SUBPROTOCOL A:
This is an open-label, multicenter, Phase 1b/2 study of RMC-6291 in combination with pembrolizumab, with or without chemotherapy (carboplatin/cisplatin and pemetrexed). There are 2 parts in the study: Part 1 – Dose Exploration (RMC-6291 + pembrolizumab) in patients with KRASG12C-mutant advanced solid tumors; and Part 2 – Dose Expansion, which is divided into Cohort 1 (RMC-6291 at selected RP2DS + pembrolizumab) and Cohort 2 (RMC-6291 + pembrolizumab + carboplatin/cisplatin and pemetrexed) in patients with KRASG12C-mutant advanced NSCLC.

SUBPROTOCOL B:
This is an open-label, multicenter, Phase 1b/2 study of RMC 6236 in combination with pembrolizumab, with or without chemotherapy (carboplatin/cisplatin and pemetrexed). There are 2 parts in the study: Part 1 – Dose Exploration (RMC-6236 + pembrolizumab) and Part 2 – Dose Expansion, which is divided into Cohort 1 (RMC-6236 at selected recommended Phase 2 dose and schedule [RP2DS] + pembrolizumab) and Cohort 2 (RMC-6236 + pembrolizumab + carboplatin/cisplatin and pemetrexed).

SUBPROTOCOL A:
RMC-6291 will be administered BID for 21 days for the duration of each 21-day cycle until treatment discontinuation.

SUBPROTOCOL B:
RMC-6236 will be administered orally QD for 21 days for the duration of each 21-day cycle until treatment discontinuation.

The purpose of these subprotocols is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of 2 novel guanosine-5’-triphosphate (GTP)-bound rat sarcoma viral oncogene protein (RAS) (active) (RAS[ON]) inhibitors, RMC-6291 in Subprotocol A and RMC-6236 in Subprotocol B, each in combination with pembrolizumab (Keytruda®), with or without chemotherapy.

SUBPROTOCOL A:
Part 2, cohort 1;
This cohort will enroll patients with locally advanced or metastatic KRASG12C-mutated NSCLC with tumor proportion score (TPS) ≥ 50% and who have received no prior systemic therapy in the metastatic setting.

Part 2, cohort 2;
This cohort will enroll patients with locally advanced or metastatic KRASG12C-mutated NSCLC (regardless of TPS) who have received no prior systemic therapy in the metastatic setting.

SUBPROTOCOL B:
Part 2, cohort 1;
This cohort will enroll patients with locally advanced or metastatic RAS-mutated NSCLC who have received no prior systemic therapy in the metastatic setting and have a tumor progression score (TPS) ≥ 50%.

Part 2, cohort 2;
This cohort will enroll patients with locally advanced or metastatic RAS-mutated NSCLC who have received no prior systemic therapy in the metastatic setting and have tumor progression score (TPS) < 50%

For all subprotocols and cohorts:

• Primary central nervous system (CNS) tumors.
• Active or untreated CNS metastases or leptomeningeal disease.
• Prior direct RAS-targeted therapy except, where specified, KRASG12C(OFF) inhibitor.
• Has discontinued treatment with a prior KRASG12C(OFF) inhibitor due to a treatment-related Grade ≥ 3 adverse event (AE) or due to a clinically significant AE of any severity (eg, pneumonitis, transaminase elevations, corrected QT [QTc] prolongation).
• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137), and experienced ≥ Grade 3 immune-related AE (irAE) or was discontinued from that treatment due to irAE of any grade.