In 2-year analysis of CodeBreaK 100 study that represents the most mature clinical data with KRASG12C inhibitor, sotorasib demonstrated long-term efficacy, without new safety signals in patients with KRASG12C-mutated advanced non–small cell lung cancer (NSCLC). A substantial proportion of patients derived long-term clinical benefit with 1- and 2-year overall survival (OS) rates of 51% and 33%, respectively.

Once-daily oral sotorasib, 960 mg did not result in cumulative late-onset severe or chronic lower-grade side effects. It demonstrated favourable safety profile and durable efficacy across subgroups in KRASG12C-mutated NSCLC. The findings are reported by Dr. Grace K. Dy of the Roswell Park Comprehensive Cancer Center in Buffalo, NY, US, and colleagues on 25 April 2023 in the JCO.

The authors reported in the background that OS remains poor for molecularly unselected, advanced NSCLC. Sotorasib specifically and irreversibly inhibits KRASG12C, with approval in over 40 countries for adult patients with KRASG12C-mutated advanced NSCLC after prior systemic treatment. In CodeBreaK 100 phase II, sotorasib demonstrated an objective response rate (ORR) of 37%, a median duration of response (DoR) of 11.1 months, a median progression-free survival (PFS) of 6.8 months, a median OS of 12.5 months, and a manageable safety profile in patients with KRASG12C-mutated advanced NSCLC.

In the latest article published in the JCO, the study team reports the long-term efficacy, safety, and biomarkers from the CodeBreaK 100 phase I/II 2-year pooled analyses, representing the longest KRASG12C inhibitor treatment follow-up to date.

This multicenter, single-group, open-label phase I/II study enroled 174 patients with KRASG12C-mutated, locally advanced or metastatic NSCLC after progression on prior treatments. All patients received sotorasib 960 mg once daily with the primary endpoints for phase I of safety and tolerability and for phase II of ORR.

Sotorasib produced an ORR of 41%, median DoR of 12.3 months, PFS of 6.3 months, OS of 12.5 months, and 2-year OS rate of 33%.

Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 patients (23%) across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations. Long-term benefit with sotorasib was associated with lower baseline ctDNA levels, consistent with ctDNA prognostic roles across therapeutics.

Sotorasib was well tolerated, with few late-onset treatment-related side effects, none of which led to treatment discontinuation.

The authors commented that these findings are encouraging, considering historically poor standard-of-care chemotherapy outcomes. Docetaxel-based regimens historically yielded approximately 10-23% response rates and a median PFS < 4.5 months; 2-year OS rate of 33% with sotorasib was higher versus docetaxel historically 14%.

The authors concluded that the results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis. Relatively small sample sizes with available biomarker data were challenging and additional analyses evaluating prognostic and predictive impact of baseline and post-progression genomic alterations are warranted. International collaboration and data sharing are key to uncovering KRAS-mutated cancer molecular complexities.

The findings were previously presented in part at the AACR 2022 Annual Meeting in New Orleans, LA, US (8-13 April 2022).

The study was supported by Amgen Inc.


Dy GK, Govindan R, Velcheti V, et al. Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100. JCO; Published online 25 April 2023. DOI: 10.1200/JCO.22.02524