Haby Henary

BACKGROUND: p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). METHODS: p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: . CONCLUSIONS: p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

BACKGROUND: . METHODS: p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

3003 Background: The KRAS G12C mutation is found in approximately 13% of lung adenocarcinomas and 1–3% of other solid tumors, but there is no approved therapy that targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state. Methods: This phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult patients (pts) with locally-advanced or metastatic KRAS G12C mutant solid tumors. The primary endpoint is safety; key secondary endpoints include PK, ORR (assessed every 6 weeks [wks]), DOR, and PFS. Key inclusion criteria: KRAS G12C mutation identified through DNA sequencing, measurable or evaluable disease, ECOG PS ≤2, life expectancy >3 months (mo). Key exclusion criteria: active brain metastases, myocardial infarction within 6 mo. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). A dose expansion will enroll pts with NSCLC, CRC, and other advanced solid tumors carrying the KRAS G12C mutation. AMG 510 will be given PO until disease progression, intolerance, or withdrawal of consent. Results: 22 pts (8 men, 14 women; median age 55.5 y) were enrolled in the first 3 dose cohorts. Tumor types: 6 NSCLC, 15 CRC, 1 other. Most pts (n=17) had ≥3 prior lines of treatment (tx). Median tx duration was 28 d (range: 8–134). 5 pts reported 10 treatment-related AEs (grade 1, n=9; grade 2, n=1); there were no DLTs. Tumor response was evaluated in 9 pts (4 with ≥2 assessments); 13 pts have not reached their first assessment.1 pt had a PR (NSCLC at wks 6 and 12, tx ongoing), 6 pts had SD (4 CRC and 2 NSCLC; median tx duration 9.7 wks [range: 6.3–19.1], tx ongoing), 2 pts had PD. 20 pts are continuing to receive AMG 510. A second PR (NSCLC at wk 6, tx ongoing) was reported after data cutoff. Conclusions: AMG 510 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to patients with advanced KRAS G12C mutant solid tumors. MTD has not been determined, and enrollment into the dose exploration is ongoing. Clinical trial information: NCT03600883.

Background This open-label, first-in-human, phase 1 study evaluated AMG 232, an oral selective MDM2 inhibitor in patients with TP53 wild-type (P53WT), advanced solid tumors or multiple myeloma (MM). Methods In the dose escalation (n = 39), patients with P53WT refractory solid tumors enrolled to receive once-daily AMG 232 (15, 30, 60, 120, 240, 480, and 960 mg) for seven days every 3 weeks (Q3W). In the dose expansion (n = 68), patients with MDM2-amplified (well-differentiated and de-differentiated liposarcomas [WDLPS and DDLPS], glioblastoma multiforme [GBM], or other solid tumors [OST]), MDM2-overexpressing ER+ breast cancer (BC), or MM received AMG 232 at the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. Results AMG 232 had acceptable safety up to up to 240 mg. Three patients had dose-limiting toxicities of thrombocytopenia (n = 2) and neutropenia (n = 1). Due to these and other delayed cytopenias, AMG 232 240 mg Q3W was determined as the highest tolerable dose assessed in the dose expansion. Adverse events were typically mild/moderate and included diarrhea, nausea, vomiting, fatigue, decreased appetite, and anemia. AMG 232 plasma concentrations increased dose proportionally. Increases in serum macrophage inhibitor cytokine-1 from baseline were generally dose dependent, indicating p53 pathway activation. Per local review, there were no responses. Stable disease (durability in months) was observed in patients with WDLPS (3.9), OST (3.3), DDLPS (2.0), GBM (1.8), and BC (1.4-2.0). Conclusions In patients with P53WT advanced solid tumors or MM, AMG 232 showed acceptable safety and dose-proportional pharmacokinetics, and stable disease was observed.