RAS-Directed Therapy and Patient Selection Are Sectors to Watch in Pancreatic Cancer

As RAS-directed therapy gains more traction in pancreatic cancer, a phase 3 trial will soon be initiated to examine the RAS(ON) multi-selective inhibitor RMC-6236, which is among the RAS inhibitors that are the furthest along in the development pipeline in this space, according to Eileen M. O'Reilly, MD.

“The field is very focused on biomarkers and treatment selection, and to date we’ve had a few validated biomarkers in the clinic, but we now are clearly going to be thinking about RAS, the different alleles, what our best approach is, and how we can tackle resistance,” O'Reilly said in an interview with OncLive®.

Updated data from the phase 1 RMS-6236-001 trial (NCT05379985) revealed that patients with RAS-mutated pancreatic ductal adenocarcinoma (PDAC) treated with RMC-6236 (n = 56) in the second-line setting achieved a median progression-free survival (PFS) of 7.6 months (95% CI, 5.3-not evaluable). In the third-line or later metastatic setting, patients (n = 62) experienced a median PFS of 4.2 months (95% CI, 4.1-6.4). The phase 3 RASolute 302 study will be initiated in the second half of 2024 to further examine RMC-6236 vs chemotherapy in the second-line setting for the treatment of patients with metastatic PDAC.¹

In the interview, O’Reilly detailed how RAS-directed therapy has the potential to change the pancreatic cancer landscape and highlighted updated data in the space. O’Reilly is the Winthrop Rockefeller Endowed Chair of Medical Oncology, chair of the Human Research Protection Program and Institutional Review Board, codirector of Medical Initiatives at the David M. Rubenstein Center for Pancreatic Cancer Research, section head of Hepatopancreaticobi, and a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: How is RAS-directed therapy changing the pancreatic cancer treatment landscape?

O'Reilly: [An important update] is what’s happening with RAS-directed therapy. RAS mutations occur in most patients with pancreatic cancer and there are many drugs now in the clinic [such as] pan-RAS, [RAS(ON) multi-selective], variant, or allele-specific inhibitors, which are targeting a narrower group of individuals with this disease. Most [inhibitors] are in early phase 1 dose finding and safety testing [studies], but 1 agent is moving forward to a phase 3 study. That’s exciting because it’s been a while since we’ve had a phase 3 study in pancreatic cancer. This is good for the field and hopefully great for patients.

The RAS inhibitor that’s furthest along in development is RMC-6236, a pan-RAS [RAS(ON) multi-selective] inhibitor. [The RASolute 302] study will be conducted in the second-line setting for patients with pancreatic cancer who have a good functional status. They will be [randomly assigned] to RMC-6236 or [investigator’s choice] of standard chemotherapy. The study will be powered for overall survival and PFS end points and will enroll approximately 400 patients.

Hopefully, the first patients will enroll in the latter part of 2024 and there’s incredible interest to accrue the study and to see if the data supports the use of this class of [RAS(ON) multi-selective inhibitor] drugs in advanced disease. Then, in parallel to try to get these and related RAS inhibitors into untreated metastatic disease, the adjuvant [and] the neoadjuvant setting is where the impacts should be more profound.

The other area that we need to learn about is [if] targeting a specific variant is going to be more efficacious and reasons that might be so—whether the safety profile may be more favorable, and whether that will be a more logical strategy for some patients [are questions].

What updated data in pancreatic cancer from ASCO 2024 are of note?

At ASCO 2024, [data from] the phase 2 GIANT trial [NCT04233866] examining 5-fluorouracil, leucovorin, and liposomal irinotecan compared with an every other week schedule of gemcitabine and nab-paclitaxel in an older or vulnerable patient population, showed that the 2 [regimens] were relatively equivalent; a subset of these individuals do very poorly and a subset do quite well. A wealth of data will emerge from this study, [evaluating] tools for patient selection, and, [for] older patients, indices of functionality, ability for daily activities, cognitive assessments, and other tools that were built into this study. We saw the first readout [of data] and there were no major surprises with the oncologic outcomes, but there is a lot to learn as to how we should best treat this patient population.

The other big study was a long-awaited trial, the phase 3 RTOG 0848 study [NCT01013649], which looked at whether radiation should be part of standard adjuvant treatment after a patient has undergone resection and completed standard chemotherapy. The study was conceived 15 to 16 years ago and completed accrual around 2019. The data readout for all comers [showed] there was not a difference in outcome for the routine inclusion of radiation. For the node-negative subset—it was a fairly small subset even though the originally study was large—there was an [indication] that disease-free survival was impacted favorably. [This] raises the question of whether we should consider the role of radiation for select patients who have no lymph node involvement. [I say] consider it because it doesn’t address the use of radiation in the current adjuvant paradigms of the era of FOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin].

What additional research is still needed to move the pancreatic cancer field forward?

A big area [is the] field of homologous repair deficiency, [which] has been validated as an area of direct treatment implication for patients who have germline and somatic BRCA1, BRCA2,and PALB2 [alterations]—for other genes there may be a signal too and the field is learning how to build on that. One of the questions is, does adding immunotherapy add to that treatment paradigm for PARP inhibition in these subsets of patients? We’ll have data coming out later this year speaking to this topic [as] it’s a key area.

There is a role for other immunotherapies to be investigated [as well]. There’s a phase 3 trial which will move forward in 2024, looking at an anti-CD73 small molecule inhibitor that has undergone [evaluation in the] phase 1 [setting in the ARC-8 study (NCT04104672)]. [There was] a very intriguing signal from the drug, [quemliclustat], with a very favorable safety profile [observed]. We’re looking forward to that. We also saw data at the 2023 ASCO Annual Meeting and the ESMO Gastrointestinal Cancers Congress 2024 looking at novel CD40 agents, [such as mitazalimab which was] combined with modified FOLFIRINOX in a single arm, non-randomized phase 1b/2 study [called OPTIMIZE-1 (NCT04888312)] and data are intriguing.

These are exciting times in pancreatic cancer and hopefully 1 or more of these approaches are going to lead to more tools. Another area is Claudin targeting and surface epithelial markers that build on the signal that’s been observed in gastric cancer; we have a completed definitive study in pancreas cancer that will hopefully read out in the latter part of 2024 or [early] 2025.

Reference

RMC-6236: pancreatic cancer update to support pivotal phase 3 trial. Revolution Medicines. July 15, 2024. Accessed July 23, 2024. https://ir.revmed.com/static-files/eeeb0690-0ef4-44b8-b5fe-8d11d8df3c9a