Phase 3 global, randomized trial of once-daily oral daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, vs investigator's-choice chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC), regardless of RAS mutation status. Presented at the #ASCO26 Plenary (LBA5) by Brian M. Wolpin, MD, MPH (Dana-Farber): median overall survival doubled — 13.2 vs 6.6 months in the RAS G12 primary population, 13.2 vs 6.7 overall (HR 0.40 in both) — called a "grand slam" from the plenary stage. On August 26, 2026, the FDA approved daraxonrasib as Rasonque for adults with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or are not candidates for multiagent systemic therapy — the first RAS inhibitor approved in pancreatic cancer.
#ASCO26 · Plenary · LBA52L Metastatic PDAC (all-comers)Daraxonrasib · Revolution MedicinesPhase 3 · n=500 · global (N. America · Europe · Asia)Published in NEJM (May 31, 2026)FDA Approved · Aug 26, 2026 · Rasonque (daraxonrasib)Pre-approval Expanded Access (May 1, 2026)
Posts about RASolute 302, newest first: physicians during ESMO 2026 week (October 17–24, 2026), then posts from the ASCO 2026 Plenary (May 30–June 1, 2026), including the journal and reporters who covered it. Reactions on approval day (August 26, 2026) are in the FDA & Regulatory section. Each post is shown in full and verbatim and linked to the original on X.
Overall Survival (Dual Primary Endpoint in RAS G12 — MET)
Daraxonrasib produced a statistically significant and clinically meaningful improvement in overall survival, doubling median OS versus chemotherapy. In the RAS G12 population (dual primary endpoint), median OS was 13.2 vs 6.6 months (HR 0.40; 95% CI 0.30–0.54; p<0.0001). In the overall (intent-to-treat) population (key secondary endpoint), median OS was 13.2 vs 6.7 months (HR 0.40; 95% CI 0.30–0.53; p<0.0001) — a 60% reduction in the risk of death. Median OS exceeding 12 months in the second-line PDAC setting is unprecedented.
Progression-Free Survival (Dual Primary Endpoint in RAS G12 — MET)
Daraxonrasib also doubled blinded independent central review (BICR) PFS. In the RAS G12 population (dual primary endpoint), median PFS was 7.3 vs 3.5 months (HR 0.45; 95% CI 0.34–0.59); in the overall population (key secondary), 7.2 vs 3.6 months (HR 0.49; 95% CI 0.38–0.64). The objective response rate was nearly tripled — 32% (95% CI 26–38) vs 11% (95% CI 7–16) in the RAS G12 population (all randomized patients, BICR; Rasonque USPI); 30% vs 11% in the overall population.
Daraxonrasib is not a benign drug — it carries real, on-target RAS-pathway toxicity that demands active, ongoing management. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 43.6% of daraxonrasib patients (vs 57.5% with chemotherapy). The most frequent Grade ≥3 TRAEs were rash (14%) and stomatitis (mouth inflammation, 12%); the most common all-grade toxicities were rash, mouth inflammation (stomatitis), nausea, and diarrhea. Treatment-related serious AEs occurred in 10.8% (vs 18.7%), and there was one Grade 5 (fatal) treatment-related pneumonitis (0.4%) in the daraxonrasib arm. The approved label lists ILD/pneumonitis under Warnings & Precautions (§5.5): incidence 2.4% across pancreatic-cancer trials, 0.9% Grade 3, one fatal event, median onset 111 days — with monitoring for new or worsening pulmonary symptoms, alongside warnings for dermatologic/soft-tissue toxicity, stomatitis, diarrhea, gastrointestinal perforation, and embryo-fetal toxicity (Rasonque USPI). Rash is significant enough that the protocol recommends prophylactic oral antibiotics and topical corticosteroids. The toxicities were consistent with prior Phase 1/2 (RMC-6236-001) experience, with no unexpected new signals. Median dose intensity was 93.1%. Treatment discontinuation due to TRAEs was 1.2% vs 11.2% with chemotherapy.
Regulatory status & clinical implications - FDA approved Aug 26, 2026 as Rasonque (daraxonrasib) for metastatic pancreatic adenocarcinoma after ≥1 prior systemic therapy or in patients not candidates for multiagent therapy - first RAS inhibitor approved in PDAC; the label carries no RAS-testing requirement and does not restrict by RAS mutation status (Rasonque USPI, revised 08/2026). RASolute 302 is the first positive Phase 3 trial of a RAS-targeted therapy in pancreatic cancer, a disease in which ~90% of tumors are KRAS-driven and second-line chemotherapy delivers only 6–7 months of median survival. ASCO leadership and discussants described the result as a "grand slam," and multiple KOLs framed daraxonrasib as a potential new second-line standard of care — a role the FDA’s August 26, 2026 approval of Rasonque now formalizes. The all-comers benefit (regardless of RAS mutation status) reinforces the rationale for the broader RAS(ON) multi-selective mechanism. Sources: Managed Healthcare Executive (ASCO 2026, Gralow "grand slam") · ecancer (Wolpin interview) · NEJM
Sponsor / drug - Revolution Medicines; daraxonrasib (RMC-6236), marketed as Rasonque.
Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated October 24, 2026.
iKRAS #Daraxonrasib in pretreated #PDAC at @myESMO #ESMO26
‼️Subgroup analysis (careful with statistical power)
👉PFS benefit for G12D, G12V and G12R
👉OS benefit for all but challenging due to small numbers
👉ORR varies
#ESMOAmbassadors https://t.co/labITIowKa
Nice update of the RASolute 302 at #ESMO26
Looking at the outcomes. Although small numbers, are we facing a roadblock with the KRAS G12R variant?
Represents between 12-15%
Could protein degraders be a viable alternative?
#ESMOAmbassadors @myESMO @GrupoTTD https://t.co/bKh7kUhKzk
[Slide 1]
PFS by RAS Genotype Subgroups
Tumor RAS mutational status(a) | PFS by BICR: Events/N Daraxonrasib | Chemo | PFS HR (95% CI)(c) || PFS by investigator: Events/N Daraxonrasib | Chemo | PFS HR (95% CI)(c)
Overall: 127/248 | 130/252 | 0.55 (0.43-0.70) || 135/248 | 149/252 | 0.48 (0.38-0.61)
RAS G12D: 53/95 | 74/121 | 0.48 (0.33-0.69) || 53/95 | 79/121 | 0.43 (0.30-0.62)
RAS G12V: 39/102 | 29/76 | 0.54 (0.33-0.87) || 46/102 | 36/76 | 0.51 (0.33-0.80)
RAS G12R: 19/30 | 16/31 | 0.80 (0.41-1.56) || 22/30 | 17/31 | 0.73 (0.38-1.39)
Other RAS mutation(b): 9/11 | 7/14 | 1.29 (0.47-3.51) || 7/11 | 9/14 | 0.57 (0.21-1.56)
RAS Q61: 9/11 | 5/11 | 1.55 (0.51-4.69) || 7/11 | 7/11 | 0.63 (0.22-1.8[cut off])
No RAS mutation identified: 6/9 | 2/7 | 1.92 (0.39-9.52) || 6/9 | 6/7 | 0.62 (0.20-1.9[cut off])
[Forest plots, axis 0.05-10; Favors Daraxonrasib / Favors Chemo]
PFS results generally favored daraxonrasib versus SOC chemotherapy across RAS genotype subgroups, although treatment-effect estimates differed between BICR and investigator assessments, particularly in smaller subgroups
Data cutoff: 10 Feb 2026.
aLocally determined. Only subgroups with >=5 patients in at least one treatment arm were included. bOther RAS mutations include RAS Q61 and RAS G13. cHRs and 95% CIs overall and for subgroups were based on the unstratified Cox model with Efron's method of tie handling.
Presented by Zev A. Wainberg, MD, MSc
[Orange hand-drawn annotation circling RAS G12R row]
#LBA82 subgroup analysis RASolute 302 #PDAC
➡️HR for OS across subtypes 0.32-0.46
➡️G12R 0.61 (0.29-1.30)
➡️RAS WT numbers small (3%) but still OS benefit!
🤔perhaps ORR and mPFS not as pronounced in these populations!
✅std second line treatment
@myESMO #ESMO26 @OncoAlert https://t.co/J43sTtOscN
[Slide 1]
RAS Genotype Distribution
• Consistent with the expected distribution of RAS mutations in PDAC, RAS G12 variants predominated; G13, Q61, and no RAS mutation identified were uncommon
RAS genotypes in PDAC1
Reported real-world prevalence
KRAS G12D (39.9%)
KRAS G12V (28.6%)
KRAS G12R (14.6%)
KRAS G12C (1.7%)
KRAS Q61 (6.3%)
KRAS G13 (0.8%)
NRAS (0.2%)
RAS WT (8%)
RAS genotypes in RASolute 302a
RAS G12D (43.2%)
RAS G12V (35.6%)
RAS G12R (12.2%)
Other RAS G12c (0.8%)
RAS Q61 (4.4%)
RAS G13 (0.6%)
No RAS mutation identifiedb (3.2%)
aLocally determined at a data cutoff of 10 Feb 2026. bPatients with no identified tumor RAS mutation but with other known driver mutations (eg, BRAF V600E, MSI-H/dMMR, NTRK gene fusion) for which there is local regulatory approval must have received appropriate targeted therapy. cOther RAS G12 includes KRAS G12N, KRAS G12A, KRAS G12C, and KRAS G12L mutations.
1. Pant S, et al. J Clin Oncol. 2025;43:777.
Presented by Zev A. Wainberg, MD, MSc
[Slide 3]
PFS by RAS Genotype Subgroups
PFS by BICR | PFS by investigator
Tumor RAS mutational statusa | Events/N Daraxonrasib | Chemo | PFS HR (95% CI)c | Events/N Daraxonrasib | Chemo | PFS HR (95% CI)c
Overall | 127/248 | 130/252 | 0.55 (0.43–0.70) | 135/248 | 149/252 | 0.48 (0.38–0.61)
RAS G12D | 53/95 | 74/121 | 0.48 (0.33–0.69) | 53/95 | 79/121 | 0.43 (0.30–0.62)
RAS G12V | 39/102 | 29/76 | 0.54 (0.33–0.87) | 46/102 | 36/76 | 0.51 (0.33–0.80)
RAS G12R | 19/30 | 16/31 | 0.80 (0.41–1.56) | 22/30 | 17/31 | 0.73 (0.38–1.39)
Other RAS mutationb | 9/11 | 7/14 | 1.29 (0.47–3.51) | 7/11 | 9/14 | 0.57 (0.21–1.56)
RAS Q61 | 9/11 | 5/11 | 1.55 (0.51–4.69) | 7/11 | 7/11 | 0.63 (0.22–1.83)
No RAS mutation identified | 6/9 | 2/7 | 1.92 (0.39–9.52) | 6/9 | 6/7 | 0.62 (0.20–1.94)
[forest plot axis 0.05 0.5 1.0 5 10; Favors Daraxonrasib | Favors Chemo]
PFS results generally favored daraxonrasib versus SOC chemotherapy across RAS genotype subgroups, although treatment-effect estimates differed between BICR and investigator assessments, particularly in smaller subgroups
Data cutoff: 10 Feb 2026.
aLocally determined. Only subgroups with ≥5 patients in at least one treatment arm were included. bOther RAS mutations include RAS Q61 and RAS G13. cHRs and 95% CIs overall and for subgroups were based on the unstratified Cox model with Efron's method of tie handling.
Presented by Zev A. Wainberg, MD, MSc
Zev Wainberg presents subgroup analyses from phase 3 RASolute 302 study of #daraxonrasib in patients with previously treated metastatic #PDAC at #ESMO26 (part 2) #ESMOAmbassadors @myESMO https://t.co/xcWXBT3xw0
RASolute 302 ph3 study: Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated mPDAC
#ESMO26 #ESMOAmbassadors
👉 mOS: 13.2 vs 6.7 mo
👉ORR improved in all RAS mutations
👉PFS & OS: small subgroups, favourable for all
🧐great data, consistent benefits for all pts
@myESMO @ASCO
[Slide 2]
ORR by RAS Genotype Subgroups
Tumor RAS mutational status(b) | ORR by BICR (PR+CR/n(a)), % Daraxonrasib (n=248) | Chemo (n=252) | ORR by investigator (PR+CR/n(a)), % Daraxonrasib (n=248) | Chemo (n=252)
Overall | 32% (75/237) | 11% (27/241) | 24% (60/248) | 8% (21/252)
RAS G12D | 24% (23/95) | 9% (11/116) | 18% (17/95) | 6% (7/121)
RAS G12V | 50% (47/94) | 15% (11/73) | 37% (38/102) | 14% (11/76)
RAS G12R | 7% (2/27) | 14% (4/29) | 10% (3/30) | 3% (1/31)
Other RAS mutation(c) | 18% (2/11) | 0% (0/14) | 18% (2/11) | 7% (1/14)
RAS Q61 | 18% (2/11) | 0% (0/11) | 18% (2/11) | 9% (1/11)
No RAS mutation identified | 11% (1/9) | 17% (1/6) | 0% (0/9) | 14% (1/7)
Daraxonrasib generally showed ORR improvements compared with SOC chemotherapy across RAS genotype subgroups by both BICR and investigator assessments, with differences seen between assessments
Data cutoff: 10 Feb 2026.
(a)Patients with measurable disease at baseline were included. (b)Locally determined. Only subgroups with ≥5 patients in at least one treatment arm were included. (c)Other RAS mutations include RAS Q61 and RAS G13.
Presented by Zev A. Wainberg, MD, MSc
[Slide 3]
OS by Preselected SOC Chemotherapy Regimen(a)
GnP: Daraxonrasib (n=140) | Chemo (n=141) — HR (95% CI)(c) 0.45 (0.32–0.65)
mFOLFIRINOX/FOLFOX(b): Daraxonrasib (n=30) | Chemo (n=30) — HR (95% CI)(c) 0.46 (0.23–0.95)
NAL-IRI + 5-FU/LV: Daraxonrasib (n=78) | Chemo (n=81) — HR (95% CI)(c) 0.32 (0.18–0.58)
[Three KM panels; y-axis: OS Probability (%); x-axis: Months 0–16]
No. at risk (low resolution, monthly 0 onward):
GnP — Daraxonrasib: 140 136 136 127 116 110 94 72 50 32 17 12 3 2 0; Chemo: 141 131 121 110 88 69 59 43 27 19 9 5 3 2 0
mFOLFIRINOX/FOLFOX — Daraxonrasib: 30 27 26 25 22 21 20 15 13 8 5 4 3 2 2 0; Chemo: 30 28 25 22 18 14 13 8 6 5 4 3 2 0
NAL-IRI + 5-FU/LV — Daraxonrasib: 78 77 75 73 70 67 51 38 27 22 15 8 5 3 2 1 0; Chemo: 81 76 71 61 55 43 36 27 20 11 8 2 0
Data cutoff: 10 Feb 2026. Median (range) follow-up time was 8.5 (3.2–15.9) months.
(a)Investigator's choice of chemotherapy was determined prior to randomization. (b)mFOLFIRINOX and FOLFOX regimens were pooled due to small individual sample sizes. (c)HRs and 95% CIs were based on the unstratified Cox model with Efron's method of tie handling.
Presented by Zev A. Wainberg, MD, MSc
Survival table
Endpoint: Overall survival by preselected SOC chemotherapy regimen (subgroups)
GnP subgroup: Daraxonrasib | 140
GnP subgroup: Chemo | 141
mFOLFIRINOX/FOLFOX subgroup: Daraxonrasib | 30
mFOLFIRINOX/FOLFOX subgroup: Chemo | 30
NAL-IRI + 5-FU/LV subgroup: Daraxonrasib | 78
NAL-IRI + 5-FU/LV subgroup: Chemo | 81
HR: GnP 0.45; mFOLFIRINOX/FOLFOX 0.46; NAL-IRI + 5-FU/LV 0.32
HR CI: 0.32–0.65; 0.23–0.95; 0.18–0.58
Zev Wainberg presents subgroup analyses from phase 3 RASolute 302 study of #daraxonrasib in patients with previously treated metastatic #PDAC at #ESMO26 (part 1) #ESMOAmbassadors @myESMO https://t.co/bj6gM2WrII
🚨 ESMO 2026 | RASolute 302 (LBA82)
Phase III: Daraxonrasib (RAS-ON inhibitor) vs chemotherapy in previously treated mPDAC (N=500).
🔹 Median OS: 13.2 vs 6.7 months (HR 0.40)
🔹 Median PFS: 7.2 vs 3.6 months (HR 0.49)
OS benefit by RAS mutation:
• G12D: HR 0.49
• G12V: HR 0.32
• G12R: HR 0.61
• Q61: HR 0.37
• No RAS mutation identified: HR 0.43
A remarkable 60% reduction in the hazard of death overall, with consistent directional benefit across RAS subgroups.
@myESMO @OncoAlert
@OncBrothers
#ESMO26 #PancreaticCancer #RAS
[Slide 1]
Proffered Paper session
LBA82 - Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): Additional subgroup analyses from the ph3 RASolute 302 study
Speakers Zev A. Wainberg (Los Angeles, United States of America)
Lecture Time 14:22 - 14:32
Abstract
Background
Multiagent systemic chemo offers limited benefit in mPDAC. Aberrant RAS(ON) signaling drives PDAC; >90% of cases harbor mutant (mut) RAS, and RAS WT PDAC remains dependent on RAS pathway signaling. Daraxonrasib is an oral, RAS(ON) multi-selective, tri-complex inhibitor of active, GTP-bound mut and WT RAS. Daraxonrasib significantly improved OS and PFS vs SOC chemo in pts with previously treated mPDAC overall (with or without an identified tumor RAS mut; mOS 13.2 vs 6.7 mo; HR, 0.40; mPFS 7.2 vs 3.6 mo; HR, 0.49) and in pts with RAS G12 mut mPDAC (OS HR, 0.40; PFS HR, 0.45) with manageable safety in the RASolute 302 primary analysis (NCT06625320). We report additional subgroup analyses from RASolute 302.
[Slide 2]
OS in subgroups
| | n (%) Daraxonrasib n=248 | Chemo n=252 | OS HR (95% CI) |
Tumor RAS mut status
| G12D | 95 (38) | 121 (48) | 0.49 (0.33-0.74) |
| G12V | 102 (41) | 76 (30) | 0.32 (0.19-0.54) |
| G12R | 30 (12) | 31 (12) | 0.61 (0.29-1.30) |
| RAS Q61 | 11 (4) | 11 (4) | 0.37 (0.09-1.44) |
| No RAS mut identified | 9 (4) | 7 (3) | 0.43 (0.09-1.98) |
Conclusions
Daraxonrasib demonstrated OS benefit vs chemo across clinically relevant subgroups including pts with or without an identified tumor RAS mut. Directionally consistent OS benefit across these subgroups further reinforces the potential for daraxonrasib to be a new SOC for eligible pts with mPDAC.
[Slide 3]
Methods
Pts with previously treated mPDAC were randomized 1:1 to daraxonrasib 300 mg PO QD or investigator's choice of SOC chemo (GnP, mFOLFIRINOX, Nal-IRI+5-FU/LV, or FOLFOX). Dual primary endpoints (EPs) were OS and PFS in the RAS G12 mut population; key secondary EPs included OS and PFS in the overall population. Additional analyses evaluated OS in clinically relevant subgroups by locally determined tumor RAS mut status, preselected chemo regimen, and disease setting of prior treatment.
Results
At data cutoff (10 Feb 2026), median follow-up was 8.5 mo (range, 3.2-15.9). OS benefit with daraxonrasib vs chemo was observed across all RAS mut subgroups (Table). Daraxonrasib showed a consistent OS treatment effect across preselected chemo subgroups (HRs, 0.32-0.46). OS data by disease setting of prior treatment will also be presented.
Table: LBA82
More slides on this page
Slides shared by KOLs at the ASCO 2026 Plenary (LBA5, presented by Brian M. Wolpin, MD, MPH, Dana-Farber) plus earlier social conversation. Click any image to expand.
[Slide 1]
Study Design
Key eligibility criteria:
+ Adults with mPDAC
* One prior fluoropyrimidine- or
gemcitabine-based regimen
in the metastatic setting
+ ECOG PS 0-1
+ Documented tumor RAS
mutational status® by local testing
Stratification factors
+ ECOG PS (0 vs 1)
+ Metastatic disease at diagnosis (yes vs no)
+ Liver metastases at baseline (yes vs no)
* Tumor RAS mutational status (RAS G12D/V vs other RAS G12
vs RAS G13 or Q61 mutation or no RAS mutation identified)
Global enrollment: 59 sites across 6 countries
NCT06625320,
202s ASCO acsomto.y: Brian M. Wolpin, MD, MPH
Daraxonrasib
300 mg, PO QD
Investigator’s choice
chemotherapy (1 of 4)
GnP, mFOLFIRINOX,
Nal-IRI + 5-FU/LV, FOLFOX
@ RASolute 302
Dual primary endpoints
+ OS and PFS® (RAS G12
population)
Key secondary endpoints
* OS and PFS? (overall
population’)
+ ORR? (RAS G12 and
overall populations)
* TTD in PROs* (RAS G12
and overall populations)
---
[Slide 2]
@ RASolute 302
Primary Endpoint: Overall Survival in the RAS G12 Population
100
Daraxonrasib | Chemotherapy
90 (n=228) (n=231)
No. of events, n (%) 72 (32) 127 (65)
mOS, months (95% Cl) 13.2 (10.0-NE) 6.6 (5.4-8.2)
80 HR (95% Cl)? 0.40 (0.30-0.54)
P-value? p=5.9x10-10
70
60
50
40
30
=
2
a
o
3
2
a
a
fo}
20
10
0
10
No. at risk Months:
Daraxonrasib 228 220 217 206 191 171 150 112 81 57 33
Chemotherapy 231 214 197 175 144 113 96 69 49 32 19
Data cutoff: 10 2026. Median (range) follow-up time was 8.5 (3.2-15.9) months.
im, modian, NE, not ostimablo, OS, overall survival
*tHR and 95% Cis wore based on the strated Cox model wih Etron's method of te handing, "P-values were calculated using the straifiod log-rank tost
y presexrcoey: Brian M. Wolpin, MD, MPH
Devens pope te mer and ASCO Pernt reqs rune crkc permasnaiccs og
---
[Slide 3]
@ RASolute 302
Progression-Free Survival by BICR
RAS G12 Population Overall Population
Daraxonrasib | Chemotherapy Daraxonrasib | Chemotherapy
(n=228} (n=231) (n=248) i (n=252)
No. of events, n (%) 112 (49) 121 (52) No. of events, n (%) 127 (51) 130 (52)
mPFS, months (95% Cl) 7.3(63-8.1) — 35(29-3.8) mPFS, months (95% Cl) 7.2(5.7-7.5) 3.6 (29-4.2)
HR (95% Cp 0.45 (0.34-0.59) HR (95% Clr 0.49 (0.38-0.64)
P-value” p=3.2x10 P-value p=5.2x108
Ey
*
®
Zn =
Fo z
is i
Eo é
Fy 3
| ee a
»
No. at risk
Daraxonrasib 228 218 18S
Chemotherapy 231 183117
Data cutoff: 10 Feb 2026. Median (range) follow-up time was 8.5 (3.2-15.9) months.
BICR, blinded indepondent central review, m, median, PFS, progression tree survival
SHIRS and 95% Cis were based on the stralifod Cox model with Efton's mathod of to handing, ®P.values wore calculated using the stratihod log-rank tost
202s ASCO’ ‘presewrcomy: Brian M. Wolpin, MD, MPH ASCO sess
ANNUAL MEETING prosctaton a peciy eh miter and ASCO Pemsson repre rane: crt peminerence op
---
[Slide 4]
@ RASolute 302
Confirmed Objective Response Rate by BICR
RAS G12 Population*® Overall Population?
p<0.0001> p<0.0001>
ze
ee
8§
g
Confirmed Best
Overall Response (%)
CR
PR
Daraxonrasib Chemotherapy Daraxonrasib Chemotherapy
(n=217) (n=221) (n=237) (n=241)
Data cutoff: 10 Feb 2026.
BBICR, bindod indopondent contral roview, CR, complote response; ORR. objective rosponso rato, PR, partial response
“Only patients wih measurable disease al baseline por BICR were included in the ORR analysis. "P-values wore calculated using stratified Cochran-Mantol-Haenszel chi-square test
2026 ASC #ASCO26 paesexreowy: Brian M. Wolpin, MD, MPH
ANNUAL MEETING Prenran op mite rd ASCO Parmar he ne crt parca on
[Slide 1]
SA tne tte
2026 ASCO
ANNUAL MEETING
Daraxonrasib, a RAS(ON) multi-selective inhibitor vs
chemotherapy in previously treated metastatic
pancreatic adenocarcinoma (mPDAC):
Primary and final analysis from the Phase 3
RASolute 302 study
rian M. Wolpin,' Zev A. Wainberg, Andrew E. Hendifar, Mitesh J. Borad, Filippo Pietrantonio, Shubham
Brian M. Wolpin
Pant, Pascal Hammel, Chiara Cremolini, Gulam A. Manji, Paul E. Oberstein, Ignacio Garrido-Laguna,
to Ueno, Stephen Y. Chui, Ying Zhang, Hina Patel, Yeonju Lee,
Christoph Springfeld, Nilofer S. Azad, Mako!
Zeena Salman, Eileen M. O'Reilly
On behalf of RASolute 302 investigators
tHale Family Center for Pancreatic Cancer Research; Dana-Farber Cancer Institute, Boston, MA, USA
ASCO =
2026ASCO
ANNUAL MEETIN
---
[Slide 2]
€ RASolute 302
Study Design
Dual primary endpoints
+ OS and PFS® (RAS G12
Daraxonrasib
population)
Key eligibility criteria:
+ Adults with mPDAC 300 mg, PO aD
+ One prior fluoropyrimidine- or si
Key secondary endpoints
= Investigator’s choice + OS and PFS? (overall
; a oe Ehenictierapyi(aron) population®)
: GnP, mFOLFIRINOX, * ORR? (RAS G12 and
mutational status® by local testing Nal-IRI + 5-FU/LV, FOLFOX overall populations)
+ TTD in PROs¢ (RAS G12
and overall populations)
gemcitabine-based regimen
in the metastatic setting
Stratification factors
+ ECOG PS (0 vs 1)
+ Metastatic disease at diagnosis (yes vs no)
+ Liver metastases at baseline (yes vs no)
+ Tumor RAS mutational status (RAS G12D/V vs other RAS G12
vs RAS G13 or Q61 mutation or no RAS mutation identified)
Global enrollment: 59 sites across 6 countries
NeT08625320,
SFU, S Arurecl ICR, binded Independent contra review, ECOG Easter, Cooperative Oncology Group; FOLFOX. leucovorin, $-FU, and oxaliplatin. GaP, gemctabine and nab-pacitaxel, LV, eset EOLESION aees CA Een
Joucovorin, and axaiipistin: POAC, stic adenocarcinoma, NalIRi, nanoliposomal innotecan, ORR, objective response rate, OS, overall survival, PFS, progression-tree survival, oral administration: PRO, patien!.reporied outcome,
Se oe re Ls PO,
“Esther mutant, defined a3 nonsynonymous mutations in KRAS, NRAS, or HRAS al codons 12, EGS 12, G13, or Q1), or no RAS mutation identified. "By BICR per RECIST 1.1. ‘inchuding patients
‘mulatons, or had no RAS mutation Kientiied. «TTD in symptom of pain and in global heath statusia aves beers BOSS OAS Gta. oat Oa
ASCO sane
MOWLIBGE CONQUERS CANCER
+6 ASCO #ASCC presexreo er: Brian M. Wolpin, MD, MPH
ANNUAL MEETING Proventaton @ procerty of he mtr ard ASCO Penrason regared toy neue Contac! permauona (hance oy
[Slide 1]
Abstract LBA5
Daraxonrasib, a RAS(ON) multi-selective inhibitor vs
chemotherapy in previously treated metastatic
pancreatic adenocarcinoma (mPDAC): Primary and final
analysis from the phase 3 RASolute 302 study.
Authors
Brian M. Wolpin, Zev A. Wainberg, Andrew Hendifar, Mitesh
J. Borad, Filippo Pietrantonio, Shubham Pant, Pascal
Hammel, Chiara Cremolini, Gulam A. Manji, Paul E.
Oberstein, Ignacio Garrido-Laguna, Christoph Springfeld,
Nilofer S. Azad, Makoto Ueno, Stephen Y. Chui, Ying Zhang,
Hina Patel, Yeonju Lee, Zeena Salman, Eileen M. O'Reilly
---
[Slide 2]
Results:
248 pts were randomized to daraxonrasib and 252 to
chemo. Baseline characteristics were balanced between
arms. At data cutoff (Feb 10, 2026; mFU: 8.5 mo), all
primary and key secondary endpoints were met.
Statistically significant, clinically meaningful
improvements in OS and PFS were observed with
daraxonrasib vs chemo in the RAS G12 and overall
populations (Table). Gr >3 TRAEs occurred in 43.6% of pts
receiving daraxonrasib vs 57.5% receiving chemo. The
most common (210%) Gr >3 TRAEs were rash (13.7%) and
stomatitis (12.0%) for daraxonrasib; neutrophil decrease
(18.2%) and anemia (16.4%) for chemo. TRSAEs occurred
in 10.8% of pts receiving daraxonrasib vs 18.7% receiving
chemo. Discontinuation due to TRAEs occurred in 1.2% of
pts for daraxonrasib vs 11.2% for chemo. Median/mean
daraxonrasib dose intensity was 93.1%/84.7%.
---
[Slide 3]
Conclusions:
Daraxonrasib demonstrated unprecedented improvements
in OS and PFS vs chemo in pts with 2L mPDAC with or
without an identified tumor RAS mut. Daraxonrasib was
generally well tolerated, with a manageable safety profile
and with no new safety signals. Results support
daraxonrasib as the new SOC for 2L mPDAC.
RASolute 302 is a global, randomized Phase 3 trial of daraxonrasib (RMC-6236) — the first oral RAS(ON) multi-selective inhibitor — versus investigator's-choice cytotoxic chemotherapy as second-line therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC) who progressed on one prior fluoropyrimidine- or gemcitabine-based regimen. The trial enrolled 500 patients globally (North America, Europe, and Asia), randomized 1:1 (daraxonrasib n=248; chemotherapy n=252); enrollment did not require a RAS mutation, though the large majority (459/500) harbored a RAS G12 mutation. Dual primary endpoints (OS and PFS in the RAS G12 population) were met, with consistent benefit in the intent-to-treat population. Full results were presented at the #ASCO26 Plenary Session (LBA5) by Brian M. Wolpin, MD, MPH (Dana-Farber) and published simultaneously in the New England Journal of Medicine.
Study Design
Phase 3, global, randomized, open-label. Patients with metastatic PDAC who progressed on one prior line randomized to oral daraxonrasib 300 mg once daily vs investigator's-choice chemotherapy. Stratified by RAS mutation status and region.
Population
n=500 with metastatic PDAC, one prior fluoropyrimidine- or gemcitabine-based regimen, ECOG 0-1. RAS mutation not required for entry; 459/500 (~92%) had a RAS G12 mutation. Primary endpoint population: RAS G12 (dual primary OS + PFS); ITT analyzed as key secondary.
Intervention
Experimental: Daraxonrasib (RMC-6236) 300 mg orally once daily until progression or unacceptable toxicity. Control: Investigator's choice of standard second-line cytotoxic chemotherapy.
Endpoints
Dual primary: OS and PFS (BICR) in the RAS G12 population. Key secondary: OS and PFS in the ITT population, objective response rate (ORR), duration of response, safety/tolerability.
FDA & Regulatory Status
FDA Approval & Regulatory Timeline
FDA APPROVEDRasonque (daraxonrasib) approved for metastatic pancreatic adenocarcinoma — August 26, 2026
On August 26, 2026, the FDA approved Rasonque (daraxonrasib), a once-daily oral RAS inhibitor, for the treatment of adults with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or are not candidates for multiagent systemic therapy — the first-in-class RAS-targeted approval in pancreatic cancer. Per the approved prescribing information, the indication carries no RAS-testing requirement and no companion diagnostic — the label does not restrict by tumor RAS mutation status. The FDA cited the pivotal RASolute 302 overall survival result (median 13.2 vs 6.7 months vs standard chemotherapy) and granted the approval 6.5 months before the user fee deadline, after Priority Review; the application was also reviewed under the Commissioner’s National Priority Voucher pilot, and the drug had prior Breakthrough Therapy and Orphan Drug designations. Most common side effects per the FDA announcement: rash, diarrhea, stomatitis, nausea, fatigue, vomiting, abdominal pain, edema, decreased appetite, and hemorrhage. The approval was granted to Revolution Medicines.
EXPANDED ACCESSPre-approval Expanded Access Program (May 1, 2026)
Prior to approval, the FDA issued a “safe to proceed” letter to Revolution Medicines, allowing the company to initiate an expanded access treatment protocol (EAP) for daraxonrasib in patients with previously treated metastatic PDAC. The FDA received the request on April 28, 2026 and signed it on April 30 — a two-day turnaround that FDA Commissioner Marty Makary, MD, MPH cited as reflecting “the FDA’s strong commitment to facilitate early access to therapies for serious and life-threatening conditions.” The EAP provided a pre-approval pathway outside a clinical trial for eligible patients with no comparable or satisfactory alternative; under FDA regulations, requests had to be initiated by a U.S.-licensed treating physician. Following the August 26, 2026 approval, Rasonque is available by prescription for the approved indication.
NDA & Approval — Commissioner’s National Priority Voucher
Revolution Medicines announced on April 13, 2026 that it intended to submit a New Drug Application (NDA) for daraxonrasib under the FDA Commissioner’s National Priority Voucher (CNPV) pilot program, which is intended to accelerate the development and review of therapies aligned with U.S. national health priorities. The FDA granted daraxonrasib a national priority voucher in October 2025. The FDA approved the application on August 26, 2026. The company previously stated (May 31, 2026) that it intended to submit the RASolute 302 data to global regulatory authorities.
The FDA previously granted daraxonrasib Breakthrough Therapy Designation and Orphan Drug Designation for the treatment of patients with previously treated metastatic PDAC harboring RAS G12 mutations. These designations expedite development and review but do not constitute approval. (Rasonque was subsequently approved on August 26, 2026 for a broader indication — see above.)
All efficacy and safety figures cited above are sourced to the Revolution Medicines ASCO Plenary press release (May 31, 2026), the simultaneous NEJM publication (O’Reilly et al.), and the Dana-Farber newsroom; ORR and discontinuation figures are from the same primary readout. RASolute 302 reflects a single data cut presented at #ASCO26.
Frequently Asked Questions
RASolute 302 FAQ
What is the RASolute 302 trial?
RASolute 302 (NCT06625320) is a global Phase 3 trial of once-daily oral daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, versus investigator's-choice chemotherapy in 500 patients with previously treated metastatic pancreatic ductal adenocarcinoma, regardless of RAS mutation status. See Trial Design.
What did RASolute 302 show for survival?
Daraxonrasib doubled median overall survival versus chemotherapy (HR 0.40), meeting both dual primary endpoints (OS and PFS in the RAS G12 population), as presented at the ASCO 2026 Plenary (LBA5) and published in NEJM. All figures and sources: At a Glance.
Is daraxonrasib FDA approved for pancreatic cancer?
Yes. On August 26, 2026, the FDA approved daraxonrasib as Rasonque for adults with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or are not candidates for multiagent systemic therapy — the first RAS inhibitor approved in pancreatic cancer. See FDA & Regulatory.
What is the safety profile of daraxonrasib in RASolute 302?
Daraxonrasib has on-target RAS-pathway toxicity, mainly rash and stomatitis, that needs active management; grade 3 or higher treatment-related adverse events and discontinuations were less frequent than with chemotherapy. Rates and label warnings: At a Glance.
Why is RASolute 302 considered a landmark trial?
It is the first positive Phase 3 trial of a RAS-targeted therapy in pancreatic cancer, a disease in which most tumors are KRAS-driven, and it led to the first RAS inhibitor approval in this disease. See At a Glance.
In the News
Media Coverage & Analysis
Selected coverage of the August 26, 2026 FDA approval and the RASolute 302 Plenary readout, newest first. External links open in a new tab.
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