In the second part of a 2-part article series, Kartik Konduri, MD, discusses the outcomes of targeting the KRAS G12C mutation in patients with metastatic NSCLC.
Targeted OncologyTM: How does the CodeBreaK 100 (NCT03600883) biomarker analysis impact your understanding of KRAS G12C targeted therapy?
KARTIK KONDURI, MD: [In this study, they looked at] various markers to see if there was any coexisting marker that might tell us which patients may not respond well to KRAS G12C–targeting drugs.1 There are some data to suggest that in patients with a higher PD-L1 score, ROS1, and secondary KRAS mutations there is a trend toward early progression on sotorasib (Lumakras). However, how much can you draw conclusions about that is unclear.
In prespecified subgroups in the study, they were looking at anti–PD-1 drugs, if they were given or if they were not given, and what were the outcomes. Those who had prior anti–PD-1 or PD-L1 treatment had a shorter median overall survival (OS) in comparison to those patients without [at 11.7 months (95% CI, 8.8-17.2) vs 24.0 months (95% CI, 7.1-not estimable [NE])].... Patients given a prior platinum therapy instead of a prior PD-1/PD-L1 therapy [had a longer median OS compared with NE on the PD-L1 therapy]. What does that mean? I'm not sure, but you can draw a significant understanding about it and it’s something to think about.
What was the design of the CodeBreaK 200 study (NCT04303780)?
CodebreaK 200 is the comparison study with daily sotorasib vs intravenous docetaxel.2 Their primary end point was progression-free survival [PFS] by BICR, and secondary end points were OS, overall response rate [ORR], and disease control rates. There was a regulatory amendment to the protocol to reduce the number [of patients] from 650 to 330, and there was an allowance of crossover from docetaxel.
What were the efficacy outcomes of this trial?
PFS [in sotorasib] had a distinction in terms of the HR at 0.66 [95% CI, 0.51-0.86] with a P value of .0017. The median PFS was 5.6 months [range, 4.3-7.8] in the sotorasib arm compared with 4.5 months [range, 3.0-5.7] in the docetaxel arm…. The OS outcomes were a median of 10.6 months [range, 8.9-14.0] in the sotorasib arm vs 11.3 months [range, 9.0-14.9] in the docetaxel arm. The docetaxel arm was slightly better so whether that means anything is unclear [as the] P value is not statistically significant [HR 1.01; 95% CI, 0.77-1.33, P = .53].
The consideration, however, is that the KRAS inhibitor [included] 33% of the docetaxel patients who crossed over to get a KRAS inhibitor.2 So, did it make a difference in the OS [analysis] is the big question, but 46 patients crossed over from docetaxel to sotorasib and the ORR was 28.1% [95% CI, 21.5%-35.4%] in the sotorasib group and 13.2% [95% CI, 8.6%-19.2%] in the other.
Key secondary outcomes…looked at lesions in the central nervous system [CNS] lesions in this study and median time to CNS progression was delayed by a median of 11.6 months vs 6 months [in the sotorasib vs docetaxel arms, respectively (HR 0.63; 95% CI, 0.25-1.62, P = .17)]. Median time to CNS progression and all-cause mortality was longer in patients with sotorasib compared with docetaxel at 9.6 months vs 4.5 months [HR 0.53; 95% CI, 0.28-1.03]. The intracranial responses with sotorasib were 20% complete response and 5% progressive disease, compared with 72% a non-partial response or non-progressive disease. Again, these are all patients who were previously treated and stable disease.
1. 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. J Clin Oncol. 2023;41(18):3311-3317. doi:10.1200/JCO.22.02524
2. de Langen AJ, Johnson ML, Mazieres J, et al; CodeBreaK 200 Investigators. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401(10378):733-746. doi:10.1016/S0140-6736(23)00221-0