An investigational drug that targets the PD-L1 pathway was associated with tumor shrinkage in about 20% of patients who had a wide array of incurable or metastatic solid cancers in a phase I study.
MPDL3280A, a PD-L1 targeted antibody with an Fc-domain designed to optimize efficacy and safety, shrank tumors by at least 50% in 29 of 140 patients, for an overall response rate of 21%. Further, there have been additional delayed responses, and the treatment responses are ongoing, with 26 of 29 patients continuing to respond at follow-ups of 3-15 months.
Dr. Roy S. Herbst
"We are impressed with the frequency and duration of the responses in these patients with very difficult-to-treat tumors," especially given that this is a phase I study designed to assess the drug’s safety and guide selection of dosing for phase II study, lead investigator Dr. Roy S. Herbst said May 15 during a presscast sponsored by the American Society of Clinical Oncology in advance of its annual meeting,
The drug also met safety measures, with no maximum tolerated dose, dose-limiting toxicities, or treatment-related deaths in an analysis of 171 patients. One patient discontinued MPDL3280A because of an immune-related adverse event; importantly, no cases of grade 3-5 pneumonitis occurred. The most common grade 3-4 adverse events, each seen in 3%-5% of patients, were hyperglycemia, fatigue, increased ALT, dyspnea, and hypoxia. These included all adverse events, irrespective of whether they were from disease, the drug, or other factors, reported Dr. Herbst, Ensign Professor of medical oncology at Yale Cancer Center and chief of medical oncology at Smilow Cancer Hospital at Yale, both in New Haven, Conn.
PD-L1 is a protein that can essentially hide cancer cells from the immune system, When MPDL3280A attaches to the protein PD-L1, it essentially reveals the cancer cell to T cells, eliciting an immune response. MPDL3280A was specifically engineered for enhanced safety and efficacy, compared with earlier PD-L1 or PD-1 targeted agents.
Based on diagnostic testing for PD-L1 expression in archived tumor tissue from 103 patients, tumor shrinkage occurred after MPDL3280A treatment in 13 of 36 (36%) of patients with PD-L1–positive tumors and in 9 of 67 (13%) of patients with PD-L1–negative tumors. The diagnostic test for PD-L1 is still evolving, so a negative result on the PD-L1 test could simply mean that tumors have less PD-L1 than the test currently detects, according to Dr. Herbst.
The study has been expanded to include more than 275 patients to date. Phase II and phase III studies are planned to confirm MPDL3280A’s anticancer activity and to validate the PD-L1 diagnostic test.
For the phase I study, MPDL3280A was administered intravenously 3 times weekly. Administered doses included 1 mg/kg or less (9 patients), 3 mg/kg (3 patients), 10 mg/kg (35 patients), 15 mg/kg (57 patients), and 20 mg/kg (67 patients). Responses were observed in multiple tumor types, including non–small cell lung cancer, renal cell carcinoma melanoma, colorectal cancer, and gastric cancer. The 24-week progression-free survival was 44%. No maximum tolerated dose was identified, and patients received MPDL3280A for a median duration of 127 days (range 1-330 days). Pharmacokinetics supports thrice-weekly dosing at 15 mg/kg or a fixed-dose equivalent.
The study was supported by Genentech. Dr. Herbst receives research support from Genentech.