Tivozanib Plus Atezolizumab Under Investigation in Immunologically Cold Tumors

The safety and efficacy of the immune checkpoint inhibitor (ICI) atezolizumab (Tecentriq) plus the VEGF TKI tivozanib (Fotivda) is being investigated in patients with unresectable or metastatic castrate-resistant prostate cancer (mCRPC), as well as those with several other immunologically cold tumors as part of the phase 1b/2 IMMCO-1 trial (NCT05000294).¹

“The increasing use of immune checkpoint inhibitors [ICIs] has truly revolutionized cancer therapy,” said Jonathan Chatzkel, MD, first study author and an assistant professor of medicine in the Division of Hematology and Oncology at the University of Florida College of Medicine, University of Florida Health, in an interview with OncLive^®. “Traditionally, immunotherapy has been heavily utilized in ‘hot’ tumors…[However], we feel that VEGF inhibition can potentiate the effect of ICIs in cold tumors through vascular normalization and decreasing inhibitory signals.”

ICI/VEGF TKI combinations are well established as a standard of care in advanced kidney, cervical, and endometrial cancers. However, the use of ICIs alone has not shown efficacy in immunologically cold tumors, including mCRPC, that are microsatellite stable and have low tumor mutational burden. Investigators hypothesized that the addition of a VEGF TKI to a PD-L1 inhibitor could bolster the effect of an immune checkpoint blockade, thereby improving antitumor immune responses.

“We’ve long since known that the combination of VEGF inhibitors and immunotherapy has been effective in various tumor types—most specifically, in kidney cancer…” Chatzkel explained. “There is also evidence for these combinations in hepatocellular cancer, as well as an increasing [amount of] new evidence in cold tumors.”

The single-center basket study is enrolling patients with mCRPC that progressed on an androgen inhibitor such as enzalutamide (Xtandi) or abiraterone acetate (Zytiga), or on cytotoxic chemotherapy in the advanced or metastatic setting. Patients who had progressed on, declined, or were intolerant to other standard treatments and had the following tumors were also eligible: biliary tract cancers like cholangiocarcinoma and gallbladder cancer; HER2-positive, hormone receptor–negative breast cancers; ovarian and vulvar cancers; soft tissue sarcoma; or well-differentiated, grade 2 or 3 neuroendocrine tumors.

Additional eligibility criteria include being at least 18 years of age, having adequate hematologic and end-organ function, a life expectancy of at least 12 weeks, and measurable disease by RECIST v1.1 criteria. Those in the phase 1b portion of the study must have an ECOG performance status of 0 or 1, and those in phase 2 portion must have a status between 0 to 2.

Key exclusion criteria include having known mismatch repair deficiency, microsatellite instability, high tumor mutational burden, or having received prior ICI therapy.

In the phase 1b 3+3 dose de-escalation portion of the study, investigators will identify the recommended dose of tivozanib. Those treated in the phase 1b portion of the study will then be examined in the phase 2 portion of the research. At dose level 0, tivozanib will be administered at a dose of 1.34 mg daily for 21 days of each 28-day treatment cycle.

To mitigate the incidence of hypertension in the phase 1b portion of the study, a protocol amendment reduced the dose to 0.89 mg daily for 21 days of each 28-day cycle at dose level 0; at dose level -1, the dose has been reduced to 0.89 mg every other day given continuously. Atezolizumab is given at a dose of 1680 mg once every 28 days. Treatment will continue until disease progression or treatment intolerance.

The phase 2 portion of the trial utilizes a Simon’s 2-stage design, wherein 2 or more responses must be observed in the first 16 evaluable patients before an additional 10 evaluable patients are accrued. Investigators aim to enroll 33 participants, accounting for a 20% study drop-out rate.

“Tivozanib is the only agent that’s currently FDA approved in the second-line setting for kidney cancer,” Chatzkel noted. “One of the things that appealed to us about including tivozanib in the study combination is that we felt its [selectivity for] VEGF would help us [better] manage the toxicity [associated with] doublet therapy.”

Computed tomography scans of the chest, abdomen and pelvis will be conducted every 12 weeks to assess disease response via RECIST v1.1 criteria. Moreover, significant adverse effects (AEs) will be reviewed by the University of Florida’s Data Integrity and Safety Committee.¹

The trial’s co-primary end points include safety and an overall response rate at or above 25% vs a null hypothesis of <7% (1-sided alpha = 0.05; 80% power), as measured by RECIST v1.1 criteria.Secondary end points include progression-free survival, overall survival, and disease control rate.²

“If this study showed an early efficacy signal, and additional studies were positive, a whole new avenue of treatment could open up [for] patients [who] traditionally have not benefited from the revolution of immunotherapy,” Chatzkel concluded.

The IMMCO-1 study is actively enrolling patients toward an upcoming preplanned interim analysis. No unexpected AEs have been reported to date.

Editor’s Note: Dr. Chatzkel reports receiving research funding from AVEO (Inst), Genentech (Inst), Merck (Inst).

References

1. Chatzkel JA, Lee JH, Ali A, et al. A phase Ib/II study (IMMCO-1) of atezolizumab plus tivozanib in castrate-resistant prostate cancer and certain other immunologically cold tumors. J Clin Oncol. 2023;41(suppl 6):TPS293. doi:10.1200/JCO.2023.41.6_suppl.TPS293
2. Atezolizumab plus tivozanib in immunologically cold tumor types. ClinicalTrials.gov. Updated January 18, 2023. Accessed March 20, 2023. https://clinicaltrials.gov/ct2/show/NCT05000294