Longest OS Reported From a Third-Line mCRC Randomized Trial Is Seen in ARC-9 Study

Tanios S. Bekaii-Saab, MD

Data from the phase 1/2 ARC-9 study (NCT04660812) revealed that patients treated with a regimen consisting of the dual A2a and A2b receptor antagonist etrumadenant; the PD-1 monoclonal antibody zimberelimab; 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6); and bevacizumab (Avastin), achieved the longest overall survival (OS) reported from a randomized trial in the third-line setting for patients with metastatic colorectal cancer (CRC).¹

Findings presented at the 2024 ASCO Annual Meeting showed that patients receiving the combination experienced a significant improvement in progression-free survival (PFS) and OS compared with patients who received regorafenib (Stivarga).

“Adenosine-mediated signaling impairs activation, proliferation, and the cytotoxic activity of the most important cells, the T cells, and by blocking adenosine those T cells will become more active, which is important,” Tanios S. Bekaii-Saab, MD, said in an interview with OncLive®. “If they become more active, and then combination [therapy is given with] a PD-1 inhibitor [such as] zimberelimab with etrumadenant, you would start seeing more activity.”

Bekaii-Saab is leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center as well as medical director of the Cancer Clinical Research Office and vice chair and section chief for Medical Oncology at Mayo Clinic in Phoenix, Arizona.

Analyses have shown that CRC has very high tumor expression levels of CD73, the main source of extracellular adenosine. Extracellular adenosine drives immunosuppression by activating the A2aR and A2bR adenosine receptors on immune cells, which inhibits their activity and allows for tumor growth.²

“ARC-9 [was a] study that struck me, and I was impressed with the results more so than any other study in that space. The nice thing about ARC-9 is that it was a randomized study looking at a number of agents.” Bekaii-Saab noted. “This [trial employed] a crossover design which is important to keep in mind as we interpret the results of the study, but when you put all these [agents] together the results are very impressive. This [combination] was compared with regorafenib used with a dose optimization strategy and the HRs were some of the best I’ve seen and the OS of 19 months was the highest I’ve seen in this setting.”

At a median follow-up of 20.4 months, the median OS in patients treated with the etrumadenant combination (n = 75) was 19.68 months (95% CI, 14.69-20.60) vs 9.49 months (95% CI, 7.95-12.52) for those treated with regorafenib (n = 37; HR, 0.37; 95% CI, 0.22-0.63; P < .001). The 6- and 12- month OS rates were 90% and 64%, respectively, with the investigational regimen, vs 71% and 34%, respectively, with regorafenib. OS as well as PFS benefits were also consistently longer with the combination vs regorafenib in all subgroups analyzed. Regarding the primary end point of PFS, a statistically significant improvement was seen with the etrumadenant combination compared with regorafenib, with a median PFS of 6.24 months (95% CI, 5.49-7.52) vs 2.07 months (95% CI, 1.84-2.96) observed, respectively (HR, 0.27; 95% CI, 0.17-0.43; P < .001).¹

Regarding safety, serious treatment-emergent adverse effects (TEAEs) occurred in 50% of patients receiving the combination compared with 26% of those treated with regorafenib. TEAEs led to discontinuation of a study drug in 59% vs 20% of patients, respectively, and no TEAEs led to death in either arm.

“[It was] very impressive seeing these results in patients with microsatellite stable disease [more so] than any other study I’ve seen. That’s very promising and hopefully we’ll continue to move forward with a larger study. The question is how do we understand the contribution of [all the] components? One of the questions is are we sure that FOLFOX is not adding most of the activity here?” Bekaii-Saab asked.

He noted that data from studies such as the phase 3 TML study (NCT00700102) have helped to answer this question as it showed that the median OS for patients who received bevacizumab plus either oxaliplatin or irinotecan-based chemotherapy (n =409) after first progression was 11.2 months compared with 9.8 months among patients who received chemotherapy (n =410; stratified HR, 0.83; 95% CI, 0.71-0.97; P = .0211 ). Serious AEs occurred in 34% vs 32% of patients, respectively.³

“In this study patients had [received] FOLFOX, but in patients who have not seen FOLFOX before, the [best] response rate is approximately 4% to 10% and survival [lengths] don’t go [past approximately] 10 months,” he said. “What we’re seeing [with the ARC-9 data] is impactful and until we get to a phase 3 study it’s difficult to say whether that’s going to be maintained. But that’s one of the most interesting studies in this space. Thinking about the areas of need and areas of future potential impact, this certainly stands out.”

References

1. Wainberg ZA, Han SW, Lee S, et al. ARC-9: a randomized study to evaluate etrumadenant based treatment combinations in previously treated metastatic colorectal cancer (mCRC). J Clin Oncol. 2024;42(suppl 16):3508. doi:10.1200/JCO.2024.42.16_suppl.3508
2. Marubayashi S, Piovesan D, Soriano F, et al. Combined administration of the dual A2aR/A2bR antagonist etrumadenant with a reduced chemotherapy regimen leads to enhanced tumor efficacy and survival. Presented at: 2023 SITC Annual Meeting; November 1-5, 2023; San Diego, CA. Abstract 793.
3. Arnold D, Andre T, Bennouna J, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). J Clin Oncol. 2012;30(suppl 18):CRA3503. doi:10.1200/jco.2012.30.15_suppl.cra3503