From Undruggable to Unstoppable: How Daraxonrasib Is Rewriting the RAS Story

Posted on 9 September, 2026 by Mehrdad Fathi

For decades, RAS proteins occupied a peculiar position in oncology: among the most commonly mutated drivers of cancer, yet effectively out of reach for targeted therapy. That designation — “undruggable” — is now being dismantled at pace.

Just one week after the US FDA granted approval to daraxonrasib (Rasonque) for advanced pancreatic cancer, new data published in the New England Journal of Medicine on September 2 show the same drug shrinking tumours in more than 30% of participants with non-small-cell lung cancer (NSCLC). The results are preliminary. But they mark a meaningful inflection point in what has become one of oncology’s most active drug development races.

The Mechanism: Molecular Glue

Daraxonrasib, developed by Revolution Medicines in Redwood City, California, works through a mechanism distinct from classical kinase inhibition. Rather than blocking an active site directly, the compound acts as a molecular glue — first binding to cyclophilin A, a ubiquitous cellular protein, and then using the resulting complex as a surface that can engage both wild-type and mutant RAS isoforms. By occupying that interface, it prevents RAS from interacting with its downstream effector partners, halting the oncogenic signaling cascade regardless of the specific mutation variant.

This approach solves a long-standing structural problem. Classical small molecules struggled to achieve sufficient selectivity against RAS proteins because the relevant binding pockets were shallow and highly conserved. The cyclophilin A-mediated glue strategy sidesteps that constraint.

The Clinical Data

The pancreatic cancer dataset established the benchmark. In a randomized trial of 500 patients with advanced disease, daraxonrasib nearly doubled median overall survival compared to standard chemotherapy — 13.2 months versus 6.7 months. That evidence base prompted the FDA’s accelerated approval on August 26, more than six months ahead of the standard review timeline.

The lung cancer data come from a smaller, non-randomized phase study. Of 136 patients with advanced NSCLC harboring RAS family mutations who had progressed on prior therapy, tumours shrank in more than 30%. Median survival reached 16 months — approximately five months longer than historical benchmarks for standard chemotherapy in this population, according to lead author Kathryn Arbour of Memorial Sloan Kettering Cancer Center.

The study was designed primarily to characterize safety, not to replace a randomized comparison. Roughly half of participants experienced serious adverse effects, with a potentially severe skin rash among the most notable. A larger randomized trial iny severe skin rash among the most notable. A larger randomized trial in NSCLC — comparing daraxonrasib directly against standard chemotherapy — is now actively enroll depend on those results.

The Resistance Question

Even in responding patients, some tumours eventually resumed growth. Understanding the mechanisms behind that acquired resistance is one of the field’s most pressing near-term questions.the mechanisms behind that acquired resistance is one of the field’s most pressing near-term questions. Arbour noted that researchers are still in early stages of characterizing how turess.

Several ongoing programs are testing daraxonrasib alongside other targeted agents or checkpoint inhibitors with the explicit goal of delaying or preventing resistance onset. Early data from these combinations are expected at major oncology conferences over the next 12 to 18 months.

The Broader Landscape

Lung and pancreatic cancer are the headline indications, but the underlying biology points further. RAS mutations are found across colorectal tumours, endometrial cancers, and melanoma, among others. Channing Der of the University of North Carolina at Chapel Hill, who has catalogued the field’s expansion, counts 79 RAS inhibitors currently in 241 active clinical trials — a number that would have seemed implausible a decade ago when the “undruggable” consensus was near-universal.

The FDA’s pancreatic cancer approval is accelerating this expansion beyond Revolution Medicines alone. Competing programs at other companies are now moving with greater urgency into diverse tumour types, each with its own RAS mutation profile and resistance landscape. The competitive dynamics are real — and likely to benefit patients across multiple indications as multiple programs advance in parallel.

Lung cancer is still the world’s leading cause of cancer death, accounting for approximately 19% of global cancer mortality according to GLOBOCAN 2024 data. Even a partial response rate improvement in later-line NSCLC represents a clinically meaningful development at population scale. The randomized trial currently underway will determine whether that promise translates into a new standard of care.

Source: Moriarty, A. “Landmark pancreatic cancer drug shows potential against lung cancer too.” Nature 657, 329 (2026). DOI: https://doi.org/10.1038/d41586-026-02745-5

References:

1. Arbour, K. C. et al. Daraxonrasib in RAS-mutant non-small-cell lung cancer. N. Engl. J. Med. 395, 882–893 (2026).

2. O’Reilly, E. M. et al. Daraxonrasib in advanced pancreatic cancer. N. Engl. J. Med. 395, 325–337 (2026).