maytansine and Peritoneal-Neoplasms

Purpose This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody-drug conjugate consisting of a humanized anti-folate receptor alpha (FRα) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRα-positive and platinum-resistant ovarian cancer. Patients and Methods Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRα positivity by immunohistochemistry (≥ 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined. Results Forty-six patients were enrolled. Adverse events were generally mild (≤ grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed. Conclusion IMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Diarrhea; Disease-Free Survival; Drug Resistance, Neoplasm; Fallopian Tube Neoplasms; Fatigue; Female; Folate Receptor 1; Humans; Hypotension; Immunoconjugates; Maytansine; Middle Aged; Nausea; Ovarian Neoplasms; Peritoneal Neoplasms; Platinum Compounds; Response Evaluation Criteria in Solid Tumors; Retreatment; Vision Disorders

Although anti-HER2 (human epidermal growth factor receptor 2) therapy is currently approved for breast, gastric, and gastroesophageal cancers overexpressing the HER2 protein or amplified for the HER2 gene, HER2 aberrations (gene amplification, gene mutations, and protein overexpression) are reported in other diverse malignancies. Indeed, about 1-37% of tumors of the following types harbor HER2 aberrations: bladder, cervix, colon, endometrium, germ cell, glioblastoma, head and neck, liver, lung, ovarian, pancreas, and salivary duct. Four HER2-targeted therapies have been approved for HER2-positive breast cancer: two antibodies (trastuzumab and pertuzumab), an antibody-drug conjugate (ado-trastuzumab emtansine), and a small molecule kinase inhibitor (lapatinib). In addition, afatinib, a small molecule kinase inhibitor that causes irreversible inhibition of EGFR (epidermal growth factor receptor) and HER2, was recently approved for EGFR-mutated non-small cell lung cancer. A large number of novel HER2-targeted agents are also in clinical trials. Herein we discuss the state of the art in understanding and targeting HER2 across anatomic tumor types.

Topics: Ado-Trastuzumab Emtansine; Adult; Afatinib; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Female; Gene Amplification; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Male; Maytansine; Molecular Targeted Therapy; Mutation; Neoplasms; Peritoneal Neoplasms; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Trastuzumab; Up-Regulation; Uterine Cervical Neoplasms