Combination Therapy With Cabozantinib and Atezolizumab Gains Foothold in Urothelial Carcinoma

Sumanta K. Pal, MD

Patients with urothelial carcinoma who progress after treatment with platinum-containing chemotherapy may receive benefit with the combination systemic therapy regimen of cabozantinib (Cabometyx) and atezolizumab (Tecentriq), according to new data from the COSMIC-021 study (NCT03170960).¹

The trial is a multicenter phase 1b study evaluating the combination of cabozantinib with atezolizumab in various solid tumors. Sumanta K. Pal, MD, a clinical professor in the Department of Medical Oncology & Therapeutics Research and codirector of the Kidney Cancer Program at City of Hope in Duarte, California, presented results from urothelial carcinoma expansion cohort 2 (n = 30) in a poster presented as part of the 2020 American Society of Clinical Oncology Virtual Scientific Program.

At a median follow-up of 19.7 months, the objective response rate (ORR) was 27%, with 2 (6.7%) complete responses and 6 (20%) partial responses. The disease control rate was 63% and 16 (53%) patients had any reduction in target lesion size.

The median duration of response was not reached with the longest response ongoing at more than 15.6 months. The median time to response was 3.0 months (range, 1-6).

Investigators observed 22 progression-free survival events (PFS). The median PFS was 5.4 months (95% CI, 1.5-7.6).

These preliminary results do not suggest an association between PD-L1 expression and tumor response.

“A combination of cabozantinib and atezolizumab demonstrated encouraging clinical activity in patients with urothelial carcinoma previously treated with platinum-containing chemotherapy, with an objective response rate of 27% and deep and durable responses,” Pal said. “Additional cohorts evaluating the combination in urothelial carcinoma have been initiated in cisplatin-ineligible and cisplatin-eligible disease without prior systemic therapy, as well as urothelial carcinoma previously treated with checkpoint-inhibitor therapy.”

Ninety percent of diagnoses of urothelial carcinoma occur in patients aged 55 or older.² It is the fourth most common cancer in men and accounts for 4.5% of all new cases of cancer in the U.S. each year.^3,4

COSMIC-021 is divided into 2 parts: a dose-escalation phase and an expansion-cohort phase.

Investigators in the dose-escalation phase determined the optimal dose of cabozantinib to be 40 mg daily when given in combination with 1200 mg atezolizumab every 3 weeks.

In the expansion-cohort phase, there are 24 cohorts across 12 tumor types: urothelial carcinoma, renal cell carcinoma, non–small cell lung cancer, metastatic castration-resistant prostate cancer (mCRPC), hepatocellular carcinoma, triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal cancer, head and neck cancer, and differentiated thyroid cancer.

To be eligible for the urothelial carcinoma cohort, patients had to be diagnosed with inoperable locally advanced, metastatic, or recurrent disease that had progressed on or after treatment with a platinum-containing chemotherapy. Patients were required to have an ECOC score of 0 or 1.

All patients in the cohort were included in the safety analysis. Twenty-seven (90%) patients experienced a treatment-related adverse event (TRAE). The most common were grade 1/2 asthenia (37%), diarrhea (27%), decreased appetite (23%), increased transaminases (23%), and mucosal inflammation (20%).

Seventeen (56.3%) patients experienced a grade 3/4 TRAE, the most common being grade 3 pulmonary embolism (13%) followed by grade 3 asthenia (6.7%). No other grade 3/4 TRAE occurred in more than 1 (3.3%) patient.

There was 1 incident of a grade 3 immune-related AE, chorioretinitis, and no incidences of grade 4 immune-related AEs.

Investigators did not observe any discontinuations due to TRAEs. “The combination exhibited an acceptable safety profile in this patient population,” Pal said.

Findings from the mCRPC cohort reported at the 2020 Genitourinary Cancers Symposium showed that the combination induced an ORR of 32%, including 2 complete responses and 12 partial responses. The ORR was 33% in subgroup of patients with high-risk clinical features, including visceral metastases and/or extra-pelvic lymph node metastases.^5,6

^References

1. ^{Pal SK, Agarwal N, Loriot Y, et al. Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study. J Clin Oncol. 38: 2020 (suppl; abstr 5013). doi:10.1200/JCO.2020.38.15_suppl.5013}
2. ^{American Cancer Society. Bladder Cancer Key Statistics. Accessed May 30, 2020. cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics}
3. ^{National Cancer Institute. SEER Stat Fact Sheets: Bladder Cancer. Accessed May 30, 2020. seer.cancer.gov/statfacts/html/urinb.html}
4. ^{American Cancer Society: Cancer Facts & Figures 2020. Accessed May 30, 2020. cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf}
5. ^{Exelixis announces encouraging results for cabozantinib in combination with atezolizumab in metastatic castration-resistant prostate cancer [news release]: Alameda, CA. Exelixis, Inc. Accessed May 30, 2020. bit.ly/39pNIcj}
6. ^{Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): results of cohort 6 of the COSMIC-021 Study. J Clin Oncol. 2020;38(suppl; abstr 139).}