Cabozantinib/Atezolizumab Combo Demonstrates Promising Clinical Activity in mCRC

Thomas A. Abrams, MD

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) elicited a meaningful overall response rate (ORR) in patients with non–microsatellite instability high (MSI-H) and mismatch repair–proficient (MMRp) metastatic colorectal cancer (mCRC), according to data from the phase 1b COSMIC-021 trial (NCT03170960).¹

The findings, which were presented during the 2022 Gastrointestinal Cancers Symposium, showed that at a median follow-up of 21.8 months, the doublet produced an ORR of 10% per RECIST v1.1 criteria in a cohort of 31 patients with mCRC; this included 3 confirmed partial responses (PRs). Notably, all 3 PRs were observed in patients with RAS wild-type disease, according to Thomas A. Abrams, MD, who was the lead author on the study.

“Most of the patients who had long-term disease stability, or all of the patients who had responses, [had] RAS wild-type [disease],” Abrams said. “RAS is a well-known gene in colon cancer; it is mutated approximately 60% of the time, [and it] confers resistance to EGFR inhibitors. The wild-type population were the [patients] who extracted the most benefit from this [approach]. That is very interesting, and it creates a hypothesis for future studies.”

In an interview with OncLive^®, Abrams, who is also a senior physician at the Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, discussed the ongoing phase 1b COSMIC-021 trial examining cabozantinib/atezolizumab, the efficacy and safety demonstrated with the regimen in those with CRC, and the next steps for research.

OncLive^®: What served as the basis and rationale for the COSMIC-021 trial?

Abrams: We have been trying to combine immune checkpoint inhibitors with other drugs to induce responses in microsatellite stable colon cancers for quite some time. A few high-profile studies have failed, and we are lagging in CRC with respect to utility of these drugs. It is natural to try to figure out logical pairings.

A lot of preclinical data suggest that cabozantinib, which is a TKI that is approved [for use] in several cancers, might have the ability to induce microsatellite stable CRC to start responding to immunotherapy. [As such,] this was a natural pairing.

What was the design of this study?

This is a phase 1b, multitumor study, and [data from] the CRC cohort [were reported during the meeting]. The cohort included 31 patients, all of whom received the treatment, which is a combination of cabozantinib and atezolizumab. They were then followed. It is a simple study, with a primary end point of ORR.

What were the efficacy data reported during the meeting?

[We saw] 3 responses, which is better than what might have been expected, [although] it is hard to say exactly. This is very preliminary. You do not necessarily know what to expect, but [these] gratifying results show that this [approach] might be efficacious for some populations with microsatellite stable colon cancer [who have] already [received] at least 1 prior therapy. [In fact,] most of the patients in the trial had already [received] 2 prior therapies. [It is important to note that] this is a heavily pretreated group of patients.

What data were reported in terms of the exploratory end points of duration of response (DOR), progression-free survival (PFS), and overall survival (OS)?

Both PFS and OS, as well as DOR, were better in the RAS wild-type population; this speaks to the fact that this combination seemed to work better in this population.

What was found in terms of safety?

The treatment-related adverse effects [AEs] observed with the combination were typically in line with what you see with these drugs. Diarrhea, fatigue, nausea, were the chief AEs, and they were generally manageable. No treatment-related deaths [occurred].

You mentioned that some of these data could inspire new research efforts. What are the next steps for further exploration of this combination?

[Although] there are not any immediate ramifications, [this study] sets us up nicely for a potentially bigger phase 2 trial, [that can look at this regimen] specifically in [patients with] RAS wild-type [disease], who have already progressed on at least 1 line of therapy, to see what their potential outcomes would be. If we can continue to see that level of efficacy, then a phase 3 study would be a reasonable thing to do. However, we are far from that [at this stage].

What was learned about this doublet in those with RAS-mutated disease?

[This combination] clearly was not as efficacious [in those with RAS mutations as it was in those with wild-type disease]. However, this is an early study, and I am not sure what you can draw from that; the trend was real, but it is hard to say. That population has fewer drugs available to them. We are desperately looking for better options for those with RAS mutations, and that that remains a very big challenge in advanced CRC treatment.

Reference

1. Abrams TA, Ali Kazmi SM, Winer IS, et al. A phase 1b multitumor cohort study of cabozantinib plus atezolizumab in advanced solid tumors (COSMIC-021): results of the colorectal cancer cohort. J Clin Oncol. 2022;40(suppl 4):121. doi:10.1200/JCO.2022.40.4_suppl.121