Phase 1b/2, open-label, multicenter study

Subprotocol C: RMC-9805 (zoldonrasib) + pembrolizumab + carbo/cisplatin + pemetrexed
Subprotocol D: RMC-9805 (zoldonrasib)

• safety and tolerability of RMC-9805
• antitumor activity of RMC-9805

Subprotocol C:

• Histologically or cytologically confirmed non-squamous NSCLC with documented Stage IV disease, or Stage IIIB-C disease not amenable to curative intent surgical resection or radiotherapy.
• No previous systemic therapy for locally advanced or metastatic disease.
• RAS G12D mutation (defined by a substitution of aspartic acid for glycine at codon 12 in __KRAS, HRAS, or NRAS) previously (independent of this trial) identified by DNA sequencing or PCR test on ctDNA or tumor tissue obtained before C1D1 (up to 3 years before C1D1), performed in a certified laboratory per local standards.
• ECOG 0-1

Subprotocol D:

• Histologically or cytologically confirmed NSCLC with documented Stage IV disease, or Stage IIIB-C disease, not amenable to curative intent surgical resection or radiotherapy.
• Evidence of progressive disease (PD), per RECIST v1.1, from prior therapy or intolerance to prior therapy. Prior therapy must include an anti-programmed cell death-1 (anti-PD-1)/ anti-programmed cell death-1 [anti-PD-(L)1] agent (unless contraindicated) and a platinum-based doublet therapy
• Documented RAS G12D mutation previously (independent of this trial) determined by DNA sequencing or polymerase chain reaction (PCR) test on tumor tissue (up to 5 years before consent), performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified (USA) or equivalently accredited laboratory per local regulation.

Subprotocol C:

• Untreated CNS metastases or leptomeningeal disease
• Diagnosed or treated for a second malignancy (ie, other than the malignancy required for inclusion) ≤5 years before enrollment,
• Uncontrolled effusion. Pleural effusion, pericardial effusion, or ascites requiring drainage within 28 days of C1D1
• Significant cardiovascular or interstitial lung disease.

Subprotocol D:

• Untreated central nervous system (CNS) metastases or leptomeningeal disease
• Prior therapy must not exceed 3 prior lines in the advanced/metastatic setting.
• Uncontrolled effusion: Pleural effusion, pericardial effusion, or ascites requiring monthly or more frequent drainage procedures. Patients with a permanent catheter in place (eg, PleurX) may be permitted if considered by the Investigator to be clinically stable.
• Other cancers: Diagnosed or treated ≤ 3 years before enrollment,
• Significant cardiovascular or interstitial lung disease.