Novel Drug Impresses in Metastatic Pancreatic Cancer

SAN DIEGO — Two phase I/II studies showed that the investigational RAS(ON) inhibitor daraxonrasib had a manageable safety profile and demonstrated promising efficacy both in combination with chemotherapy and as monotherapy in patients with previously untreated metastatic pancreatic cancer.

Among 40 patients treated with daraxonrasib plus gemcitabine and nab-paclitaxel, the confirmed objective response rate (ORR) was 58% and the disease control rate (DCR) was 90%, reported Brian Wolpin, MD, MPH, of the Dana-Farber Cancer Institute in Boston, at the American Association for Cancer Research (AACR) annual meeting.

In addition, the 6-month landmark progression-free survival (PFS) rate was 84%, and the 6-month landmark overall survival rate was 90%. “As reference, a landmark PFS with chemotherapy in the first-line setting is about 50% in larger trials,” Wolpin noted.

When daraxonrasib was evaluated as a monotherapy among 38 patients in the same setting, Eileen M. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues, including Wolpin, reported an ORR of 47%, a DCR of 92%, and 6-month PFS and OS rates of 71% and 83%, respectively.

“Pancreatic cancer is a very difficult disease,” Wolpin said. “It does present late and we don’t have nearly as many treatment options as we would like.”

Currently in the first-line metastatic setting across a number of different clinical trials, response rates have been in the 30% to 40% range, median PFS has ranged from 5 to 7 months, and median OS from 9 to 12 months. “So, this really does leave a lot to be desired,” Wolpin noted.

“Over 90% of pancreas cancers carry an activating oncogenic mutation in RAS,” he said. “This really provides us an opportunity to target this as a novel therapeutic approach for patients with metastatic pancreatic cancer.”

Daraxonrasib is an oral potent RAS(ON) multi-selective, non-covalent inhibitor designed to address a broad range of cancers driven by oncogenic RAS, including pancreatic ductal adenocarcinoma, non-small cell lung cancer, and colorectal cancer. The drug suppresses RAS signaling by blocking the interaction of wild-type and mutant RAS with its downstream effectors.

Daraxonrasib entered the spotlight earlier this month when former Sen. Ben Sasse (R-Neb.), who announced that he had been diagnosed with stage IV pancreatic cancer in December, told the New York Times that he was taking the drug.

Meanwhile, Revolution Medicines announced that daraxonrasib nearly doubled median OS in patients with previously treated metastatic pancreatic cancer (13.2 vs 6.7 months) in a randomized phase III trial comparing the drug against chemotherapy.

“With more and more data seemingly every day, and not just on daraxonrasib, but other RAS inhibitors too, it’s time to conclude ‘this is real,’ and we need to focus on getting these drugs to patients quickly,” Robert Vonderheide, MD, DPhil, of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, and the president-elect of AACR, told MedPage Today.

The three-arm randomized phase III RASolute 303 trial of daraxonrasib with or without chemotherapy as first-line treatment for metastatic pancreatic cancer is currently enrolling patients.

Trial Design and Safety

The study by Wolpin included a subset of patients with first-line metastatic disease who were evaluated as part of the phase I/II, open-label, multicenter GI-102 Platform Study of RAS(ON) inhibitors in patients with RAS-mutant gastrointestinal tumors.

Patients had a median age of 69 years, 63% were men, and half had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. The majority (70%) had liver metastases at enrollment, 45% had received prior anti-cancer therapy in the non-metastatic setting, and 43% had prior pancreatic resection.

Half of the patients had KRAS G12D mutations, 25% had KRAS G12V mutations, and 18% had KRAS G12R mutations.

Patients received daraxonrasib (200 mg orally once daily) plus gemcitabine and nab-paclitaxel on days 1 and 15 in 28-day cycles.

The combination as first-line treatment for metastatic pancreatic cancer showed a “manageable safety profile, consistent with known toxicities of each component,” Wolpin reported.

The most common treatment-related adverse event (TRAE) of any grade was rash — which Wolpin noted is frequently seen with daraxonrasib — with 15% of patients having grade ≥3 rash. Overall, other grade ≥3 toxicities, such as anemia, fatigue, diarrhea, decreased neutrophil count, and stomatitis/mucositis, are expected with daraxonrasib or the chemotherapy regimen.

Dose reductions or discontinuations due to daraxonrasib-related TRAEs occurred in 35% and 5% of patients, respectively, while those due to chemotherapy-related TRAEs occurred in 58% and 15% of patients.

The monotherapy study, which was presented during a poster session, was part of a phase I/II trial evaluating the safety, tolerability, pharmacokinetics, and clinical activity of escalating doses of daraxonrasib in adults with advanced solid tumors harboring specific RAS mutations.

The patients with metastatic pancreatic cancer in this study had similar demographic and baseline characteristics as those in the combination study and received daraxonrasib 300 mg orally once daily in 21-day cycles.

All-grade TRAEs occurred in 95% of patients, with grade ≥3 TRAEs reported in 38%. The most common TRAEs included rash, diarrhea, and stomatitis, each of which occurred as grade 3 events in 10% of patients.

TRAEs led to dose modifications in 70% of patients, and discontinuation in just one patient.

When asked about plans to mitigate toxicity going into the RASolute 303 trial, Wolpin said oncologists are used to managing the toxicity that comes from chemotherapy, “and that needs to be done in the 303 study, as we would do in our standard of care.”

“For the toxicities that are specific to daraxonrasib, there are two that require proactive management — one is rash, and one is mucositis,” he said, adding that with prophylaxis, “what you’ll see is the intensity of these side effects are less, and we are also learning with our dermatology colleagues how to manage the rash.”