Introduction Somatic KRAS mutations occur in 25% of patients with NSCLC. Treatment with MEK inhibitor monotherapy has not been successful in clinical trials to date. Compensatory activation of FGFR1 was identified as a mechanism of trametinib resistance in KRAS-mutant NSCLC, and combination therapy with trametinib and ponatinib was synergistic in in vitro and in vivo models. This study sought to evaluate this drug combination in patients with KRAS-mutant NSCLC. Methods A phase 1 dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with KRAS mutations. A standard 3-plus-3 dose escalation was done. Patients were treated with the study therapy until intolerable toxicity or disease progression. Results A total of 12 patients with KRAS-mutant NSCLC were treated (seven at trametinib 2 mg and ponatinib 15 mg, five at trametinib 2 mg and ponatinib 30 mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in five patients, including one death in the study and four cardiovascular events. Serious events were observed at both dose levels. Of note, 75% (9 of 12) were assessable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days. Conclusions In this phase 1 study, in patients with KRAS-mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring the combination of MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability.
3025 Background: Human epidermal growth factor receptor 2 ( HER2, ERBB2) amplification occurs in 5% of non-breast non-gastric solid tumors. Ado-trastuzumab emtansine (T-DM1) showed preliminary efficacy in patients with HER2 amplified lung, endometrial, salivary gland, biliary tract and ovarian cancers, but the extent of its differential effects across histologies is unknown. Methods: Patients with HER2 amplified solid tumors were enrolled and received treatment 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1 or PERCIST. A basket trial expansion used a Simon two stage optimal design applied to each of 5 histology cohorts with type I error rate under 2%, power of 90%, H0 10%, H1 40%, with family-wise error rate at 10%. After first stage, lung, salivary gland and endometrial cohorts were expanded to 23 patients. The null hypothesis was rejected for each cohort separately, if at least 6 responses were observed in each cohort. Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and toxicity. HER2 amplification was identified by fluorescence in situ hybridization (FISH), or next generation sequencing (NGS). Correlative studies were performed using tissue immunohistochemistry (IHC). Plasma cell-free DNA (cfDNA) was collected throughout study treatment. Results: 88 patients with 8 unique cancer types were treated across 5 cohorts of HER2 amplified lung, salivary gland, colorectal, endometrial and other cancers. The median age was 66 (26-90). Median line of prior therapy was 2 (1-7). ORR was 33% (29/87 including 11 CRs, 95% CI 24-44%), including 47% (9/19) for lung cancers, 87% (13/15, 8 CRs) for salivary gland cancers, 22% (5/23, 3 CRs) for endometrial cancers, 12% (1/8) for biliary cancers, 14% (1/7) for ovarian cancers. Median DOR was 9.7 months (95% CI 4.8, 20.2), median PFS was 2.76 months (95% CI 2.53, 5.39). There were 8 (9%) G3 treatment related toxicities. HER2 fold change corrected for purity and ploidy by FACETS algorithm correlated with response (p=0.04) and PFS>=3 months (p=0.0037). HER2 amplification by NGS correlated with HER2/CEP17≥2 by FISH (67/71 tested) and IHC3+ (54/68 tested). We observed persistent HER2 amplification in plasma cfDNA during acquired resistance and progression on T-DM1 in patients with salivary gland cancers. Conclusions: Ado-trastuzumab emtansine showed promising efficacy in patients with HER2 amplified lung and salivary gland cancers as identified by NGS, meeting the primary endpoint. However, its efficacy did not meet prespecified response rate in patients with HER2 amplified endometrial, colorectal and other cancers. Histologic lineage differences in HER2 amplified cancers affect response and translational research is critical for further drug development. Clinical trial information: NCT02675829 .
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