Groundbreaking Pancreatic Cancer Drug Shows Promise in Lung Cancer

The landmark oral RAS inhibitor daraxonrasib (Rasonque) showed efficacy in previously treated patients with metastatic RAS-mutant non-small cell lung cancer (NSCLC) in a phase I/II trial.

Among 136 patients treated with daraxonrasib, the percentage who had an objective response was 31% with a dose of 120 mg or less, 34% with doses of 160 to 220 mg, and 37% with a dose of 300 mg, reported Kathryn C. Arbour, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues in the New England Journal of Medicine.

Grade 3 or higher adverse events (AEs) were reported in 54% of patients, with pneumonia (10%), diarrhea (9%), rash (8%), and anemia (5%) occurring in at least 5% of patients. Four grade 5 adverse events occurred.

Mutations in the RAS gene family are among the most common oncogenic drivers of NSCLC, occurring in about 30% of patients, with the majority of tumors harboring RAS mutations for which no targeted therapies are approved.

Daraxonrasib recently received FDA approval for metastatic pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, based on the RASolute 302 trial, which showed that second-line treatment with the RAS inhibitor doubled median overall survival (OS) versus investigator’s choice of chemotherapy in patients with RAS G12 mutations (13.2 vs 6.7 months, P<0.001).

In this study, the drug demonstrated promising antitumor activity in a subgroup of docetaxel-naive patients who had previously received first- or second-line platinum-based chemotherapy and anti-PD-(L)1 therapy.

“Docetaxel is our standard second-line chemotherapy that is used in non-small cell lung cancer after treatment with platinum-doublet chemotherapy and immunotherapy,” Arbour told MedPage Today. “In prior randomized clinical trials of docetaxel, we would typically expect the overall survival to be approximately 9 to 11 months based on a variety of clinical trials including all patients with NSCLC, not just patients with lung cancer harboring KRAS mutations.”

In terms of other efficacy measures, the benefit of second-line docetaxel is equally modest, with an objective response observed in 9% to 14% of patients, and a median progression-free survival (PFS) of 3 to 4.5 months.

Arbour and her team — acknowledging that cross-trial comparisons are “imprecise” — evaluated 38 patients with any RAS mutation who were treated at doses of 160 to 220 mg (the range selected for the ongoing phase III RASolve 301 trial) and had previously received first- or second-line platinum-based chemotherapy and anti-PD-1 or anti-PD-L1 therapy, but not docetaxel.

They found that after a median follow-up of 18.3 months, the confirmed objective response rate was 42%, with a median PFS of 8.3 months, and a median OS of 16 months, “which is a very encouraging signal,” Arbour said. “Ultimately, the phase III clinical trial that is currently underway will provide a more direct comparison and confirmatory results.”

At the dose range of 160 to 220 mg, 51% of patients experienced a grade 3 or higher AE, with 71% requiring dose modifications and 10% discontinuing treatment.

These AEs were managed with routine clinical interventions including topical glucocorticoid therapy, antibiotics, sun protection, and antidiarrheal therapy.

Arbour and colleagues noted that a higher 300-mg dose was selected for phase III pancreatic cancer trials, which reflects differences in the side-effect profiles observed in NSCLC and pancreatic cancer patients and “underscores the need for disease-specific daraxonrasib dosing.”

“In patients with NSCLC treated with daraxonrasib, 200 mg once daily was selected to balance efficacy and safety,” Arbour said. “Patients treated with this dose required fewer dose modifications and had lower rates of nausea and diarrhea. This difference in tolerability may reflect underlying disease- and patient-specific factors, particularly for patients with non-small cell lung cancer.”

This phase I/II, multicenter, dose-escalation and dose-expansion study enrolled patients with previously treated advanced RAS-mutant NSCLC who received daraxonrasib once daily, with 26 patients receiving a dose of 120 mg or less, 59 receiving a dose ranging from 160 to 220 mg, and 51 receiving a dose of 300 mg.

Median age was 66, 38% were men, 75% were white, and 79% had an Eastern Cooperative Oncology Group performance status score of 1. The most common RAS mutations were RAS G12V (37%) and RAS G12D (30%).

Patients had received a median of two previous lines of treatment for metastatic disease, with 99% receiving previous platinum-based chemotherapy and 99% receiving previous anti-PD-1 or anti-PD-L1 therapy.

The authors acknowledged that these results should be interpreted with caution considering it was a phase I/II trial. In addition, the small sample size within individual RAS mutation categories and co-mutation subgroups “limit the precision of the efficacy analyses and preclude firm conclusions.”