Analysis of the Likelihood of Successful Phase 3 Clinical Trials for RMC-9805

Based on my in-depth research, I have identified an important clarification:

. Let me break down the details of these two drugs for you and analyze the likelihood of successful Phase 3 clinical trials.

• ORR of
  61%
  (n=18) in monotherapy for KRAS G12D-mutated NSCLC, not 63%
• Disease Control Rate (DCR) of
  89%
• Median Time to Response (TTR) of 1.4 months
• FDA has granted
  Breakthrough Therapy Designation
  (January 2026)
• Currently in
  Phase 1 Clinical Trial
  (NCT06040541)

• First disclosed NSCLC data at the 2025 April AACR Annual Meeting
• Disclosed preliminary pancreatic ductal adenocarcinoma (PDAC) data at the October 2024 EORTC-NCI-AACR Conference
• Published a mechanism of action research paper in Science in July 2025

• RMC-6236 combined with mFOLFIRINOX chemotherapy has indeed shown high response rates in pancreatic cancer
• However, this is data for
  a different drug
  ; RMC-6236 is a broad-spectrum RAS inhibitor

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1. Phase 3 trials not yet initiated
   - currently still in Phase 1 dose escalation/expansion stage
2. Expected initiation time is unclear
   - the company has not yet announced a specific Phase 3 initiation plan
3. Breakthrough Therapy Designation provides an opportunity for accelerated development
   - may be initiated after obtaining more Phase 1 data

• RASolute 302
  : RMC-6236 vs standard chemotherapy (docetaxel) for previously treated metastatic PDAC
  • Primary endpoints: PFS and OS
  • Expected to complete enrollment in 2025
• RASolute 303
  : Phase 3 trial for first-line treatment of PDAC
• RASolute 304
  : Phase 3 trial for adjuvant treatment of pancreatic cancer

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• FDA’s BTD indicates that it deems the drug to have significant clinical advantages
• Eligible for priority review and rolling submission mechanisms
• Drugs that have received BTD historically have a higher success rate

• An ORR of 61% is
  best-in-class
  in refractory NSCLC
• A DCR of 89% demonstrates broad anti-tumor activity
• Rapid onset of action (median 1.4 months)
• Tolerable safety profile (most common adverse events: nausea 39%, diarrhea 24%, vomiting 18%)

• First-in-class covalent inhibitor of RAS(ON) G12D
• High selectivity reduces the risk of off-target toxicity
• Preclinical studies show broad anti-tumor activity

• Current ORR data is based on only 18 NSCLC patients
• PDAC data has not yet been fully disclosed
• Expanded cohort data requires further validation

• The ‘combination chemotherapy’ data mentioned in the question may belong to RMC-6236
• Clinical data for RMC-9805 in combination with chemotherapy has not yet been disclosed
• Need to determine the optimal combination regimen

• Competition from other KRAS inhibitors (e.g., MRTX1133)
• Relatively limited patient pool with KRAS G12D mutations
• Pricing and accessibility issues

---

1. Expanded cohort data validation
   - need to replicate the excellent Phase 1 ORR data in more patients
2. Development of combination chemotherapy regimens
   - need to clarify the clinical benefits and optimal combinations of combination chemotherapy
3. Rapid enrollment capability
   - leverage BTD to accelerate Phase 3 initiation
4. Safety data update
   - long-term safety data is critical

• 2025-2026: Complete Phase 1 expanded cohort, initiate Phase 2 combination chemotherapy studies
• 2026-2027: Initiate pivotal Phase 3 trials
• 2028-2029: Potential New Drug Application (NDA) submission

• RMC-9805 shows potential to become an important treatment option for KRAS G12D-mutated tumors
• Success in Phase 3 clinical trials
  depends on
  maintaining high ORR in expanded cohorts and establishing advantages in combination chemotherapy
• It is recommended to closely monitor upcoming expanded cohort data disclosures and the initiation of combination chemotherapy studies

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[1] Revolution Medicines Announces FDA Breakthrough Therapy Designation for Zoldonrasib. (January 8, 2026). https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-fda-breakthrough-therapy-1

[2] Revolution Medicines Presents Initial Data from Zoldonrasib (RMC-9805) at AACR 2025. (April 27, 2025). https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-initial-data-zoldonrasib-rmc-9805

[3] Zoldonrasib Nets Breakthrough Therapy Designation in KRAS G12D NSCLC. OncLive. (January 2026). https://www.onclive.com/view/zoldonrasib-nets-breakthrough-therapy-designation-in-kras-g12d-mutated-nsclc

[4] Study of RMC-9805 in Participants With KRAS G12D-Mutant Solid Tumors. ClinicalTrials.gov. NCT06040541. Updated: August 28, 2025. https://www.clinicaltrials.gov/study/NCT06040541

[5] Revolution Medicines Announces Publication of Peer-Reviewed Research Paper in Science on Zoldonrasib. (July 24, 2025). https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-publication-peer-reviewed

[6] RMC-6236 Shows Activity With Favorable Toxicity Profile in Previously Treated PDAC. OncLive. (July 2024). https://www.onclive.com/view/rmc-6236-shows-activity-with-favorable-toxicity-profile-in-previously-treated-pdac