A phase I, dose escalation study to determine the maximum tolerated dose of erlotinib when combined with pertuzumab in previously treated non-small-cell lung cancer patients

Abstract

19134 Background: Pertuzumab (P), a monoclonal antibody, targets the HER2 receptor and prevents dimerization of HER2 and HER2, HER2 and HER1 or HER2 and HER3. P is active against HER2 overexpressing breast cancer (Baselga et al, ASCO 2007) but has no meaningful single agent activity against non-small-cell lung cancer (NSCLC). Erlotinib (E) inhibits HER1 tyrosine kinase signalling, is active against a number of tumour types and is widely registered for the treatment of relapsed NSCLC. By combining E and P signaling via HER1, HER2 and HER3 are inhibited. Inhibition of multiple HER signaling pathways could prove to be clinically useful. Methods: This is a phase I, dose escalating study. Consenting NSCLC patients (pts) with ECOG performance status of 0 or 1, progression after previous chemotherapy and adequate cardiac reserve (baseline LVEF ≥55%) were recruited in 2 cohorts. All pts had tumour specimen for evaluating biomarkers potentially associated with response. The 1st cohort received P at the full dose of 840mg iv loading dose with 420mg iv maintenance every 3 weeks plus E at a dose of 100mg orally daily. If the maximum tolerated dose (MTD) was not reached, a 2nd cohort was to be recruited (these pts were to receive the full dose of P plus E at the full dose of 150mg orally daily). Dose limiting toxicity (DLT) was initially defined as any adverse event (AE) ≥ grade 3; an incidence of DLT in 2 out of 6 pts was defined as MTD. Based on experience with the 1st cohort, the protocol was modified to exclude rash as a DLT (rashes encountered were manageable and responded to interruption or reduction of E). Subsequently a 2nd cohort (9 pts) has been recruited. Results: In the 1st cohort tolerability was good, the common AEs being diarrhea in 3 pts (50%) which was generally mild and self-limiting and rash which was reported by all 6 pts (100%). Rash was severe (grade 3) in 3 pts, but responded to either dose reduction of E to 50 mg orally daily or to withdrawal of treatment. In the 2nd cohort, the combination has been well tolerated with no DLTs reported to date. Conclusions: For Phase II evaluation, a full dose of E (150mg orally daily) with full dose of P appears to be suitable. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche Clinical Trial Costs