FDA Approves Rasonque

August 26, 2026 — The U.S. Food and Drug Administration has granted approval to RASONQUE™ (daraxonrasib; RMC-6236), an oral RAS(ON) tri-complex inhibitor developed by Revolution Medicines, for the treatment of adult patients with metastatic pancreatic adenocarcinoma (PDAC) who have received at least one prior systemic therapy, or who are not candidates for multiagent systemic therapy.^1,2 The approval represents a turning point in oncology, as it is the first broad RAS-targeted medicine approved in metastatic pancreatic cancer, a disease that has for decades lacked targeted therapeutic options despite KRAS mutations being present in approximately 92% of cases. Rasonque represents a paradigm shift from decades of reliance on intravenous cytotoxic chemotherapy for this aggressive disease.

1. A 60% Reduction in Risk of Death

The approval was supported by results from RASolute 302, a global, randomized, open-label Phase III trial evaluating Rasonque (300 mg once daily) compared to investigator’s choice of four cytotoxic chemotherapy regimens, the standard of care across the globe, in previously treated metastatic PDAC.³ Furthermore, the trial enrolled patients harboring a wide range of RAS variants (G12D, G12V, G12R, and others at codons 12, 13, and 61), as well as patients without an identified RAS mutation.

In the intent-to-treat (ITT) population, Rasonque reduced the risk of death by 60% compared with chemotherapy, with a hazard ratio of 0.40. The trial met all primary and key secondary endpoints in both the RAS G12 mutant population and the overall ITT population, which included patients with or without an identified tumor RAS mutation. The study demonstrated statistically significant and clinically meaningful improvements across progression-free survival (PFS), overall survival (OS), objective response rate, duration of response, and patient-reported quality of life measures.

“For decades, despite RAS being the main driver and potential drug target for pancreatic cancer, physicians have largely relied on intravenous cytotoxic chemotherapy to treat this aggressive disease,” said Brian M. Wolpin, M.D., M.P.H., Director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute and principal investigator of RASolute 302.4 “This approval gives physicians the confidence that directly inhibiting RAS can make a striking difference for patients and provides a critically needed new approach to treating patients with metastatic pancreatic cancer.”

Overall, the trial demonstrated statistically significant and clinically meaningful improvements across all primary and key secondary endpoints in both the RAS G12 mutant population and the overall ITT population. This consistent benefit across the ITT population, including wild-type patients, suggests that the mechanism may also suppress compensatory feedback reactivation pathways that limit the efficacy of single-mutant approaches.

2. Breaking the “Undruggable” Paradigm

The RAS protein family (KRAS, NRAS, HRAS) is one of the most frequently mutated oncogene families in human cancer, with driver mutations occurring in approximately 19 – 30% of all malignancies.⁵ For over four decades, RAS was considered undruggable due to:

1. The dynamic conformational changes between GTP-bound and GDP-bound states.
2. A strong affinity of RAS for GTP and the intrinsic elevated concentrations of GTP that confers GTP-competitive inhibitors unviable.
3. The absence of suitable small-molecule binding pockets.

However, recent developments in medicinal chemistry have afforded sotorasib and adagrasib, both of which are covalent inhibitors selective for the KRAS G12C mutation in its inactive GDP-bound (OFF) state.⁶ While these first-generation agents demonstrated activity in non-small cell lung cancer (NSCLC), they are limited to a single mutation, G12C, representing a small fraction of RAS-driven cancers. Sotorasib and adagrasib target the OFF state rather than the active ON state, and face well-characterized resistance mechanisms including secondary RAS mutations and switch II binding pocket alterations.

On the other hand, Rasonque represents a fundamentally different approach. It is an orally bioavailable bRo5 (beyond rule of five) macrocyclic molecule that functions as a tri-complex inhibitor (TCI).⁷ The molecule was discovered
through a structure-guided SAR campaign through iterative optimization of
potency, selectivity, metabolic stability, and oral bioavailability. And as a bRo5, the drug exceeds Lipinski’s traditional Rule of 5 limits while maintaining drug efficacy and bioavailability. The structure affords a noncovalent interaction with the target protein chaperone protein Cyclophilin A (CypA) through a cation–π interaction with Tryptophan 121 (W121) of CypA, which drives KD1 enhancement and contributes to improved aqueous solubility and metabolic stability.

Rasonque’s activity is referred to as a TCI due to its simultaneous engagement with three components: the intracellular CypA, the drug molecule itself, and protein RAS in its active GTP-bound state (RAS(ON)) to form a ternary complex that physically blocks effector binding, thereby inhibiting downstream RAS signaling and tumor cell proliferation. The compound occupies a unique composite binding pocket spanning CypA and the Switch I/Switch II regions of RAS(ON), leveraging interactions with residues conserved across multiple mutant and wild-type RAS isoforms. The dual-domain engagement enables Rasonque’s broad-spectrum activity across multiple RAS isoforms, as it relies on interactions with residues that are conserved between mutant and wild-type RAS variants.

RAS mutations are among the most common driver mutations in human cancers, occurring in approximately 19% of cancer patients. The RAS gene family includes three members: HRAS, NRAS, and KRAS. Driver mutations predominantly occur at hotspot codons: Glycine 12 (primarily D, V, C, R, and S), Glycine 13 (primarily C and D), and Glutamine 61 (primarily R and H). These mutated RAS proteins disrupt intrinsic GTPase activity and/or accelerate GDP-to-GTP nucleotide exchange, shifting the cellular equilibrium toward the active, oncogenic GTP-bound state (RAS(ON)). Ultimately leading to increased oncogenic flux through activation of downstream effectors and signaling pathways linked to cell proliferation and survival.

3. Why Pancreatic Cancer?

The selection of PDAC as the lead indication reflects a well-established biological rationale. KRAS G12X-mutant pancreatic tumors are profoundly “addicted” to oncogenic RAS signaling.⁸ A dependency demonstrated by KrasG12D inactivation studies in genetically engineered mouse models, pharmacologic inhibition in preclinical models, and now confirmed clinically. Approximately 92% of pancreatic cancer coincides with KRAS mutations. Unlike colorectal cancer, which requires APC loss as a cooperating event and exhibits strong EGFR-mediated adaptive feedback, PDAC appears to depend more directly on the RAS signaling axis for survival, making it particularly vulnerable to RAS pathway disruption. Therefore, Rasonque inhibition of the RAS GTPase family has demonstrated significant efficacy in treating metastatic pancreatic adenocarcinoma.⁹

4. Safety Profile: Manageable and Predictable

In RASolute 302 (NCT06625320), Rasonque demonstrated a manageable safety profile with a favorable tolerability comparison to traditional chemotherapy.^3,10 The most prominent class-effect adverse reaction is dermatologic toxicity (rash), consistent with RAS pathway inhibition affecting keratinocyte biology.

Other reported adverse reactions include mucositis/stomatitis, nausea/vomiting, and diarrhea. At the recommended dose of 300 mg once daily, no mean increase in QTc interval >20 msec was observed. The drug demonstrated a low-risk profile in hERG, off-target safety panel, and in vitro genotoxicity assays during development.

Dose modifications are straightforward: first reduction to 200 mg once daily, second reduction to 150 mg once daily, with permanent discontinuation if 150 mg cannot be tolerated. Grade 2 dermatologic reactions warrant consideration of withholding until recovery to ≤ Grade 1.

5. Pharmacokinetics and Administration

Rasonque is administered as a 300 mg oral tablet once daily (available in 100 mg and 150 mg strengths).¹⁰ Key pharmacokinetic parameters include:

The drug exhibits approximately dose-proportional AUC with minimal accumulation.

6. Other KRAS Inhibitors

For over four decades, KRAS was considered undruggable due to the absence of suitable small-molecule binding sites within its mutant isoforms.¹¹ The recent approval of direct KRAS G12C inhibitors: sotorasib and adagrasib broke this paradigm, but these agents target only the inactive GDP-bound state (KRAS(OFF)). Therefore, sotorasib and adagrasib are only selective for G12C mutations, which represent a small fraction of RAS-driven cancers, about 15% of RAS cancers.¹² And suffer limitations due to possible resistance through secondary RAS mutations and switch II pocket mutations.

• Sotorasib (Lumakras): Approved for KRAS^G12C mutant NSCLC
• Adagrasib (Krazati): Also approved for KRAS^G12C mutations in similar indications as sotorasib

Both inhibitors target the inactive GDP-bound state (KRAS(OFF)) rather than the active GTP-bound state (KRAS(ON)). Neither sotorasib and adagrasib are approved for metastatic pancreatic adenocarcinoma.

7. Broader Implications and Future Directions

The approval of Rasonque carries implications well beyond pancreatic cancer. The broad-spectrum mechanism targets multiple RAS mutants and wild-type protein in the active state. Thereby positioning Rasonque as a potential therapeutic across the full landscape of RAS-driven solid tumors, including NSCLC (~29% KRAS-mutant), colorectal cancer (~49%), ovarian cancer (9%), and gastric adenocarcinoma (12%).

Multiple additional clinical trials are ongoing (NCT05379985; NCT06040541; NCT06162221; NCT06445062; NCT06128551), evaluating Rasonque in RAS-mutant advanced solid tumors beyond PDAC. The 2024 translational evaluation published by Revolution Medicines demonstrated objective responses in patients with KRAS^G12X-mutant lung and pancreatic adenocarcinoma in the Phase I/Ib trial, validating the preclinical predictions that deep, durable RAS pathway suppression translates into clinical tumor regression.

“Today’s landmark approval is the most significant advance we have seen in the fight against pancreatic cancer, a devastating disease,” said Anna Berkenblit, M.D., Chief Scientific and Medical Officer of the Pancreatic Cancer Action Network (PanCAN). “An oral pill can offer a less burdensome treatment experience than standard intravenous chemotherapy. This drug will transform how pancreatic cancer is treated, giving people the opportunity for more time with loved ones, the possibility of a better quality of life, and optimism that continued research may lead to even greater advances.”

About Rasonque: RASONQUE (daraxonrasib) tablets are indicated for the treatment of adult patients with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy. For full prescribing information including warnings, precautions, and adverse reactions, consult the FDA-approved label.

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References

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