From ‘Undruggable’ to Breakthrough: Pan-RAS Inhibitors Transform GI Oncology Practice

Pan-RAS inhibitors like RMC-6236 are showing unprecedented 30% response rates in previously treated pancreatic cancer, potentially ending the decades-long frustration of targeting “undruggable” KRAS mutations. Meanwhile, durvalumab plus FLOT (D-FLOT) and zolbetuximab are reshaping treatment paradigms in gastroesophageal cancers with improved survival outcomes.

Expert Commentary Scope & Focus

• Speaker: James M. Cleary, MD, PhD, Associate Professor at Harvard Medical School, GI Oncologist
• Focus Areas: Pancreatic cancer and gastroesophageal cancer treatment advances
• Perspective: Clinical practice implications of recent therapeutic breakthroughs
• Context: September 2025 update on paradigm-shifting developments

Key Clinical Developments

Pan-RAS Inhibitors in Pancreatic Cancer

• RMC-6236 (Revolution Medicine) showing 30% response rate in previously treated pancreatic cancer
• Progression-free survival over 7 months in early-phase trials
• RASolute 302 phase 3 trial comparing RMC-6236 vs standard chemotherapy in second-line setting
• Addresses 90-95% of pancreatic cancers with KRAS mutations
• Manageable toxicity profile with rash as primary side effect

Gastroesophageal Cancer Advances

• MATTERHORN trial: D-FLOT showed improved recurrence-free survival (HR 0.7) vs FLOT alone
• ESOPAC trial: Perioperative FLOT superior to neoadjuvant chemoradiation
• Zolbetuximab FDA-approved October 2024 for CLDN18.2-positive gastroesophageal cancer

Practice Implications

• Pan-RAS inhibitors expected to be “paradigm shifting” across colorectal, pancreatic, and biliary tract cancers
• D-FLOT anticipated to become new standard of care pending FDA approval
• Zolbetuximab provides first-line option for PD-L1 negative, CLDN18.2-positive patients
• On-target nausea with zolbetuximab requires enhanced supportive care management

Development Pipeline & Future Outlook

• KRAS G12D inhibitors in development alongside pan-RAS agents
• Multiple GI malignancies positioned to benefit from RAS targeting
• Transition from “undruggable” to actionable targets representing major therapeutic advance
• Continued expansion of targeted options in historically chemotherapy-dependent cancers

Source: https://www.medscape.com/viewarticle/treatment-updates-pancreatic-gastrointestinal-cancer-2025a1000m99