PD-L1 Antibody Demonstrates Promising Results in Phase I Expansion Study

Roy S. Herbst, MD, PhD

MPDL3280A, an antibody that targets the programmed death ligand 1 (PD-L1), demonstrated a 21% response rate in a phase I study of patients with multiple solid tumors, according to results presented at ASCO 2013.

MPDL3280A produced durable responses with no dose-limiting toxicities and a favorable adverse-event (AE) profile in heavily pretreated patients. Nearly all of the responses were ongoing at the time of the study presentation, and many patients reported improvements in cancer-related symptoms, such as the need for oxygen supplementation or the use of narcotics for pain control.

PD-L1 is often overexpressed on the surface of cancer cells and allows the cells to evade the immune system. MPDL3280A is an immune checkpoint therapy that blocks PD-L1 from binding to its receptors, including PD-1 and B7.1. Results of a phase I dose escalation trial of MPDL3280A were presented in April at the American Association for Cancer Research (AACR) Annual Meeting 2013 (see page 17).

In the study presented at ASCO, MPDL3280A was administered intravenously every 3 weeks to patients with metastatic tumors including non-small cell lung cancer (NSCLC), melanoma, colorectal cancer, gastric cancer, and renal cell carcinoma. Responses were assessed with computed tomography scans every 6 weeks for 6 months, and then every 12 weeks.

A total of 29 of 140 evaluable patients (21%) exhibited tumor shrinkage according to RECIST version 1.1, with the highest overall responses in patients with NSCLC and melanoma. Of the 29 responders, 26 patients continued responding as of their last assessment. Responders were on the study from 3 months to more than 15 months.

In a biomarker analysis of archived tumor tissue from 103 patients, there were more responses in patients with higher levels of PD-L1 expression. The response rate among PD-L1-positive patients was 36% (13 of 36 patients), compared with 13% (9 of 67 patients) who were PD-L1-negative.

Among 171 patients available for the safety analysis, 43% experienced grade 3/4 AEs, most commonly hyperglycemia (5%), fatigue (4%), and increased alanine aminotransferase levels (3%). However, investigators determined that 13% of the grade 3/4 AEs were attributable to the drug, and there were no treatment-related deaths. Only 4 patients (2%) experienced grade 3/4 AEs that were deemed to be immune-related, and only 1 patient discontinued treatment because of an immune-related AE.

There were no incidences of high-grade pneumonitis, which may mean the drug was targeting only PD-L1 and sparing some of the mechanisms that would allow for the lung to become inflamed, according to Roy S. Herbst, MD, PhD, professor of Medicine at Yale Cancer Center, lead author of the study.

The role of PD-L1 expression in response to MPDL3280A has not been clearly delineated. Furthermore, a diagnostic test for PD-L1 is still evolving. Currently, negative results of an investigational diagnostic test may simply mean that PD-L1 levels are lower than what the test can detect.

Compared with earlier PD-L1 or PD-1 targeted agents, MPDL 3280A was specifically engineered for enhanced safety, and Herbst speculated that the agent could potentially be combined with targeted therapies or with chemotherapy.

The MPDL3280A study is continuing with an expanded cohort of patients with a larger range of solid tumors and blood cancers; more than 275 patients have been enrolled, according to an ASCO press release.

Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J Clin Oncol. 2013;31(suppl; abstr 3000).

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