. Lancet 5 June 2023 [Epub ahead of print].