Two-Dimensional Phase I Study Of Neratinib (Ner) Combined With Temsirolimus (Tem) In Patients (Pts) With Solid Tumors.

3027 Background: NER (HKI-272) is an irreversible pan-ErbB tyrosine kinase inhibitor with antitumor activity in pts with HER2-amplified tumors. TEM inhibits mTOR (TORC1). Hyperactivation of the PI3K-Akt-mTOR axis mediates resistance to anti-HER2 therapies. Preclinical data in mouse models of HER2-driven cancers suggest that the combination of both mTOR and HER2 inhibitors improves anti-tumor efficacy compared with HER2 inhibition alone. Methods: This open-label trial evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of NER plus TEM in pts with advanced solid tumors. A novel bi-directional ascending/descending trial design involved 4 dose levels of each drug (NER: 120, 160, 200 and 240 mg/d orally; TEM: 15, 25, 50 and 75 mg/wk iv) to determine the maximum tolerated dose (MTD) contour. Initial cohorts of 2 pts were enrolled to each tested dose level and observed for 28 days; the MTD(s) identified will enroll ≥6 pts for confirmation. For determination of NER and TEM plasma concentrations, blood samples were collected at pre-dose and at selected time points following treatments on Week 4. Results: 53 pts have been treated, including 10 with non-small cell lung cancer (NSCLC), 14 with breast cancer (BC) and 29 with other tumors. The most common dose-limiting toxicities were grade 3 mucositis, grade 3 diarrhea and grade 3 neutropenia. 12 of 16 possible dose combinations have been explored; MTDs to be confirmed are (NER/TEM) 200/25 and 160/50. PK of NER and TEM are evaluated. Of 6 pts with NSCLC HER2 exon 20 insertion mutation: 2 PR (17, 8 wks) and 2 SD (24, 13 wks). Among 9 HER2+ BC: 1 CR (32 wks), 1 PR (49 wks) and 3 SD (43, 23 and 16). Additional efficacy seen in pts with thymoma (CR), endometrial (PR) and urothelial (PR) cancers, and SD ≥24 wks in 1 pt each with NSCLC (genotype unk) and vulvar cancer. Conclusions: The combination of NER and TEM has demonstrated preliminary antitumor activity in pts with HER2-dependent NSCLC and BC, as well as other solid tumors, with an expected and manageable AE profile. HER2-mutant NSCLC, like other molecular subgroups, may be uniquely sensitive to the appropriate targeted therapy. An expansion cohort of 12 pts with NSCLC harboring HER2 mutation is planned at the 200/25 dose.