Data Provides Insight for Using KRAS Inhibition in NSCLC

CASE

• A 68-year-old woman presented with dyspnea on exertion, fatigue, and anorexia, with a past medical history of diabetes mellitus that was medically controlled.
• Former smoker who quit smoking 10 years ago; 20 pack years
• The patient’s laboratory results were within normal limits, but a chest x-ray showed 2 left lower lobe masses and a CT scan confirmed the 2 masses (3.5 cm and 5.2 cm) in left lower lobe of lung and multiple liver lesions​.
• Bronchoscopy with transbronchial biopsy of the left lower lobe confirmed lung adenocarcinoma with a PD-L1 score of 20%.
• Diagnosis: stage IV adenocarcinoma
• ECOG performance status: 1
• Next-generation sequencing (NGS) of the tumor showed it was positive for KRAS G12C.
• The patient achieved a partial response after completing 4 cycles of carboplatin-pemetrexed plus pembrolizumab (Keytruda).
• After 16 months, the patient reported worsening back pain and shortness of breath, with further CT scans showing a progression of the lung tumor and metastases sites, along with a new site in the brain.

Targeted Oncology^TM: 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.

Kartik Konduri, MD

Medical Director, Chest Cancer Research and Treatment center

Texas Oncology-Baylor Charles A. Sammons Cancer Center

Baylor Scott & White Health

Dallas, Texas

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.

^Reference

^{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}