Cabozantinib/Atezolizumab Active in Cisplatin-Eligible/Ineligible, Prior ICI-Exposed Urothelial Carcinoma

• Abstract 4504 includes data on the first-line treatment of patients with urothelial carcinoma who were cisplatin-ineligible (Cohort 3) or cisplatin eligible (Cohort 4) or patients with 1 prior immune checkpoint inhibitor (ICI) and no prior VEGF tyrosine kinase inhibitor therapy (Cohort 5).
• The overall response rate was 20% in cisplatin-ineligible patients, 30% in cisplatin-eligible patients, and 10% in those who had received prior ICI.
• The disease control rate was 80% for cisplatin-ineligible patients, 63% for cisplatin-eligible patients, and 61% for those with prior ICI. The majority of patients in Cohort 3 (74%), Cohort 4 (62%), and Cohort 5 (63%) had a reduction in tumor size.

Combination treatment with cabozantinib and atezolizumab showed encouraging clinical activity with a manageable toxicity profile in certain patients with urothelial carcinoma, according to data from 3 cohorts of the phase 1 COSMIC-021 trial.

Data on Cohorts 3, 4, and 5 (Abstract 4504) were presented during the 2022 ASCO Annual Meeting by Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center.

COSMIC-021 is assessing the safety and efficacy of 40 mg cabozantinib daily plus 1,200 mg atezolizumab every 3 weeks in various solid tumor types. Abstract 4504 includes data on the first-line treatment of patients with urothelial carcinoma who were cisplatin-ineligible (Cohort 3) or cisplatin eligible (Cohort 4) or patients with 1 prior immune checkpoint inhibitor (ICI) and no prior VEGF tyrosine kinase inhibitor (TKI) therapy (Cohort 5). There were approximately 30 patients in each group.

The overall response rate was 20% in cisplatin-ineligible patients, 30% in cisplatin-eligible patients, and 10% in those who had received prior ICI. Complete responses occurred in 1% of patients with cisplatin-ineligible disease, 2% of patients with cisplatin-eligible disease, and no patients who received prior ICI.

The overall response rate was 20% in cisplatin-ineligible patients, 30% in cisplatin-eligible patients, and 10% in those who had received prior ICI.

To put these data in perspective, Dr. McGregor said that results of the phase 3 IMvigor130 trial, which studied atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma, showed responses to immunotherapy around 20% in the treatment-naive setting.¹

The combination of cabozantinib plus atezolizumab in patients with urothelial carcinoma previously treated with platinum-containing chemotherapy (Cohort 2 of COSMIC-021) was shown to have an objective response rate of 27%.²

"While responses are less than 30%, the disease control rate is significant," Dr. McGregor said.

The disease control rate was 80% for cisplatin-ineligible patients, 63% for cisplatin-eligible patients, and 61% for those with prior ICI. Additionally, the majority of patients in Cohort 3 (74%), Cohort 4 (62%), and Cohort 5 (63%) had a reduction in tumor size (Table).

Early survival analyses showed median progression-free survival of 5.6 months, 7.8 months, and 3.0 months for cisplatin-ineligible, cisplatin-eligible, and prior ICI, respectively. Median overall survival was 14.3 months, 13.5 months, and 8.2 months, for these 3 cohorts, respectively.

"When combining therapies, adverse events are always a concern," Dr. McGregor said; however, the combination of cabozantinib and atezolizumab was well-tolerated with no new toxicity signals. Common adverse events included diarrhea, liver dysfunction, fatigue, and decreased appetite. Of note, pancreatitis occurred in approximately 10% patients.

The clinical activity of cabozantinib and atezolizumab has also been shown in patients with treatment-refractory prostate cancer (Cohort 6) and renal cell carcinoma (Cohort 10). ^3,4 Dr. McGregor said that there is a phase 3 trial examining the drug combination in treatment-refractory prostate cancer (NCT04446117) and in renal cell carcinoma in the post-ICI setting (NCT04338269).

Dr. McGregor also acknowledged that the treatment landscape of urothelial carcinoma has changed somewhat since the initiation of the COSMIC-021 trial. In patients with prior ICI exposure, there are now 2 drugs approved: enfortumab vedotin, based on a phase 3 study, and sacituzumab govitecan, based on encouraging phase 2 study results; erdafitinib remains an option for those with an activating FGFR mutation.

"When this trial was initiated, enfortumab vedotin wasn't readily available and sacituzumab govitecan wasn't approved," Dr. McGregor said. "Even though we now have those options, if a patient progresses on enfortumab vedotin or sacituzumab govitecan following immunotherapy and is still treatment eligible, we need more options. These data are looking at a way to enhance immunotherapy options, and Cohort 5 is intriguing."

Study Discussant Shilpa Gupta, MD, of Cleveland Clinic Taussig Cancer Institute, pointed out that the current standard of care in the frontline for patients who are cisplatin eligible and cisplatin-ineligible is platinum-based chemotherapy with either gemcitabine/cisplatin or gemcitabine/carboplatin, followed by maintenance avelumab.

Notably, the patients had received prior immunotherapy as well.

"There is an unmet need to explore new therapies to add to our armamentarium of already approved antibody-drug conjugates and targeted therapies for prior platinum-chemotherapy and immunotherapy-treated patients. Further studies are needed to study this combination further in larger cohorts to establish its efficacy," Dr. Gupta said.

Dr. McGregor called the results "encouraging" for the combination at this point in time. "Discussions are ongoing about how best to take this combination forward in patients with urothelial carcinoma," he said.

— Leah Lawrence