Sumanta Pal, M.D., co-director of the Kidney Cancer Program at City of Hope ESMO Virtual Congress 2020: COSMIC-021, Cabozantinib in Combination with Atezolizumab as First-Line Therapy for Advanced Clear Cell Renal Cell Carcinoma.
(UroToday.com) COSMIC-021 is a clinical trial platform investigating the combination of a cabozantinib inhibitor of MET/VEGF/TAM kinase in combination with an atezolizumab anti-PD-L1 drug. The justification for this combination is based on evidence indicating that cabozantinib supports an immune-permissive environment that may boost responses to blockade of immune checkpoints and clinical data showing promising combination activity in multiple types of tumors. In this presentation, Dr. Pal shared data from the COSMIC-021 (NCT03170960) cohort investigating the efficacy (by objective response rate) and safety of the combination of this medication in previously untreated patients with advanced clear-cell renal cell carcinoma (ccRCC).
Below the study design is displayed. The initial dosage of cabozantinib was 40 mg per day, but this was raised in January 2019 to 60 mg. Data from 70 ccRCC patients enrolled as of July 21, 2020, is presented in total. In the 40 mg dosing group (25.8 months), the median follow-up was longer compared with the 60 mg dosing group (15.3 months).
Researchers determined the tumor responses. In each cabozantinib dosing group, the objective response rates were identical, and each group had a disease control rate of over 90 percent. The response was long-lasting, with a median period of response not reached in the 40 mg community of cabozantinib.
Importantly, as shown by the patients denoted with a '+' symbol, many patients with tumors that contained sarcomatoid characteristics sustained decreases in tumor size on treatment.
In this study, median progression-free survival and exploratory endpoints were 19.5 months in the 40 mg cabozantinib and 15.1 months in the 60 mg cabozantinib classes respectively. More than 40 percent of patients were already under care in each arm at the time of the data cut-off. Features of opioid exposure and patient temperament.
Adverse events associated with care are noted below. Grade 3⁄4 diarrhea occurred in more patients in the 60 mg cabozantinib treatment community. An immune-related adverse event was sustained by 35 percent of patients. For the treatment of IrAEs, three patients in the 40 mg group and 9 patients in the 60 mg group required high-dose steroids.
PD-L1 status was assessed using the Ventana SP142 assay for correlative studies, given its higher affinity for PD-L1 immune cell expression. In the tumor tissue, the number of CD8 positive T cells was counted. Therapy was more likely to react to tumors with PD-L1 expression and/or large numbers of CD8 T cells.
Tumors enriched with T-cells were more likely to respond to therapy in general.
Dr. Pal concluded by suggesting that the combination of cabozantinib and atezolizumab, with acceptable safety profiles, showed promising clinical efficacy. Correlative studies indicated that tumors of PD-L1+ with high infiltrates of CD8+ T cells were more likely to respond to therapy. A Phase 3 research (CONTACT-03) comparing cabozantinib +/- atezolizumab in mRCC previously treated with immune checkpoint blockade is now underway to confirm the activity of this combination.