Cabozantinib combo induces clinical activity in advanced ccRCC

Treatment with cabozantinib (Cabometyx) in combination with atezolizumab (Tecentriq) demonstrated promising clinical activity in patients with advanced clear cell renal cell carcinoma (ccRCC), according to results from the phase 1b COSMIC-021 study presented at the virtual 2020 ESMO Congress.

Objective response rates (ORRs) per investigator by RECIST v1.1 were 53% (80% CI, 41-65) in the 40-mg cohort and 58% (80% CI, 46-70) in the 60-mg cohort. Complete responses were observed in 1 patient in the 40-mg group and 4 patients in the 60-mg group; while 17 partial responses in each cohort were also seen. Fourteen patients in the 40-mg group and 12 patients in the 60-mg group experienced stable disease. Moreover, only 2 patients in each group had progressive disease.

“The combination of cabozantinib and atezolizumab demonstrated encouraging clinical activity in previously untreated patients with advanced ccRCC,” Sumanta Kumar Pal, MD, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, said during a presentation of the ccRCC cohort at the virtual Congress.

In the trial, the initial cohort of patients received 40 mg of cabozantinib, while an expansion cohort was administered 60 mg. Median follow-up for the 40- and 60-mg dose groups were 25.8 months and (range, 20-33) and 15.3 months (range, 10-32), respectively.

The 40-mg group demonstrated a disease control rate (DCR) of 94%, while the 60-mg group showed a DCR of 92%. Duration of response has not been reached in the 40-mg cohort (12.4 months to not evaluable), while the 60-mg group’s DOR was 15.4 months (8.1 to not evaluable).

The time to objective response in the 40- and 60-mg groups were 1.4 months (range, 1-19) and 1.5 months (range, 1-7), respectively.

Cabozantinib administered at 40 mg induced a median progression-free survival (PFS) of 19.5 months (95% CI, 11.0 to not reached), while the 60-mg dose showed a median PFS of 15.1 months (95% CI, 8.2-22.3).

Any reduction in tumor target lesions occurred in 94% of the 40-mg cohort and 92% of the 60-mg group. “Many patients with sarcomatoid features had a large target reduction,” Pal added.

The investigators also evaluated baseline tumor PD-L1 and CD8 T-cell status to determine lesion change and response. They found that baseline PD-L1-positive status and CD8-positive T cells were associated with greater tumor lesion reductions and with overall response (P = .0003). In addition, T cell Rich tumors (CD68high and CD8high) were associated with greater tumor shrinkage from baseline and higher overall response, with 10 of 13 patients who responded to treatment with cabozantinib (77%). “The status of the pretreatment tumor with respect to the immune cell population may contribute to tumor susceptibility to study treatment and warrants further investigation,” Pal said.

At data cutoff, 14 and 18 patients, respectively, in the 40- and 60-mg cohorts remained on treatment with cabozantinib in combination with atezolizumab.

In total 19 adverse events (AEs; 56%) in the 40-mg group and 31 (86%) in the 60-mg group led to cabozatinib dose reductions. Seven (21%) and 11 (31%) patients, respectively, discontinued treatment due to radiographic progression. In addition, 8 (24%) and 7 (19%) patients discontinued treatment due to treatment-related AEs (TRAEs) from cabozatinib and/or atezolizumab.

Almost all patients experienced TRAEs, which included diarrhea, fatigue, nausea, dysgeusia, hypertension, increased ALT, palmar-plantar erythrodysesthesia, stomatitis, increased AST, hypophosphatemia, decreased appetite, pruritus, hypothyroidism, decreased weight, increase lipase, mucosal inflammation, and proteinuria.

“Cabozantinib inhibits tyrosine kinases, including MET, VEGF receptors, and TAM family of kinases,” Pal explained. “It promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors.”

The agent has shown promising activity in combination with immune checkpoint inhibitors in tumor types including renal cell carcinoma, urothelial carcinoma, prostate cancer, lung cancer, and hepatocellular carcinoma.

The phase 1b COSMIC-021 study was designed to evaluate cabozantinib in combination with atezolizumab in patients with solid tumors.

To be eligible for the study, patients must have been diagnosed with advanced or metastatic ccRCC, had no prior systemic therapy for RCC, had measurable disease per RECIST v1.1, and had an ECOG performance score of 0 or 1.

The initial cohort of patients in the trial received 40 mg of cabozantinib oral once daily and 1200 mg of atezolizumab intravenously (IV) every 3 weeks (n = 34). Subsequently, in the expansion cohort, additional patients received 60 mg of cabozantinib oral once daily with the same atezolizumab regimen (n = 36) to evaluate the safety and efficacy of the higher dose.

ORR by the investigator per RECIST v1.1 served as the primary end point of the expansion phase of the study. Safety served as the secondary end point, while exploratory end points included PFS and correlations of biomarkers with outcomes.

Ten patients with ccRCC (4 at the dose level of 40 mg and 6 at the dose level of 60 mg) were included in the presentation at the virtual Congress. Data were presented for all 70 patients with ccRCC at the data cutoff of July 21, 2020.

Median age was 68 years (range, 39-87) in the 40-mg dose group and 60 years (range, 42-82) in the 60-mg dose group. In both groups, the majority of patients were male (79% vs 72%, respectively), and had an ECOG score of 0 (79% vs 69%), intermediate IMDC risk (76% vs 58%), prior nephrectomy (85% vs 89%), and metastases in the lung (79% vs 75%).

The investigators are now conducting the phase 3 CONTACT-03 trial (NCT04338269), designed to evaluate cabozantinib, with or without atezolizumab, in patients with RCC who were previously treated with an immune checkpoint inhibitor.

Reference

1. Pal S, Tsao CK, Suarez C, et al. Cabozantinib (C) in combination with atezolizumab (A) as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from the COSMIC-021 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 702O.