Researchers unveiled results of a first-in-human phase I/II study of MCLA-128 in solid tumors, including final phase I data and promising preliminary activity in patients with HER2-positive metastatic breast cancer (MBC) from the phase II portion of the trial at the 2017 ASCO Annual Meeting (Abstract 2522). MCLA-128 is a full-length IgG bispecific antibody with enhanced antibody-dependent cell-mediated cytotoxicity activity targeting HER2 and HER3 receptors.
In the phase I portion of the phase I/II study, the recommended phase II dose (RP2D) for future studies with MCLA-128 was established as 750 mg every 3 weeks, based on safety and pharmacokinetic data. The phase II portion of the study is ongoing, exploring selected metastatic indications including breast, endometrial, ovarian, gastric, and non-small cell lung cancers. MCLA-128 was well-tolerated, with the ongoing phase II portion confirming the safety profile seen in the dose escalation cohort. The most frequent adverse events observed were mild (G1/G2) infusion-related reactions and gastrointestinal toxicities. No clinically significant cardiotoxicity was reported.
As part of the ongoing study, a cohort of 11 HER2-positive MBC patients has been treated with single agent MCLA-128 (nine patients at RP2D and two patients at 480 mg q3 weeks from part 1). These MBC patients were all heavily pretreated, having received a median of six prior lines of metastatic therapy, all having 2-5 prior HER2 inhibitor therapies, and some of the patients with outright disease progression to the last line of therapy. One MBC patient achieved a confirmed partial response (>8+ months) and seven had stable disease (including four sustained stabilizations lasting ≥5 months). The clinical benefit rate (complete and partial responses plus stable disease lasting at least 12 weeks) among the cohort of MBC patients was 64 percent (7/11). Evaluation of additional MBC patients and other indications is ongoing.
With single agent activity established in MBC, researchers plan to initiate a phase II, open-label, multicenter, international clinical study to evaluate MCLA-128-based combinations in two MBC populations: 1) confirmed HER2-positive MBC patients (progressing on anti-HER2 therapies including TDM-1) who will receive MCLA-128 in combination with trastuzumab and chemotherapy, and 2) confirmed hormone receptor positive status and HER2-low (IHC HER2 1+ or 2+ and FISH negative for HER2 amplification) MBC patients progressing on hormone therapies and CDK4/6 who will receive MCLA-128 in combination with fulvestrant. In addition to these early clinical results, study of MCLA-128 in these combinations and populations is supported by activity observed in preclinical models. This phase II study is expected to be launched in Europe and the U.S. in the second half of 2017.
“These clinical results demonstrate that single agent MCLA-128 is active and well-tolerated in heavily-pretreated metastatic breast cancer patients.” noted Josep Tabernero, MD, PhD, Head of Medical Oncology and the Institute of Oncology at Vall d'Hebron University Hospital, Barcelona. “This positions MCLA-128 as a promising agent for further development as combination therapy in the treatment paradigm of metastatic breast cancer. I look forward to seeing how these results translate in the planned phase II combination studies.”