HOUSTON—While declines have been noted in recent years, U.S. veterans use tobacco at considerably higher rates than those who have never served in the military. In recent decades that rate has been as high as 30%.
The high smoking rate has increased the incidence of non-small cell lung cancer (NSCLC) within VA healthcare and has complicated treatment, especially since so many patients have specific mutations. “Improving the clinical outcomes of patients with KRASG12C-mutated non-small cell lung cancer (NSCLC), the majority of whom are current or former smokers, has been a barrier to improving population-level outcomes in NSCLC,” authors from the VA’s Center for Clinical Management Research in Ann Arbor, MI, wrote recently.1
(For example, past research has determined that heavy smokers more frequently have KRASG12C mutations and less frequently have EGFRdel19 and EGFRL858R mutations. )
The VA review in Expert Opinion on Pharmacotherapy pointed out, “Novel and effective KRASG12C inhibitors are emerging, and sotorasib is the first member of that class to achieve commercial availability.”1
“While sotorasib’s development has been unique and exciting, questions persist regarding its intracranial penetrance, optimal dose, and efficacy relative to standard-of-care therapy,” the reviewers advised. “Improvements in the clinical activity of KRAS inhibition will hinge on better understanding of resistance mechanisms, the development of broad-spectrum inhibitors with activity beyond G12C mutations, and combination therapy targeting multiple mediators of KRAS signaling and alternative pathways. From a regulatory perspective, sotorasib’s development may, in time, prove to be an instructive example for early-phase clinical trialists and regulators focused on dose optimization.”
More recently, an international study presented at the recent American Society of Clinical Oncology (ASCO) meeting in Chicago looked at sotorasib vs. docetaxel in patients with pretreated KRAS G12C-mutated advanced NSCLC.2
The research led by the University of Houston’s MD Anderson Cancer Center examined data from 931 patients treated for NSCLC between 2013 and 2020.
The study noted that sotorasib is a first-in-class oral, irreversible KRASG12C inhibitor approved for adults with pretreated KRAS G12C-mutated advanced NSCLC. “In CodeBreaK 200, the first KRASG12C inhibitor randomized phase 3 trial, sotorasib demonstrated superior progression-free survival (PFS) and overall response rate (ORR) vs docetaxel and a more favorable safety profile.”
In their presentation, the authors reported prespecified exploratory biomarker analyses comparing sotorasib vs. docetaxel efficacy in molecularly-defined KRAS G12C-mutated advanced NSCLC subsets.
In CodeBreaK 200, 345 patients with KRAS G12C-mutated advanced NSCLC who progressed after receiving platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to oral sotorasib 960 mg daily or IV docetaxel 75 mg/m2 Q3W. Defined as the primary endpoint was progression-free survival as confirmed by blinded independent central review (RECIST 1.1; key secondary endpoint: ORR). In prespecified exploratory analyses, the study also used central targeted next-generation sequencing to analyze baseline tissue and plasma samples for key genomic alterations, such as STK11, KEAP1, EGFR, MET, TP53, as well as PD-L1 protein level by local standard of care testing in biomarker-evaluable cases. Biomarker status was correlated with survival rates.
“Inferred tumor mutation burden by plasma circulating tumor DNA (sum of mutant molecular variant reads) was assessed,” the researchers stated. “Association of baseline genomic alterations with long-term benefit (PFS ≥ 6 m) vs early progression (PFS < 3 m; no complete/partial response) was evaluated.”
Researchers noted that the most prevalent KRAS G12C co-alterations in 317 biomarker-evaluable cases with available tumor and/or plasma samples were TP53 (181 [57.1%]), STK11 (119 [37.5%]), and KEAP1 (82 [25.9%]) in CodeBreaK 200, which was consistent with CodeBreaK 100. In addition, 55 (17.4%) patients had STK11 and KEAP1 co-alterations.
“Sotorasib showed superior clinical benefit vs docetaxel independently of PD-L1 expression and across all prespecified subgroups (eg, STK11, KEAP1, TP53),” the authors concluded. “No clinical response occurred with either treatment in 26 (8.2%) pts with additional KRAS alterations, including amplifications. High baseline plasma tumor burden was associated with greater odds of early progression vs long-term benefit in both arms (odds ratio, 3.54 [95%CI 1.83-6.85] per tertile increase; p<0.0001). Correlation of KRAS G12C co-alterations with response detected a signal toward shorter median PFS (sotorasib, 2.8 m [95%CI 1.6-3.4]; docetaxel, 7.5 m [95%CI 3.0-NE]) with sotorasib vs docetaxel in pts with KRAS G12C and NOTCH1 co–altered tumors.”
The study pointed out that sotorasib “demonstrated consistent clinical benefit vs docetaxel in all prespecified molecularly-defined subgroups (eg, STK11, KEAP1, TP53) in this exploratory analysis of CodeBreaK 200. No predictive biomarkers were confirmed, but novel hypothesis-generating signals were observed.”
- Strohbehn GW, Sankar K, Qin A, Kalemkerian GP. An evaluation of sotorasib for the treatment of patients with non-small cell lung cancer with KRASG12C mutations. Expert Opin Pharmacother. 2022 Oct;23(14):1569-1575. doi: 10.1080/14656566.2022.2134777. Epub 2022 Oct 20. PMID: 36217844.
- Skoulidis F, De Langen A, Pas-Ares LG, Mountzios GS, et. al. Biomarker subgroup analyses of CodeBreaK 200, a phase 3 trial of sotorasib versus (vs) docetaxel in patients (pts) with pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC).2023 ASCO annual meeting. June 2-6, 2023. Abst. e16299. J Clin Oncol 41, 2023 (suppl 16; abstr 9008)
