2-Year Follow-up Shows Durable Responses With Sotorasib in KRAS G12C–Mutated Non–Small Cell Lung Cancer

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Sotorasib, the first KRAS G12C inhibitor approved for the treatment of KRAS G12C–mutated non–small cell lung cancer (NSCLC), continues to demonstrate meaningful and durable efficacy at 2-year follow-up in the phase II CodeBreaK 100 trial. At a median follow-up of 24.9 months, the 2-year overall survival was 32.5% in patients with pretreated KRAS G12C–mutated NSCLC. These data were presented by Grace K. Dy, MD, Chief of Thoracic Oncology and Professor of Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, at the American Association for Cancer Research (AACR) Annual Meeting 2022.1

“Thirty-two percent of patients treated with sotorasib had a survival of 2 years or more. This compares favorably with historical treatment of pretreated NSCLC.”
— Grace K. Dy, MD

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“This is the longest follow-up for a KRAS G12C inhibitor, including 2-year survival, updated safety, and genomic profiles in patients with durable clinical benefit. A total of 32% of patients treated with sotorasib had a survival of 2 years or more. This compares favorably with historical treatment of pretreated NSCLC. For example, the 2-year overall survival rate in patients with nonsquamous NSCLC treated with the chemotherapy agent docetaxel with or without the anti-VEGFR antibody ramucirumab as second-line therapy is expected to range between 15% and 22%,” said Dr. Dy.

“These results are highly encouraging and set expectations for the confirmatory CodeBreaK 200 trial [of sotorasib],” she added.

Study Details

The prognosis of patients with KRAS G12C–mutated NSCLC remains poor following disease progression on first-line treatment with currently used therapies. Sotorasib was approved by the U.S. Food and Drug Administration for the treatment of previously treated KRAS G12C–mutated NSCLC based on the primary results of CodeBreaK 100.

The global phase II CodeBreaK 100 trial enrolled patients with advanced or metastatic KRAS G12C–mutated NSCLC who were pretreated with at least one prior systemic therapy or who were ineligible/intolerant to prior therapy. The pooled analysis that Dr. Dy presented included 174 patients enrolled in phase I (n = 48) and II (n = 126) of the study who were treated with sotorasib at 960 mg orally once daily.

At baseline, 52% were male, mean patient age was 64.1, and 6.3% of participants had never smoked. Sites of metastases included the liver (21.8%), brain (23%), and bone (46.8%). The median number of prior lines of therapy was two; 92.5% had prior platinum-based chemotherapy, and 90% had prior anti–PD-L1 therapy; 83% had both prior platinum-based chemotherapy and immunotherapy.

Key Findings

The median time to response was 6 weeks. The centrally confirmed objective response rate was 40.7%, and the disease-control rate was 83.7%. The median duration of response was 12.3 months; 50.6% of responders remained in response for 12 months or more.

Median progression-free survival was 6.3 months. The updated analysis of CodeBreaK 100 showed no change in median overall survival, which remained 12.5 months. The 1-year overall survival was 50.8%, and the 2-year overall survival was 32.5%.

“For the first time, this 2-year analysis showing an overall survival of 32% means one out of three patients [treated with sotorasib] remain alive,” Dr. Dy said.

Adverse Events

“Sotorasib was well tolerated in the long term. Late-onset treatment-related adverse events were mild and manageable,” said Dr. Dy.

A total of 70% of patients experienced any treatment-related adverse event; 24% had onset of a treatment-related adverse event after 1 year. Grade 3 or 4 treatment-related adverse events occurred in 21%, and one of those patients had onset (of hemolytic anemia) after 1 year.

No fatal treatment-related adverse events were reported, and no treatment-related adverse events led to discontinuation of therapy after 1 year. Treatment-related adverse events occurring in more than 10% of patients included diarrhea (31%), elevated liver enzymes (18%), nausea (16%), and fatigue (12%).

“Most adverse events were grade 1 or 2. There was no delayed onset of adverse events, contrary to what we would expect with chemotherapy or immunotherapy,” Dr. Dy said. “These data support the clinical observation that adverse events [with sotorasib] are manageable. Minimal or no cumulative toxicity contrasts with what we would expect with docetaxel.”

Other Analyses

An exploratory analysis looking at two groups of patients—those with progression-free survival of 12 months or longer and nonresponders with progression-free survival of up to 3 months—suggested the baseline characteristics of both groups were similar for age, gender, median number of lines of prior therapy, and type of prior anticancer therapy (platinum-based chemotherapy, immunotherapy, or the combination).

Biomarker analysis of tumor and blood samples showed that prolonged tumor response to sotorasib was independent of PD-L1 expression and STK11 comutation status. In addition, a modest correlation was observed between response and higher tumor mutational burden.

Circulating tumor DNA (ctDNA) analysis demonstrated no difference in ctDNA in tissue samples of patients who achieved long-term benefits with sotorasib. “However, lower plasma ctDNA at baseline was observed in patients who achieved long-term benefit. This suggests that lower plasma ctDNA and lower tumor burden correlated with benefit,” Dr. Dy stated.

“We see a benefit [of sotorasib] in patients with low levels of PD-L1 expression and STK11 comutations. Our findings provide a rationale for studies that investigate the incorporation of sotorasib earlier in the course of treatment to improve outcomes for patients with NSCLC who are less likely to benefit from immunotherapy,” Dr. Dy said.

Comment on Study

At a press conference where this study was discussed, AACR Clinical Trials Committee Co-Chair Timothy Yap, MBBS, PhD, FRCP, of The University of Texas MD Anderson Cancer Center, said that the optimal use of sotorasib either as monotherapy or in combination with different rational antitumor agents remains to be defined. “There is no simple answer just now, given the large number of sotorasib combinations being explored in NSCLC and other cancer types,” Dr. Yap said.

Timothy Yap, MBBS, PhD, FRCP

Timothy Yap, MBBS, PhD, FRCP

“A range of rational combinatorial approaches are currently being studied in the clinic. Resistance mechanisms come about with monotherapy, and therefore, a potential solution may be to try to proactively identify the resistance mechanisms involved in each type of cancer and then apply combinatorial agents that match the molecular profile at resistance,” he added. 

DISCLOSURE: CodeBreaK 100 was funded by Amgen. Dr. Dy has served as a consultant or advisor to AstraZeneca, Eli Lilly, GlaxoSmithKline, and Takeda; and has received institutional research funding from Amgen, AstraZeneca, Bristol Myers Squibb, and Tesaro. Dr. Yap has received institutional research funding from Acrivon, Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace, and Zenith; has consulted for AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, BeiGene, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, ProLynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, XinThera, Zai Lab, and ZielBio; and holds stock in Seagen.


1. Dy GK, Govindan R, Velcheti V, et al: Long-term outcomes with sotorasib in pretreated KRAS p.G12C-mutated NSCLC: 2-year analysis of CodeBreaK 100. AACR Annual Meeting 2022. Abstract CT008. Presented April 10, 2022.

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