KRAS G12C Inhibitors: Durability of Response, Efficacy in Combination, in NSCLC

Get Permission

At the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer, the benefit of two KRAS G12C inhibitors in advanced non–small cell lung cancer (NSCLC) was upheld by the 2-year follow-up analysis of adagrasib in the KRYSTAL-11 and the early-phase CodeBreaK 101 trials showing value in adding sotorasib to conventional agents.2


Adagrasib, a differentiated KRAS G12C inhibitor, was granted accelerated approval for patients with previously treated KRAS G12C–mutated advanced or metastatic NSCLC, based on data from KRYSTAL-1, a multicohort phase I/II study evaluating adagrasib as monotherapy or in combination.3

“In the current pooled analysis with longer follow-up, adagrasib demonstrated durable clinical activity, with a median overall survival of 14.1 months and approximately one in three patients alive at 2 years,” said Shirish Gadgeel, MBBS, Associate Director of Hematology/Oncology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit.1

Shirish Gadgeel, MBBS

Shirish Gadgeel, MBBS

The analysis included 16 patients in the dose-escalation/dose-expansion phase I/Ib cohort and 116 patients in the phase II cohort. They were followed for a median of 26.9 months after receiving adagrasib at 600 mg twice daily.

At 2 years, median overall survival was 14.1 months, and 31.3% were alive. Median progression-free survival was 6.9 months, and 13.9% were without disease progression at 2 years. Objective response was observed in 43%, and median duration of response was 12.4 months, Dr. Gadgeel reported. This median duration of response is longer than in previous studies, he noted.

“Exploratory analyses suggested some heterogeneity of clinical benefit based on the presence of co-mutations, which should be further evaluated,” Dr. Gadgeel continued. In particular, median overall survival was 18.7 months for patients with concomitant TP53 mutations, 13.0 months for those with CDKN2A mutations, 9.2 months for those with STK11 mutations, and 5.7 months for those with KEAP1 mutations. “The numbers in these subsets are small, but our data show efficacy in all,” he noted. The exploratory analyses also pointed to durable clinical benefit in patients with treated, stable central nervous system metastases at baseline, whose median overall survival was 14.7 months, according to Dr. Gadgeel.

Dose modifications were not associated with shorter treatment duration and did not seem to compromise overall survival. Patients requiring dose modifications had a 1-year overall survival rate of 53.3% and a 2-year overall survival rate of 32.1%, he reported.

Adagrasib was associated with a low rate of grade ≥ 3 hepatotoxicity. This complication was not observed in any patient who received adagrasib within 30 days of prior immunotherapy.

A confirmatory phase III study—KRYSTAL-12—is evaluating adagrasib vs docetaxel in previously treated patients in North America, Europe, Asia, and Australia.

About CodeBreaK 101

The combination of sotorasib, pemetrexed, and carboplatin showed clinical activity in KRAS G12C–mutated advanced NSCLC in both the first- and second-line settings in the global phase Ib CodeBreaK 101 study. These findings were presented at the 2023 WCLC by Jeffrey M. Clarke, MD, Associate Professor of Medicine, Duke Cancer Institute, Durham, North Carolina.2

Jeffrey M. Clarke, MD

Jeffrey M. Clarke, MD

In the previous pivotal phase III trial, sotorasib, the first oral, irreversible KRAS G12C inhibitor, significantly improved progression-free survival over docetaxel (hazard ratio = 0.66; P = .0017) in pretreated patients.4 Based on enhanced antitumor efficacy for the combination of sotorasib and carboplatin in mouse models, and the high response rate (89%) for sotorasib plus carboplatin and pemetrexed in the small phase II SCARLET study by the West Japanese Oncology Group,5 the global phase Ib CodeBreaK 101 study was initiated to evaluate the triplet.

The analysis presented by Dr. Clarke was based on 25 patients treated in the first-line setting and 13 in the second-line setting in the dose-exploration and dose-expansion phases of the study. For the second-line cohort, prior treatment was with anti–PD-1/L1 and/or platinum-based combinations in the neoadjuvant or adjuvant setting. There was a predominance of patients with PD-L1–positive disease in the second-line cohort, as might be expected, and the majority of patients had PD-L1–negative disease in the front-line cohort, he said. 

Patients received sotorasib at 960 mg daily plus pemetrexed at 500 mg/m2 and carboplatin AUC 5 every 3 weeks, for up to four cycles, with continued treatment with pemetrexed and sotorasib. The primary endpoint was safety.

Previously untreated patients with KRAS G12C–mutated disease had an objective response rate of 65% and a disease control rate of 100%. In the second-line setting, 54% responded, and 31% of the other patients achieved stable disease. The response rates were similar across PD-L1 expression levels. Progression-free survival and overall survival were immature at the time of analysis.

This combination was reported to be safe and tolerable, with treatment-related adverse events consistent with sotorasib and platinum doublet-based regimens. Overall, 58% of patients had grade 3 or 4 toxicity, with the most common being neutropenia/decreased neutrophil count, anemia, and thrombocytopenia/decreased platelet count. Rates of grade ≥ 3 adverse events were higher (77%) in the second-line setting than in the first-line setting (48%)

“Combination treatment is an important approach to prevent or delay the onset of drug resistance and improve the depth and durability of targeted response in KRAS G12C–mutated NSCLC,” Dr. Clarke said. He concluded: “This study adds to a growing body of data, suggesting high response rates and promising clinical activity with the combination of adagrasib, pemetrexed, and carboplatin.”

Based on these results, the phase III CodeBreaK 202 study will soon evaluate sotorasib plus carboplatin and pemetrexed as first-line treatment of advanced NSCLC with KRAS G12C mutations and no expression of PD-L1. 

DISCLOSURE: Dr. Gadgeel reported financial relationships with AstraZeneca, Genentech, Roche, Pfizer, Mirati, Takeda, Arcus, AnnHeart Therapeutics, Daiichi Sankyo, AbbVie, Bristol Myers Squibb, Merck, Esai, GSK, and Gilead Sciences. Dr. Clarke reported financial relationships with Adaptimmune, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, G1 Therapeutics, Grid Therapeutics, Merck, Novartis, Pfizer, Turning Point, and Vavacitas Oncology.


1. Gadgeel S, et al: 2023 World Conference on Lung Cancer. Abstract MA06.04. Presented September 10, 2023.

2. Clarke JM, et al: 2023 World Conference on Lung Cancer. Abstract MA06.05. Presented September 10, 2023.

3. Jänne PA, et al: N Engl J Med 387:120-131, 2022.

4. de Langen AJ, et al: Lancet 401:733-746, 2023.

5. Sakata S, et al: 2023 ASCO Annual Meeting. Abstract 9006.