Cabozantinib Plus Atezolizumab Active in mCRPC

Neeraj Agarwal, MD

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) demonstrated clinically meaningful activity in patients with metastatic castration-resistant prostate cancer (mCRPC), including those with high-risk clinical features, according to cohort findings of the phase Ib COSMIC-021 trial (NCT03170960) that were presented at the 2020 Genitourinary Cancers Symposium.^1,2

Results showed that the combination elicited an overall response rate (ORR) of 32%, including 2 complete responses and 12 partial responses, in the overall cohort of patients with mCRPC. In a subgroup of patients with high-risk clinical features, which included those with visceral metastases and/or extra-pelvic lymph node metastases, the ORR was 33%.

“Given the poor prognosis for men with metastatic castration-resistant prostate cancer, measurable visceral disease and/or extra-pelvic lymph node metastases who have progressed on novel hormone therapies, we are excited to observe clinically meaningful activity with the combination of cabozantinib and atezolizumab in this COSMIC-021 cohort,” study investigator Neeraj Agarwal, MD, professor, Huntsman Cancer Center, University of Utah, stated in a press release. “Emerging data suggests a tolerable safety profile and encouraging efficacy for this combination that may hold promise for these patients with limited treatment options, potentially providing patients with more time before the need for treatment with chemotherapy. We look forward to additional results as the trial progresses.”

The multicenter, open-label, phase Ib COSMIC-021 trial is evaluating the combination of atezolizumab and cabozantinib in patients with locally advanced or metastatic solid tumors. The trial is divided into 2 parts: a dose-escalation phase and an expansion-cohort phase. In the dose-escalation phase, investigators enrolled patients either with advanced renal cell carcinoma (RCC) with or without prior systemic therapy, or with inoperable, locally advanced, metastatic or recurrent urothelial carcinoma following prior platinum-based therapy. However, all 12 patients enrolled in this trial stage comprised those with advanced RCC. Results showed that the optimal cabozantinib dose was 40 mg daily when added to 1200 mg of atezolizumab infusion once every 3 weeks.³

In the expansion-cohort phase, there are 24 cohorts spanning 12 tumor types: RCC, urothelial carcinoma, non—small cell lung cancer (NSCLC), CRPC, hepatocellular carcinoma (HCC), triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, head and neck cancer, and differentiated thyroid cancer.

Up to 1720 patients may enroll in this phase of this trial, and each expansion cohort will initially enroll approximately 30 patients. Up to 10 cohorts could further expand enrollment, leading to up to 1000 patients across potential additional expansion cohorts. Four cohorts are exploratory; 3 cohorts are enrolling approximately 30 patients each with advanced urothelial carcinoma, CRPC, or NSCLC, who will receive single-agent cabozantinib, and 1 cohort is enrolling approximately 10 patients with advanced CRPC who will be treated with single-agent atezolizumab.

In January 2020, Exelixis, the developer of cabozantinib, announced that the mCRPC cohort of COSMIC-021, known as cohort 6, had been expanded to enroll up to 130 patients.

In the ongoing mCPRC cohort, patients must have measurable disease as per RECIST v1.1 criteria and progressed on prior novel hormonal therapy; prior treatment with docetaxel was permitted for those who had hormone-sensitive disease. Patients also must have an ECOG performance status of 0 or 1, as well as adequate organ and marrow function.

Those who have received prior treatment with cabozantinib or a checkpoint inhibitor, have known brain metastases or cranial epidural disease, or have had concomitant anticoagulation cannot enroll on the trial.

Cabozantinib was administered orally at 40 mg once daily and intravenous atezolizumab was given at 1200 mg every 3 weeks. The cabozantinib dosage could be reduced to 20 mg daily, and then further to 20 mg every other day to manage adverse events (AEs); atezolizumab treatment could be delayed to manage AEs.

Thirty-six (82%) patients had high-risk mCRPC, which was defined as having visceral and/or extra-pelvic lymph node metastases; 15 patients (34%) had visceral metastases and 27 (61%) had extra-pelvic lymph node metastases. Twenty-five patients (57%) had a Gleason score ≥8 at diagnosis. Moreover, 12 patients (27%) received prior docetaxel for metastatic castration-sensitive disease, and all 44 patients had received prior novel hormonal therapy, including abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa).

The primary endpoint is recommended dose/maximum-tolerated dose in the dose-escalation phase and ORR in the dose-expansion phase. Safety is a secondary endpoint. Investigators assessed tumors by CT/MRI at screening, every 6 weeks for the first 12 months, and then every 12 weeks thereafter.

The interim analysis of the mCRPC cohort included 54 patients; the data cutoff date was December 20, 2019. The median duration of treatment was 6.3 months (range, 1-18 months); the median time to objective response was 1.6 months (range, 1-7).

At a median follow-up of 12.6 months, additional results showed that the disease control rate was 80%, and the median duration of response was 8.3 months. Among 12 patients who had an objective response and ≥1 post-baseline prostate-specific antigen (PSA) evaluation, 67% of patients had a PSA decline of ≥50%.

The treatment discontinuation rate due to adverse events (AEs) was 7%. Moreover, no new safety signals were identified in this cohort. The rate of grade 3/4 AEs was 59%; treatment-related grade 3/4 AEs occurring in ≥5% of patients were fatigue (7%), diarrhea (7%) and hyponatremia (7%). One treatment-related grade 5 AE of dehydration was reported in a 90-year-old patient with a 6-month history of heart failure.

“We’re happy to share these encouraging results from the metastatic CRPC cohort from COSMIC-021, our first trial evaluating the combination of cabozantinib and atezolizumab,” Gisela Schwab, MD, president, Product Development and Medical Affairs, chief medical officer, Exelixis, stated in the press release. “We look forward to receiving data from the most recent expansion of this CRPC cohort while we are also preparing for the initiation of a phase III pivotal trial in this indication. We are excited about the emerging data in metastatic CRPC and elsewhere and the potential of combining cabozantinib with immunotherapies in this and other difficult-to-treat tumor types.”

The company also stated in the press release that it is expecting to file for an accelerated approval of atezolizumab and cabozantinib for use in patients with mCRPC as early as 2021, pending regulatory feedback from the FDA and supportive clinical data.

Cabozantinib is currently indicated for the treatment of patients with advanced RCC, as well as for the treatment of patients with HCC who received prior treatment with sorafenib (Nexavar). Atezolizumab has approved indications in urothelial carcinoma, NSCLC, metastatic triple-negative breast cancer, and extensive-stage small cell lung cancer.

References

1. Exelixis announces encouraging results for cabozantinib in combination with atezolizumab in metastatic castration-resistant prostate cancer [news release]: Alameda, CA. Exelixis, Inc. Published February 10, 2020. https://bit.ly/39pNIcj. Accessed February 11, 2020.
2. 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).
3. Agarwal N, Vaishampayan U, Green M, et al. Phase 1b study (COSMIC-021) of cabozantinib in combination with atezolizumab: results of the dose escalation stage in patients (pts) with treatment-naïve advanced renal cell carcinoma (RCC). Ann Oncol. 2018;29(suppl_8):viii303-viii331. doi: 10.1093/annonc/mdy283.

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