Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and about 30% of people with this form of cancer have RAS mutations.
In a phase 1-2 clinical trial, researchers found that daraxonrasib, an oral drug designed to block active RAS proteins that help cancer cells grow, could help people with NSCLC.
While the results are promising, the study was small and did not compare daraxonrasib directly with another treatment.
The study is published in the New England Journal of Medicine.
NSCLC makes up around 85% of lung cancer cases. According to the National Cancer Institute’s SEER data, doctors diagnose 51% of lung and bronchus cancers after the cancer has spread to distant parts of the body.
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The RAS gene family includes the KRAS, NRAS, and HRAS genes, which encode proteins that help control when cells grow and stop growing.
When RAS mutations occur, this leaves the process switched “on,” allowing cancer cells to continue growing and spreading.
Researchers have historically found RAS proteins difficult to target with drugs. Treatments now exist for cancers with specific mutations, such as KRAS G12C, but most RAS mutations still lack an approved targeted therapy.
Daraxonrasib is a targeted drug known as a RAS(ON) multiselective inhibitor. Unlike treatments that target a single inactive form of RAS, it blocks active RAS across multiple proteins and mutations.
For the phase 1-2 study, the research team recruited adults with previously treated, advanced RAS-mutant NSCLC. The participants had either experienced cancer progression or had “unacceptable side effects” during their prior treatments.
The researchers tested daily doses of daraxonrasib ranging from 10 to 400 milligrams (mg). However, frequent dose modifications at 400 mg led them to limit the main analysis to 136 participants who received 300 mg or less.
The researchers primarily evaluated the drug’s safety. They also examined tumor response and survival outcomes.
More than 30% of participants responded to treatment.
Tumors shrank in 31% of participants taking 120 mg or less, 34% taking 160-220 mg, and 37% taking 300 mg.
In an exploratory analysis, the researchers examined 38 participants who received 160-220 mg of daraxonrasib. The people in this group had previously received chemotherapy and immunotherapy but had not received docetaxel, the chemotherapy drug researchers plan to compare with daraxonrasib in the phase 3 trial.
In this smaller group, tumors shrank in 42% of participants. Daraxonrasib controlled the cancer in 89% of this group, meaning their tumors either shrank or did not grow for at least 4 weeks.
For the participants whose tumors responded, the response lasted a median of 11.5 months. They lived for a median of 8.3 months without their cancer worsening, and median overall survival was 16 months.
However, the study did not compare daraxonrasib directly with another treatment, so researchers cannot conclude that the drug extends survival at this point. They plan to investigate it further in a randomized phase 3 trial.
Nearly all participants experienced at least one adverse event during the study, although researchers did not consider every event related to daraxonrasib.
More than half of participants experienced grade 3 or higher adverse events, including pneumonia, diarrhea, rash, and anemia. Researchers attributed adverse events of this severity to daraxonrasib in 30% of participants.
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Some common side effects the group had included rash, mouth sores, diarrhea, nausea, and vomiting. Their doctors managed many of the side effects by adjusting their medication dose and providing other care.
Nilesh Vora, MD, a board-certified hematologist and medical oncologist and medical director of the MemorialCare Todd Cancer Institute at Long Beach Medical Center in California, spoke with Medical News Today about the findings.
“I find these results encouraging because they could potentially give us another tool to improve both the quality and length of life for patients with cancer,” said Vora, who was not involved in the study.
However, he stressed the need to compare the drug directly with existing treatments.
“I would like to see daraxonrasib directly compared with the current standard of care in a phase 3 clinical trial,” Vora added. “That kind of head-to-head comparison will be important in determining whether this approach provides a meaningful benefit over the treatments we currently use.”
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Sonia Thomas, PharmD, a clinical oncology pharmacist and professor and vice chair of pharmacy practice at the Philadelphia College of Osteopathic Medicine, also told MNTthat she found the results encouraging.
Thomas, who was likewise not involved in this study, explained that most existing KRAS drugs target a specific mutation, while daraxonrasib targets the active form of several RAS proteins.
“Rather than having one key that fits one specific KRAS mutation, daraxonrasib may be able to interfere with several different forms of RAS-driven cancer,” said Thomas.
Thomas said this approach could make targeted therapy available to people whose RAS mutations currently have few or no targeted treatment options. However, she cautioned that promising early findings do not necessarily lead to a new standard treatment.
