1416TiP CodeBreak 200: A phase III multicenter study of sotorasib (AMG 510), a KRAS(G12C) inhibitor, versus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC) harboring KRAS p.G12C mutation

Abstract

Background: Acquired resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors (eg, osimertinib) may result in MET gene amplification and/or c-MET protein overexpression. Telisotuzumab vedotin (ABBV-399; teliso-v), an antiec-MET antibody-drug conjugate that can both disrupt c-MET signaling and deliver a cytotoxic payload into tumor cells, has shown antitumor activity in a phase 1/1b trial (NCT02099058) in patients (pts) with non-small cell lung cancer (NSCLC) with c-MET overexpression. Here we describe the teliso-v plus osimertinib cohort (arm E) of this trial.Trial design: Arm E of this phase 1/1b open-label study evaluates safety, pharmacokinetics, and preliminary efficacy of teliso-v, administered intravenously once every 2 weeks, in combination with oral osimertinib (80 mg once a day) in pts with metastatic NSCLC whose disease progressed on osimertinib. Pts must have documented osimertinib-sensitive EGFR mutations, and c-MET overexpression (defined by central immunohistochemistry test) in tumor tissue obtained post-osimertinib progression. Arm E consists of safety lead-in (SLP; n¼3e6), safety evaluation (SEP; n¼3e12), and expansion (n¼3e12) phases. Teliso-v will first be evaluated at 1.6 mg/kg and escalated to 1.9 mg/kg on the basis of safety signals in SLP and SEP phases. Radiographic tumor assessments will continue until disease progression, start of a new anticancer therapy, death, or consent withdrawal. Response evaluation will be based on Response Evaluation Criteria in Solid Tumors version 1.1. Planned enrollment is 3e24 pts; to date, 3 pts are enrolled.Clinical trial identification: NCT02099058.

On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma

“…A global randomized phase III trial in NSCLC, comparing sotorasib daily versus standard-of-care docetaxel in second-line therapy, is currently ongoing (CodeBreaK 200, NCT04303780)[90]. Sotorasib is also currently being tested in combination with other anticancer therapies (including EGFR, MEK, SHP2, pan-ErbB, mTOR, and CDK inhibitors, as well as immunotherapy [PD-1/PD-L1 inhibitors] and chemotherapy) in the CodeBreaK 101 trial in patients with advanced solid tumors (NCT04185883)…”

Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies

“…Overall, these studies evidence promising pre-clinical rationales to revert or delay the emergence of acquired resistance to sotorasib and adagrasib ( Figure 3 ). Several clinical trials are currently ongoing to evaluate the efficacy of KRAS G12C inhibitors in combination with chemotherapy ( 133 , 134 ) or with targeted therapies including cetuximab, afatinib, pembrolizumab and SHP2, mTOR, CDK4/6 inhibitors ( 91 , 135 , 136 ). These results would be of interest to evaluate whether combined treatments increased response rate to KRAS G12C inhibitors, thereby contributing to prevent or delay acquired resistance.…”

Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors

“…The randomized, phase III CodeBreak 200 trial (NCT04303780), comparing sotorasib WITH docetaxel in advanced NSCLC patients with KRAS G12C mutation who have progressed after platinum-based doublet chemotherapy and checkpoint inhibitor, is currently recruiting [ 35 ]. Table 1 shows the characteristics of ongoing clinical trials of KRAS mutated tumors (direct KRAS targeting), while Table 2 shows ongoing clinical trials of drugs targeting KRAS pathways.…”