First-Line Treatment Strategy
Q: Will you pursue first-line lung cancer trials sooner?
A: We prioritize moving RMC-6236 into first-line settings, leveraging emerging data to enable earlier treatment where benefits are greater. While committed to our second-line monotherapy trial, we are actively exploring first-line options and will adjust plans if necessary.

Impact of Competing G12C Inhibitors
Q: How do other G12C inhibitors affect your trials?
A: In pancreatic cancer, impact is minimal due to low G12C incidence. In lung cancer, despite crowded G12C space, our RMC-6236 targets both G12C and non-G12C mutations, serving patients without G12C inhibitor options. We expect RMC-6236 to be active on G12C mutations, based on preclinical data.

FDA Endpoint Requirements
Q: Will FDA require overall survival endpoints?
A: In non-small cell lung cancer, the FDA's stance on requiring overall survival (OS) is unclear. They may accept clinically meaningful progression-free survival (PFS) improvements for approval. The upcoming adagrasib review will provide more insight into FDA's position on OS requirements.

Combination Therapy Development
Q: What will drive further combo therapy development?
A: We aim to establish safety and combinability for RMC-6236 with mutant-selective inhibitors and pembrolizumab. Efficacy benchmarks include improving response rates over current standards, such as achieving higher than 50% response rate seen with chemotherapy plus pembrolizumab.

Business Development Plans
Q: How are you approaching partnerships?
A: We plan to commercialize our RAS(ON) inhibitors independently in the U.S., given our integrated portfolio. Outside the U.S., we're open to partnering for marketing and development, seeking alignment to avoid strategic conflicts. We're investing in U.S. commercialization capabilities to field a competitive sales force at the right time.

Safety Profile and Dose Reductions
Q: Does safety vary with mutation profile?
A: The safety profile of RMC-6236 is consistent across mutation types. Dose reductions observed were not representative of broader tolerability and were chosen to illustrate mechanistic points. Side effects exist, but responses remain strong even after dose adjustments.

Combination Rationale of RAS Inhibitors
Q: Why combine RAS inhibitors with overlapping targets?
A: Combining mutant-selective inhibitors with our RAS multi-inhibitor addresses tumor escape mechanisms by inhibiting both the original mutation and emergent mutations or wild-type RAS upregulation, potentially enhancing response depth and frequency.

Data Presentation and Timing
Q: Will combination data be presented with monotherapy updates?
A: Our priority is the second-line monotherapy data for regulatory purposes. Combination data may be presented separately as they inform future studies, but exact timing and context are undecided.

Patient Demographics in G12D Study
Q: Will G12D study reflect real-world patient types?
A: Yes, the RMC-9805 trial enrolls patients with G12D mutations across all tumor types, primarily gastrointestinal cancers like pancreatic and colorectal cancer, reflecting real-world incidence.

PFS Data Availability
Q: Will PFS data be available in second-half updates?
A: We expect progression-free survival data to be part of upcoming presentations, which will support the initiation of late-stage trials, particularly for pancreatic cancer. PFS will be an important component of these updates.