Trial Outcomes & Findings for Combination Study of RMC-4630 and Sotorasib for NSCLC Subjects With KRASG12C Mutation After Failure of Prior Standard Therapies (NCT NCT05054725)

Last Updated: 2026-01-06

Results Overview

Evaluation of the antitumor effects of RMC-4630 and sotorasib in locally advanced or metastatic NSCLC patients with KRASG12C mutation with and without co-existing genetic aberrations in specific genes such as STK11/LKB1, KEAP1, and PIK3CA after failure of prior standard therapy. Objective Response Rate (%) is defined as the proportion of patients with Best Overall Response of confirmed CR, or PR. Response was confirmed by a repeat assessment no less than 28 days.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

47 participants

Primary outcome timeframe

31 months

Results posted on

2026-01-06

Participant Flow

This Phase 2 study (RMC-4630-03) had a safety run-in period in which RMC-4630 was administered at 140 mg twice weekly (BIW) on D1D2 of each week in a 21-day cycle and sotorasib 960 mg once daily (QD) in a 21-day cycle as the starting dose with the option of escalating to RMC-4630 200 mg BIW on D1D2 of each week in a 21-day cycle. Patients were evaluated for dose limiting toxicities (DLTs).

Participant milestones

Participant milestones
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg D1D2 + Sotorasib 960 mg QD The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Overall Study STARTED	4	43
Overall Study COMPLETED	0	3
Overall Study NOT COMPLETED	4	40

Reasons for withdrawal

Reasons for withdrawal
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg D1D2 + Sotorasib 960 mg QD The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Overall Study Withdrawal by Subject	3	4
Overall Study Sponsor's Decision to Terminate the Study	0	3
Overall Study Death	1	21
Overall Study Sponsor amended protocol to terminate Long Term Follow Up (LTFU)	0	3
Overall Study PI's decision that there is no benefit from LTFU	0	6
Overall Study Due to AE#17 - Angiosarcoma of the breast with possible relation to study drug	0	1
Overall Study Agreed between patient and PI as safety follow up is not for benefit of the patient	0	1
Overall Study Physician discretion due to subject progression	0	1

Baseline Characteristics

Combination Study of RMC-4630 and Sotorasib for NSCLC Subjects With KRASG12C Mutation After Failure of Prior Standard Therapies

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	Total n=47 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=37 Participants	0 Participants n=56 Participants	0 Participants n=82 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=37 Participants	23 Participants n=56 Participants	24 Participants n=82 Participants
Age, Categorical >=65 years	3 Participants n=37 Participants	20 Participants n=56 Participants	23 Participants n=82 Participants
Sex: Female, Male Female	2 Participants n=37 Participants	25 Participants n=56 Participants	27 Participants n=82 Participants
Sex: Female, Male Male	2 Participants n=37 Participants	18 Participants n=56 Participants	20 Participants n=82 Participants
Race/Ethnicity, Customized Race: American Indian or Alaska Native	0 participants n=37 Participants	0 participants n=56 Participants	0 participants n=82 Participants
Race/Ethnicity, Customized Race: Asian	1 participants n=37 Participants	8 participants n=56 Participants	9 participants n=82 Participants
Race/Ethnicity, Customized Race: Black or African American	0 participants n=37 Participants	0 participants n=56 Participants	0 participants n=82 Participants
Race/Ethnicity, Customized Race: Native Hawaiian or Other Pacific Islander	0 participants n=37 Participants	0 participants n=56 Participants	0 participants n=82 Participants
Race/Ethnicity, Customized Race: White	3 participants n=37 Participants	31 participants n=56 Participants	34 participants n=82 Participants
Race/Ethnicity, Customized Race: Other	0 participants n=37 Participants	0 participants n=56 Participants	0 participants n=82 Participants
Race/Ethnicity, Customized Ethnicity: Hispanic or Latino	0 participants n=37 Participants	2 participants n=56 Participants	2 participants n=82 Participants
Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino	4 participants n=37 Participants	40 participants n=56 Participants	44 participants n=82 Participants
Race/Ethnicity, Customized Ethnicity: Missing/Not Reported	0 participants n=37 Participants	1 participants n=56 Participants	1 participants n=82 Participants
Race/Ethnicity, Customized Race: Missing/Not Reported	0 participants n=37 Participants	4 participants n=56 Participants	4 participants n=82 Participants

PRIMARY outcome

Timeframe: 31 months

Population: Objective Response Rate (%) is defined as the proportion of patients with Best Overall Response of confirmed CR, or PR.

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Objective Response Rate (ORR) as Assessed Per RECIST v1.1	0 Participants	11 Participants

SECONDARY outcome

Timeframe: 31 months

Characterization of the safety, tolerability of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC after failure of prior standard therapy

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Clinically Significant Changes in Vital Signs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 31 months

Characterization of the safety, tolerability of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC after failure of prior standard therapy

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Clinically Significant Changes in Laboratory Tests Grade 4 Aspartate Aminotransferase Increased	0 Participants	2 Participants
Clinically Significant Changes in Laboratory Tests Grade 3 Alanine Aminotransferase Increased	1 Participants	5 Participants
Clinically Significant Changes in Laboratory Tests Grade 3 Aspartate Aminotransferase Increased	2 Participants	5 Participants
Clinically Significant Changes in Laboratory Tests Grade 3 Bilirubin Increased	0 Participants	5 Participants
Clinically Significant Changes in Laboratory Tests Grade 4 Alanine Aminotransferase Increased	0 Participants	2 Participants

SECONDARY outcome

Timeframe: 31 months

Characterization of the safety, tolerability of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC after failure of prior standard therapy

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Clinically Significant Changes in ECGs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 31 months

Population: Summary of PK of RMC-4630 concentration for subjects with KRASG12C mutant NSCLC (All Treated Subjects). Timepoints beyond Cycle 4 do not any value for the PK profile per sponsor. The decreasing number in participants analyzed is due to various factors such as missed samples or patient drop out as timepoints progressed.

Characterization of PK of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC.

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Trough and Approximate Peak Concentrations of RMC-4630 Cycle 1 Day 15 pre-dose (within 1 hour pre-dose)	21.04 ng/ml Geometric Coefficient of Variation 138.51	27.55 ng/ml Geometric Coefficient of Variation 127.22
Trough and Approximate Peak Concentrations of RMC-4630 Cycle 1 Day 15 post-dose (2 hour +/- 10 minutes post-dose)	187.64 ng/ml Geometric Coefficient of Variation 106.19	276.29 ng/ml Geometric Coefficient of Variation 122.66
Trough and Approximate Peak Concentrations of RMC-4630 Cycle 2 Day 1 pre-dose (within 1 hour pre-dose)	24.75 ng/ml Geometric Coefficient of Variation 269.94	22.34 ng/ml Geometric Coefficient of Variation 179.87
Trough and Approximate Peak Concentrations of RMC-4630 Cycle 3 Day 1 pre-dose (within 1 hour pre-dose)	82.40 ng/ml Geometric Coefficient of Variation 166.30	18.35 ng/ml Geometric Coefficient of Variation 155.47
Trough and Approximate Peak Concentrations of RMC-4630 Cycle 4 Day 1 pre-dose (within 1 hour pre-dose)	33.48 ng/ml Geometric Coefficient of Variation 535.67	14.67 ng/ml Geometric Coefficient of Variation 128.88

SECONDARY outcome

Timeframe: 31 months

Population: Summary of PK of Sotorasib concentration for subjects with KRASG12C mutant NSCLC (All Treated Subjects). Timepoints beyond Cycle 4 do not any value for the PK profile per sponsor. The decreasing number in participants analyzed is due to various factors such as missed samples or patient drop out as timepoints progressed.

Characterization of PK of RMC-4630 in combination with Sotorasib for subjects with KRASG12C mutant NSCLC

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Trough and Approximate Peak Concentrations of Sotorasib Cycle 1 Day 15 pre-dose (within 1 hour pre-dose)	615.6 ng/mL Geometric Coefficient of Variation 173.5	375.4 ng/mL Geometric Coefficient of Variation 134.4
Trough and Approximate Peak Concentrations of Sotorasib Cycle 1 Day 15 post-dose (2 hour +/- 10 minutes post-dose)	6009.3 ng/mL Geometric Coefficient of Variation 119.2	4603.3 ng/mL Geometric Coefficient of Variation 77.3
Trough and Approximate Peak Concentrations of Sotorasib Cycle 2 Day 1 pre-dose (within 1 hour pre-dose)	674.7 ng/mL Geometric Coefficient of Variation 193.2	336.4 ng/mL Geometric Coefficient of Variation 170.8
Trough and Approximate Peak Concentrations of Sotorasib Cycle 3 Day 1 pre-dose (within 1 hour pre-dose)	342.2 ng/mL Geometric Coefficient of Variation 12146.3	190.3 ng/mL Geometric Coefficient of Variation 125.7
Trough and Approximate Peak Concentrations of Sotorasib Cycle 4 Day 1 pre-dose (within 1 hour pre-dose)	803.5 ng/mL Geometric Coefficient of Variation 152.3	404.5 ng/mL Geometric Coefficient of Variation 367.3

SECONDARY outcome

Timeframe: 31 months

Population: Duration of Response (DOR) Based on Investigator Assessments (Subjects with Confirmed CR or PR Responders only).

Characterization of efficacy or RMC-4630 in combination with Sotorasib as assessed by DOR, DCR, PFS, and OS in patients with KRAS G12C-mutant locally advanced or metastatic NSCLC after failure of prior standard therapy

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=11 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Duration of Response (DOR) as Assessed Per RECIST v1.1	—	12.19 months Interval 8.31 to NE means 'The upper limit of the confidence interval is not estimable because not enough events occurred beyond that point.' For the NE, it means not applicable since there's no patient.

SECONDARY outcome

Timeframe: 31 months

Population: Disease Control Rate (%) is defined as the proportion of subjects with best overall response of CR, PR, or stable disease

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=42 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Disease Control Rate (DCR) as Assessed Per RECIST v.1.1	3 Participants	34 Participants

SECONDARY outcome

Timeframe: 31 months

Population: Summary of Progression-Free Survival (PFS) Based on Investigator Assessments (All Treated Subjects).

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Progression-free Survival (PFS) as Assessed Per RECIST v1.1	2.64 months Interval 1.28 to NE means 'The upper limit of the confidence interval is not estimable because not enough events occurred beyond that point.' For the NE, it means not applicable since there's no patient.	7.66 months Interval 3.98 to 10.45

SECONDARY outcome

Timeframe: 31 months

Population: Summary of Overall Survival (OS) (All Treated Subjects).

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Overall Survival (OS)	5.80 months Interval 4.34 to NE means 'The upper limit of the confidence interval is not estimable because not enough events occurred beyond that point.' For the NE, it means not applicable since there's no patient.	12.45 months Interval 9.72 to NE means 'The upper limit of the confidence interval is not estimable because not enough events occurred beyond that point.' For the NE, it means not applicable since there's no patient.

SECONDARY outcome

Timeframe: 31 months

Characterization of the safety, tolerability of RMC-4630 in combination with sotorasib for patients with KRASG12C-mutant NSCLC after failure of prior standard therapy. The specifics of the incidence, nature and severity data can be found under the Adverse Events section.

Outcome measures

Outcome measures
Measure	RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD n=4 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.	RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD n=43 Participants The two arms have been broken down per dose level rather than by phase or cohort per the CSR, which is provided to FDA and not uploaded to ct.gov. Participants were administered 140 or 200 mg of RMC-4630 twice weekly (BIW) on D1D2 of each week in a 21-day cycle and Sotorasib 960 mg once daily (QD) in a 21-day cycle. The 140mg and 200mg dose levels were explored at the safety run-in stage, and after completion of the safety run-in (DLT clearance) of both dose levels, additional patients were enrolled at both dose levels for the purpose of dose optimization before selecting the final expansion dose. Therefore, both the 140mg and 200mg dose levels included patients in the safety-run in and dose optimization. After that, 200mg was identified as the RP2D dose, which moved to the expansion phase. Statistical analysis for all sections in the results was performed for all treated patients by dose level, i.e., 140mg vs 200mg. For patients enrolled at the RP2D dose level of 200mg, analysis was further performed based on mutation status, i.e., cohorts 1 vs 2.
Incidence, Nature and Severity of TEAEs, SAEs Serious Adverse Events	3 participants	43 participants
Incidence, Nature and Severity of TEAEs, SAEs Other (Not Including Serious) Adverse Events	4 participants	43 participants

Adverse Events

RMC-4630 200 mg BIW D1D2 + Sotorasib 960 mg QD

Serious events: 43 serious events

Other events: 43 other events

Deaths: 21 deaths

RMC-4630 140 mg BIW D1D2 + Sotorasib 960 mg QD

Serious events: 3 serious events

Other events: 4 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Vice-President Clinical Operations

Revolution Medicines

Phone: 650-779-2300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Publications by investigators must be reviewed and approved by the sponsor.
Publication restrictions are in place

Restriction type: OTHER