NSCLC Phase III Trial Design
Q: How will KRAZATI approval affect your NSCLC Phase III trial design?
A: Management acknowledged that KRAS G12C is the most complicated part of their lung cancer trial for RMC-6236. They have not yet laid out their plan but noted that potential FDA approval of KRAZATI may impact whether KRAZATI becomes the standard of care comparator or if docetaxel remains acceptable. They will determine the trial design after further discussion and data disclosure.

Competitive PFS in NSCLC
Q: What PFS data would be competitive for 6236 in NSCLC?
A: Management emphasized that they need to clear the standard of care bar but did not provide specific numbers. They stated it's difficult to answer while gathering and analyzing data. They have internal target product profiles but prefer to present data in context once available.

First-Line Pancreatic Cancer Strategy
Q: How much more data is needed to move 6236 to first-line pancreatic cancer?
A: They believe RMC-6236 monotherapy already qualifies for inclusion in a first-line trial. The main question is how to combine it with chemotherapy, which is a safety and tolerability issue. They are working to ensure that combining with chemotherapy will not cause excessive side effects for patients.

Combination of 6236 with 6291
Q: Who is enrolled in the 6236 and 6291 combo study, and what's the efficacy bar?
A: The study enrolls patients with previously treated G12C tumors, mainly lung and colorectal cancers. They acknowledged that determining efficacy requires large randomized trials and are looking for qualitative differentiation. There is no preset response rate, PFS, or OS number they can ascribe to the combination at this time.

Timing of Data Updates
Q: How will upcoming data disclosures be timed and presented?
A: Management said that data updates expected in the fourth quarter could happen sequentially or be bundled. They did not provide specific timing or venues but will decide the format at the right moment.

Censoring in Pancreatic Cancer Data
Q: Was there unusual censoring in the pancreatic PFS data affecting Phase III relevance?
A: They explained that the censoring was standard due to patients enrolling later and not having progression events by data cutoff. This does not affect translatability to the registrational trial, as future analyses will be based on prespecified events rather than real-time data cuts.

Rash Impact on Combinations
Q: Could 6236-related rash impact combinations with pembrolizumab or chemo?
A: They do not think so. The rash associated with RMC-6236 is acneiform and responds to antibiotics, differing from immune-mediated rashes. Combining 6236 with other treatments is unlikely to mutually enhance rash severity.

Colorectal Cancer Data Timing
Q: When will we see 6236 data in colorectal cancer studies?
A: They have not provided guidance on timing. They view colorectal cancer as primarily requiring combination strategies and are focusing on that approach.

G12D Inhibitor Tumor Types
Q: Which tumor types are included in the upcoming G12D data?
A: The study includes patients with solid tumors harboring G12D mutations, predominantly gastrointestinal tumors, but also some lung cancers. The representation reflects the prevalence of G12D mutations in these cancers.

Fixed Dose Combinations
Q: Are you planning any fixed dose combinations of your molecules?
A: They consider it possible in the future but need to establish doses first. Fixed dose combinations may be complex due to different dosing schedules (e.g., once daily vs twice daily). They will pursue it if it adds convenience without unnecessary complexity.