Early Data With Copanlisib/Nivolumab Combo Support Further Exploration in MSS CRC

Although the addition of the PI3K inhibitor copanlisib (Aliqopa)to the PD-1 inhibitor nivolumab (Opdivo) elicited durable responses in a small subset of patients with microsatellite stable (MSS) colorectal cancer (CRC) in a phase 1/2a trial (NCT03711058), a significant clinical benefit was achieved, according to Eric S. Christenson, MD. He added that this study supports further evaluation of PIK3Ca-targeted therapies in this disease, and underscores the need for improved identification of those with these pathway alterations who are most likely to derive benefit from this approach.

In a presentation at the 2024 AACR Annual Meeting, the trial was reported to have met its primary end point of overall response rate at 6 months in the PIK3Ca-mutant cohort (n = 22), with 3 patients experiencing partial responses (PRs) and 2 patients achieving stable disease (SD). Moreover, 1 patient in the PIK3Ca wild-type cohort (n = 17) who harbored a PIK31R amplification experienced a PR, and 4 patients had SD. Notably, all responders across both cohorts maintained their responses for more than 24 months.

“[Copanlisib plus nivolumab] is an interesting combinatorial approach that deserves further investigation,” said Christenson, who is an assistant professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland. “Although a minority of patients [in this study achieved] dramatic benefits [with the combination], we could benefit a lot more patients [going forward] if we’re able to figure out who they are.”

In an interview with OncLive^®, Christenson discussed efficacy and safety findings from the phase 1/2 study of copanlisib plus nivolumab in this population, and the importance of further investigation into combinatorial approaches targeting the PI3K pathway.

OncLive: What was the rationale for investigating copanlisib in combination with nivolumab in patients with MSS CRC and why was the trial population limited to those with MSS disease?

Christenson: Copanlisib is a PIK3 inhibitor that hits multiple isoforms. These isoforms have both direct antitumor activities, but also help to modify antitumor immunity. We’re very interested in both of those activities and how they may interplay with nivolumab, which is an anti–PD-1 therapy that’s approved for many other disease types but has struggled as a monotherapy in MSS colorectal cancer. [We limited the scope to MSS patients because] mismatch repair–deficient [tumors; dMMR] are an exception to that rule in terms of the issues [experienced] with PD-1 monotherapy. This [trial aimed] to expand the number of patients that can benefit from these therapies.

What were some of the other key eligibility criteria for the phase 1/2 study?

We enrolled patients into 2 different cohorts. [Cohort 1 included] PIK3Ca wild-type tumors, with the rationale that some of the tumor immune-modifying effects may be relevant for both PIK3Ca-mutant and wild-type disease. The PIK3Ca-mutant cohort would probably have more in the way of direct antitumor effects, but also have that antitumor immunity. Other than that, we were targeting patients who had already seen first- and second-line chemotherapy, and were willing to undergo biopsies that will help hone [in] on the patients who will benefit the most from this approach.

What early efficacy and safety findings from the study were reported at the 2024 AACR Annual Meeting?

We had a total of 39 patients in the 2 cohorts, 22 [of whom] had PIK3Ca-mutant disease, and 17 with PIK3Ca wild-type disease. Four patients [achieved] a PR, 3 of whom had PIK3Ca-mutant disease and the fourth had wild-type disease. Interestingly, this patient did have an alteration within that PI3K/AKT pathway, which may explain why they responded. Additionally, some patients had SD, were able to stay on therapy, and did derive some clinical benefit. The most striking thing about this trial was that the 4 patients who did achieve a PR were all able to stay on therapy for more than 24 months, which we do not tend to see in these later-line MSS CRC trials. Although it unfortunately represented a minority of the patients we treated, those patients derived a huge clinical benefit from [copanlisib plus nivolumab]. Figuring out who those patients are is going to be critical to maximizing the impact of this trial.

In terms of safety, this regimen was generally well tolerated. PI3K inhibitors have a class effect of hyperglycemia, as well as hypertension. We didn’t see [high rates of] those [effects] with copanlisib, with grade 3/4 hypertension being present in less than half of patients. Hyperglycemia was a rare event for us; we only saw it in 3 patients. [This toxicity was] uncommon, but still something that we kept note of.

What does this research indicate about the future of PIK3Ca-targeted therapies in MSS CRC? Are any next steps planned?

We’re very excited to [see] a long durability of response, which we don’t see [in this space]. The next step is to understand what distinguishes those patients [who benefit from copanlisib plus nivolumab from the others.] Approximately 3% to 5% of CRC cases [can be classified as] dMMR. Depending on the cohort, PIK3Ca mutations are present in [approximately] 15% to 32% of patients, and the number [of patients who] have mutations within the PIK3/AKT pathway is [approximately] 50%. In terms of which segment of that population is going to benefit from [the combination], it does seem to be a smaller minority based on our trial.

What main message would you like to convey to colleagues regarding this trial and the overall meeting?

PI3K inhibition probably will have a place in the MSS CRC armamentarium going forward because of its direct antitumor and [indirect] tumor immune effects. [However], a lot needs to be done to push that further into the clinic in the best way.

Overall, I was left with a lot of optimism [after seeing the research presented at the 2024 ACCR Annual Meeting]. There are a lot of great targets, both from an immunotherapy perspective and the targeted therapy perspective, [including] ADCs. There is a lot of hope that we’ll be making huge breakthroughs in the near future, which we desperately need.

Editor’s Note: Dr Christenson disclosed serving as a consultant for Seres Therapeutics and SIRTex, and receiving grant/research support from Regeneron, NextCure, Affimed Gmbh, Haystack, and Pfizer.

Reference

Christenson ES, Wala JA, Parkinson R, et al. Phase 1/2 trial of copanlisib in combination with nivolumab for microsatellite stable (MSS) colorectal cancer (CRC). Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT007.