Tanios S. Bekaii-Saab, MD
Knowledge from the section 1/2 ARC-9 examine (NCT04660812) revealed that sufferers handled with a routine consisting of the twin A2a and A2b receptor antagonist etrumadenant; the PD-1 monoclonal antibody zimberelimab; 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6); and bevacizumab (Avastin), achieved the longest general survival (OS) reported from a randomized trial within the third-line setting for sufferers with metastatic colorectal most cancers (CRC).1
Findings offered on the 2024 ASCO Annual Assembly confirmed that sufferers receiving the mix skilled a major enchancment in progression-free survival (PFS) and OS in contrast with sufferers who acquired regorafenib (Stivarga).
“Adenosine-mediated signaling impairs activation, proliferation, and the cytotoxic exercise of an important cells, the T cells, and by blocking adenosine these T cells will turn out to be extra lively, which is essential,” Tanios S. Bekaii-Saab, MD, stated in an interview with OncLive®. “In the event that they turn out to be extra lively, after which mixture [therapy is given with] a PD-1 inhibitor [such as] zimberelimab with etrumadenant, you’d begin seeing extra exercise.”
Bekaii-Saab is chief of the Gastrointestinal Most cancers Program on the Mayo Clinic Complete Most cancers Heart in addition to medical director of the Most cancers Scientific Analysis Workplace and vice chair and part chief for Medical Oncology at Mayo Clinic in Phoenix, Arizona.
Analyses have proven that CRC has very excessive tumor expression ranges of CD73, the principle supply of extracellular adenosine. Extracellular adenosine drives immunosuppression by activating the A2aR and A2bR adenosine receptors on immune cells, which inhibits their exercise and permits for tumor development.2
“ARC-9 [was a] examine that struck me, and I used to be impressed with the outcomes extra so than another examine in that house. The good factor about ARC-9 is that it was a randomized examine various brokers.” Bekaii-Saab famous. “This [trial employed] a crossover design which is essential to remember as we interpret the outcomes of the examine, however while you put all these [agents] collectively the outcomes are very spectacular. This [combination] was in contrast with regorafenib used with a dose optimization technique and the HRs have been a few of the greatest I’ve seen and the OS of 19 months was the best I’ve seen on this setting.”
At a median follow-up of 20.4 months, the median OS in sufferers handled with the etrumadenant mixture (n = 75) was 19.68 months (95% CI, 14.69-20.60) vs 9.49 months (95% CI, 7.95-12.52) for these handled with regorafenib (n = 37; HR, 0.37; 95% CI, 0.22-0.63; P < .001). The 6- and 12- month OS charges have been 90% and 64%, respectively, with the investigational routine, vs 71% and 34%, respectively, with regorafenib. OS in addition to PFS advantages have been additionally persistently longer with the mix vs regorafenib in all subgroups analyzed. Relating to the first finish level of PFS, a statistically vital enchancment was seen with the etrumadenant mixture in contrast 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) noticed, respectively (HR, 0.27; 95% CI, 0.17-0.43; P < .001).1
Relating to security, critical treatment-emergent antagonistic results (TEAEs) occurred in 50% of sufferers receiving the mix in contrast with 26% of these handled with regorafenib. TEAEs led to discontinuation of a examine drug in 59% vs 20% of sufferers, respectively, and no TEAEs led to dying in both arm.
“[It was] very spectacular seeing these ends in sufferers with microsatellite secure illness [more so] than another examine I’ve seen. That’s very promising and hopefully we’ll proceed to maneuver ahead with a bigger examine. The query is how will we perceive the contribution of [all the] elements? One of many questions is are we certain that FOLFOX will not be including many of the exercise right here?” Bekaii-Saab requested.
He famous that information from research such because the section 3 TML examine (NCT00700102) have helped to reply this query because it confirmed that the median OS for sufferers who acquired bevacizumab plus both oxaliplatin or irinotecan-based chemotherapy (n =409) after first development was 11.2 months in contrast with 9.8 months amongst sufferers who acquired chemotherapy (n =410; stratified HR, 0.83; 95% CI, 0.71-0.97; P = .0211 ). Severe AEs occurred in 34% vs 32% of sufferers, respectively.3
“On this examine sufferers had [received] FOLFOX, however in sufferers who haven’t seen FOLFOX earlier than, the [best] response charge is roughly 4% to 10% and survival [lengths] don’t go [past approximately] 10 months,” he stated. “What we’re seeing [with the ARC-9 data] is impactful and till we get to a section 3 examine it’s troublesome to say whether or not that’s going to be maintained. However that’s one of the attention-grabbing research on this house. Excited about the areas of want and areas of future potential impression, this definitely stands out.”
References
- Wainberg ZA, Han SW, Lee S, et al. ARC-9: a randomized examine to guage etrumadenant based mostly therapy mixtures in beforehand handled metastatic colorectal most cancers (mCRC). J Clin Oncol. 2024;42(suppl 16):3508. doi:10.1200/JCO.2024.42.16_suppl.3508
- Marubayashi S, Piovesan D, Soriano F, et al. Mixed administration of the twin A2aR/A2bR antagonist etrumadenant with a lowered chemotherapy routine results in enhanced tumor efficacy and survival. Introduced at: 2023 SITC Annual Assembly; November 1-5, 2023; San Diego, CA. Summary 793.
- Arnold D, Andre T, Bennouna J, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued past first development in sufferers with metastatic colorectal most cancers (mCRC) beforehand handled with BEV plus CT: outcomes of a randomized section III intergroup examine (TML examine). J Clin Oncol. 2012;30(suppl 18):CRA3503. doi:10.1200/jco.2012.30.15_suppl.cra3503
