Washington, DC—The immunotherapy anti-programmed death-ligand 1 (anti-PD-L1) antibody MPDL3280A is effective for several different cancers and was well tolerated. Responses were seen in several different tumor types including lung, kidney, colon, and stomach cancer patients. All patients who responded are continuing to respond to the treatment.
These results of the first phase I clinical trial with MPDL3280A were presented at the American Association for Cancer Research (AACR) annual conference, held April 6–10 in Washington, DC, by Michael S. Gordon, MD, research director at Pinnacle Oncology Hematology in Scottsdale, Arizona. MPDL3280A is a human monoclonal antibody being developed by Genentech.
Results from 30 patients enrolled in the initial dose escalation portion of the trial were presented. Patients were treated with various doses of the antibody from 0.01 mg/kg to 20 mg/kg at either 2-week or 3-week intervals. Patients had previously received a median of two prior therapies and received a median of 5.5 doses of the antibody.
Thus far, no dose-limiting toxicities attributed to MPDL3280A of grade 4 or greater have been reported at any dose. A single grade 3 toxicity, in the form of rash was reported and no pneumonitis has been observed in this cohort.
Based on the pharmacokinetics, the optimal dosing schedule is likely to be every 3 weeks and in the range of 15 to 20 mg/kg, Gordon told Cancer Network in an email correspondence.
The international phase I advanced solid tumor trial is still enrolling and is expected to accrue approximately 344 patients of different tumor types.
MPDL3280A is an engineered antibody against PD-L1, a protein expressed on the surface of different cancer types. The corresponding receptor that recognizes the PD-L1 ligand on these tumor cells is found on the surface of T cells. The binding of PD-1 on the immune cells to PD-L1 on tumor cells results in a signal that blocks the ability of the immune cells to recognize and facilitate the destruction of the tumor cells.
Several immunotherapy antibodies that target the family of immune checkpoint signaling molecules are currently in various stages of development. Another anti-PD-L1 antibody, BMS-936559 is currently being tested in a phase I trial for advanced solid tumors. Other checkpoint inhibitors in development target the PD-1 protein, including CT-011, MK-3475, and nivolumab. Nivolumab is currently in several phase III trials for melanoma, non–small-cell lung cancer, and renal cell carcinoma. These anti-PD-1 antibodies block the interaction of PD-1 with its two ligands—PD-L1 and PD-L2.
“The PD-L1 antibody differs most significantly [from anti-PD-1 antibodies] in that it binds PD-L1, the tumor-expressed ligand for PD-1, as opposed to the PD-1 receptor itself,” said Gordon. “One key difference is that the anti-PD-L1 antibody does not affect the interaction between the PD-L2 protein expressed in lung tissue and the PD-1 receptor. This may provide an additional safety benefit by reducing the risk of pneumonitis and pulmonary toxicity.” Results from a phase I trial with the antibody against PD-1 have shown pneumonitis as a very rare, but serious toxicity. The target of the anti-PD-L1 antibody is on the tumor itself rather than on the T cell, which could also result in more specific tumor targeting and less off-target effects, according to Gordon.
Further research and clinical trial data will continue to add to our knowledge of how this class of antibodies targets various tumor types and their efficacy and safety. There is so far limited data for all of the immune checkpoint modulator antibodies.
“In terms of antitumor activity, all of [these immune checkpoint targeting] agents seem to have exciting activity in patients with metastatic solid tumors,” said Gordon. The remaining question is whether some of these outstanding responses will be long lasting.”
The anti-PD-L1 antibody is likely to be active against any tumor type as long as the tumor expresses the PD-L1 protein on its cell surface and that PD-L/PD-L1 signaling is important for the tumor’s growth. Gordon emphasized that expression of PD-L1 is likely to be an efficient biomarker to identify patients who are eligible for anti-PD-L1 therapy.
MPDL3280A is also being explored as part of a combination therapy with the BRAF inhibitor vemurafenib (Zelboraf) in a phase I trial for metastatic melanoma. Vemurafenib is an approved therapy for BRAF-positive metastatic melanoma. Another MPDL3280A phase I trial is testing the antibody in combination with the antiangiogenesis antibody bevacizumab in patients with advanced cancer. A phase II non–small-cell lung cancer trial with MPDL3280A will be started soon.