FDA Approves Oral Pan-RAS Inhibitor Daraxonrasib for Metastatic Pancreatic Cancer
核心洞察
The FDA has approved daraxonrasib (Rasonque (搜索)), an oral once-daily pan-RAS (搜索)(ON) inhibitor, for metastatic pancreatic adenocarcinoma (搜索) after prior systemic therapy or in patients unfit for multi-agent chemotherapy.
In the phase 3 RASolute 302 trial of 500 patients, median overall survival was 13.2 months with daraxonrasib versus 6.7 months with chemotherapy (HR, 0.40; P < .0001).
Median progression-free survival was 7.2 months versus 3.6 months and objective response rates were 30% versus 11%, both favoring daraxonrasib.
The FDA has approved daraxonrasib (Rasonque (搜索)), an oral, once-daily pan-RAS (搜索)(ON) inhibitor, for patients with metastatic pancreatic adenocarcinoma (搜索) whose disease has progressed after prior systemic therapy, and for patients who are not candidates for multi-agent systemic therapy. The approval marks the first oral targeted pill available in this disease and the first agent in this setting to roughly double median overall survival compared with chemotherapy.
RASolute 302 Efficacy
The approval was supported by findings from the phase 3 RASolute 302 trial (NCT06625320), which randomly assigned 500 patients whose disease had progressed after one prior line of systemic therapy to daraxonrasib or standard-of-care chemotherapy.
In the overall population, median overall survival was 13.2 months (95% CI, 10.0-not estimable) with daraxonrasib (n = 248) versus 6.7 months (95% CI, 5.8-8.0) with chemotherapy (n = 252; HR, 0.40; 95% CI, 0.30-0.53; P < .0001). Median progression-free survival was 7.2 months (95% CI, 5.7-7.5) versus 3.6 months (95% CI, 2.9-4.2), respectively (HR, 0.49; 95% CI, 0.38-0.64; P < .0001). Objective response rates were 30% (95% CI, 25%-36%) with daraxonrasib versus 11% (95% CI, 7%-15%) with chemotherapy (P < .0001).
"The median OS was nearly doubled [with daraxonrasib], which is impressive in this population," Benjamin Weinberg, MD, associate professor of medicine at MedStar Health and in the Division of Hematology and Oncology at the Lombardi Comprehensive Cancer Center at Georgetown University, said in an interview with OncLive.
The trial focused on patients with KRAS G12-mutated tumors but also evaluated the overall population regardless of RAS (搜索) mutational status. Weinberg said there was no significant difference in daraxonrasib efficacy between the KRAS G12-mutated population and the overall population. The chemotherapy arm performed as expected, with a median overall survival of approximately 6 to 7 months across subpopulations, while daraxonrasib produced a median overall survival of approximately 12 to 13 months depending on the subpopulation. Some patients have remained on daraxonrasib for longer than one year with stable disease or responses.
Mechanism of Action
Daraxonrasib is a pan-RAS (搜索) inhibitor that blocks all RAS signaling in both RAS-mutated and RAS wild-type tumors, so the specific molecular alteration in the tumor does not appear to determine response. Weinberg noted that KRAS mutations are seen in approximately 90% to 92% of pancreatic adenocarcinomas and that efforts to target RAS at the molecular level have spanned more than 40 years.
The agent exploits a distinct vulnerability of RAS (搜索). RAS is a GTPase that becomes stuck in its GTP-bound, or ON, state, cycling between that state and its GDP-bound, or OFF, state. Earlier drugs targeting specific KRAS alleles such as KRAS G12C bind the OFF state, which suits an allele that cycles predictably. The KRAS mutations most common in pancreatic cancer (搜索), G12D, G12V and G12R, require hitting the ON state effectively. Daraxonrasib is incorporated intracellularly and binds to cyclophilin A (搜索), which allows it to reach a molecular pocket and act as a glue, dislodging the ON state and preventing signaling down the MAPK pathway and, to a lesser extent, the PI3K/mTOR pathway. Because normal cells also use this pathway, adverse effects are expected, but the mechanism allows tumors to be killed more preferentially than with chemotherapy.
Safety and Tolerability
Rash and stomatitis are the key adverse effects associated with daraxonrasib. Weinberg said the rash is common and tends to affect the head, neck and trunk. Prophylaxis started before treatment, along with dose adjustment when needed, can mitigate it. He described a regimen similar to that used for EGFR-directed antibody-associated rash: a tetracycline antibiotic, usually minocycline, twice daily, plus two different topical corticosteroids, one for the face and one for the neck and trunk, applied twice daily, along with an antiseptic and sunscreen.
For stomatitis, Weinberg recommended avoiding alcohol, alcoholic mouth rinses and foods with sharp edges, such as chips, that could damage the mucosa. Diarrhea, nausea, vomiting and fatigue also require monitoring. The FDA lists rash, nausea and abdominal pain among the most common side effects.
Despite the skin and mucosal toxicity, few patients discontinued daraxonrasib for toxicity. The discontinuation rate was 1.2% on daraxonrasib versus 11.2% on the chemotherapy arm.
Patient-Reported Outcomes
RASolute 302 collected patient questionnaires on pain and general quality of life. Weinberg said the trial showed a significant prolongation in time to deterioration for both pain and overall quality of life in the daraxonrasib arm versus chemotherapy. He added that patients can sometimes experience quick relief of some symptoms, especially pain, after starting daraxonrasib, which is seen less often with chemotherapy.
Clinical Context
Pancreatic cancer (搜索) is the third deadliest cancer in the United States, and most patients present with vague symptoms. Jonathan Mizrahi, a gastrointestinal medical oncologist at Ochsner MD Anderson Cancer Center (搜索), said some patients present with yellow eyes, jaundice and dark urine when the tumor blocks the bile duct, while others have few symptoms until the disease has spread widely. He said 80% to 85% of patients are diagnosed too late for surgery.
Mizrahi described the survival doubling as a first in this setting. "We never had an oral targeted pill for pancreatic cancer (搜索), and we never had something in this setting that doubled survival," he said. He added that daraxonrasib is still being studied for earlier lines of therapy.
Jonelle Bershad, a retired operating room nurse diagnosed with pancreatic cancer (搜索) in November, began daraxonrasib in June after chemotherapy left her fatigued for days at a time. She described the pill as easy to take and reported no untoward reactions. "Hopefully it's the cure, but if it's not, it gives you more quality of life of the life you have left to live," she said.
Combination Strategies Under Study
Weinberg characterized the approval as the first successful shot on goal for RAS (搜索)-targeted therapy in this disease and pointed to a pipeline of agents that hit common alleles such as KRAS G12D (搜索) rather than all of RAS. Emerging data suggest that combining a KRAS G12D inhibitor with a pan-RAS inhibitor may have synergistic effects.
Findings from an earlier phase 1/2 study (NCT05379985) in patients with previously treated, advanced RAS (搜索)-mutated solid tumors, including pancreatic cancer (搜索), treated with daraxonrasib at different dose levels suggested that progression is not necessarily driven by a new RAS mutation but by amplification of the existing KRAS mutation or KRAS amplification more generally. Weinberg said there is interest in combining pan-RAS inhibitors with allele-specific inhibitors, with chemotherapy, particularly the more targeted inhibitors that may be safer and easier to combine, and with immunotherapy, which could give immune cells more time to act against the tumor and potentially disrupt stromal features that have limited immunotherapy's effectiveness in this disease.
Since approval, production of the medication is expected to ramp up quickly.