Pan-RAS (Fog Pharma)

SAN DIEGO — Since Herceptin’s approval in 1998, breast cancer has been reshaped from a near-term death sentence into — in many cases — a chronic disease. Now, researchers hope daraxonrasib from Revolution Medicines will launch the same type of transformation in pancreatic cancer. A recent Phase 3 finding on daraxonrasib “is one of the most important things that’s happened in cancer therapeutics in the last 30 to 40 years,” Stifel healthcare director Tim Opler said. “This is very much a Herceptin-type moment.” Before Herceptin’s approval, chemotherapy was often the only treatment for breast cancer, potentially keeping the cancer at bay for a few months. But the tumors would recur in most cases, leaving patients without further options. Herceptin, the first targeted cancer therapy, extended response rates by three months. Now, almost three decades later, many patients respond to targeted breast cancer therapies for multiple years. The most impressive figure comes from an Enhertu-Perjeta combination that recorded a 40.7-month progression-free survival mark and was approved late last year. Cancer outcomes broadly have improved in the same period, and even dating back to the 1970s. About 70% of individuals diagnosed with cancer between 2015 and 2021 lived for at least five years after their diagnosis , up from 63% in the three years before Herceptin’s approval. Between 1975 and 1977, only 49% of cancer patients reached the five-year mark. But pancreatic cancer outcomes remain poor, with five-year survival rates sitting at 13%, according to the American Cancer Society , among the lowest in major cancers. That figure drops to 3% for patients whose tumors have metastasized. The stunning success of Revolution Medicines’ daraxonrasib in a Phase 3 study, where it doubled patients’ survival times, is expected to shake up that dynamic — and shake it up robustly. The data represent a transformative moment on a scale similar to Herceptin’s impact on breast cancer. Prior to the Phase 3 trial success announced last week, only a mere handful of past late-stage pancreatic cancer trials had succeeded. “It reinvigorates the whole field,” said Daniel Von Hoff of the Translational Genomics Research Institute and City of Hope. Von Hoff, who led trials of the current chemotherapy regimen for pancreatic cancer, was not involved in the daraxonrasib trial. The once-a-day pill is a “pan-RAS” inhibitor, targeting cancer-driving mutants of RAS — long believed to be undruggable — that underlie more than 90% of pancreatic cancer cases. And physicians and scientists are eagerly awaiting the first-line results for daraxonrasib from a large, Phase 3 trial. In early-stage data shared at AACR, daraxonrasib alongside chemotherapy resulted in a 58% response rate across 40 patients after at least 18 weeks (just over 4 months). However, the data are still early, with a median follow-up time of just under 10 months. Meanwhile, in 38 first-line patients who received daraxonrasib alone, the response rate was 47% at a median follow-up of 13.7 months, according to results that will be shared Tuesday at AACR. The Phase 3 trial RASolute 303 will compare daraxonrasib alone and daraxonrasib plus chemotherapy versus chemotherapy alone, with an expected primary result in mid-2028. “Everybody’s hoping those will really come quickly,” Von Hoff said of the first-line readout. While some Wall Street analysts predict the drug could bring in over $10 billion one day, it remains to be seen how broadly daraxonrasib will be used. RevMed and many other companies are also developing mutation-specific KRAS inhibitors and degraders. Researchers say more work needs to be done to see which drugs come out on top, and where and how each drug should be used. The true payoff for Herceptin has come in the decades since its first approval. It got the ball rolling on HER2-positive breast cancer, especially in the advanced and metastatic settings. Combinations are now the norm and continue to improve outcomes. Daraxonrasib provides hope that something similar is in store for pancreatic cancer as well. “It’s just the beginning of the role of all types of inhibitors of the RAS pathway in making major impacts in the clinic,” said Robert Vonderheide of the University of Pennsylvania and AACR president-elect. Endpoints is fielding the next Biopharma Sentiment Index (BPSI) — a concise, three-minute survey that distills thousands of industry views into a clear quarterly benchmark. This year is pivotal for biopharma, and we need your perspective on where things are going. Take the survey here.