Merck & Co, Bristol-Myers Squibb, Roche, and AstraZeneca are among the companies advancing anti-PD-1 and anti-PD-L1 inhibitors in their pipelines.

Oncology is an important area of drug development for pharmaceutical companies, so what is the next important area of development? This year’s meeting of the American Society of Clinical Oncology (ASCO), which was held in Chicago from May 30 to June 3, highlights the latest advances in oncology drugs, and immunotherapies represent one area of biologic-based drug development that is drawing strong attention, in particular, anti-programmed death-1 (PD-1) antibodies and anti-programmed death-ligand 1 (PD-L1) antibodies. Merck & Co., Bristol-Myers Squibb, Roche, and AstraZeneca are among the companies advancing their drug candidates in this area in what has become a promising area for biologic-based oncology drugs.

Sizing up the competition
Immunotherapy agents, PD-1 modulators and anti-PD-L1 therapies represent the next phase of targeted agents in oncology, according to a recent analysis, Innovation in Cancer Care and Implications for Health Systems: Global Oncology Trend Report, by the IMS Institute for Healthcare Informatics. Anti-PD-1 inhibitors and anti-PD-L1 inhibitors are a new class of immune checkpoint inhibitors. The immune system has checkpoints to keep itself from attacking other normal cells in the body. Cancer cells sometimes take advantage of these checkpoints to avoid being attacked by the immune system. An important checkpoint molecule is the PD-1 protein found on T cells, especially those in tumors and the nearby environment. Cancer cells sometimes have large amounts of the corresponding PD-L1 protein on them, which allow them to escape immune system attack. Drugs that target PD-1 or PDL-1 boost the immune system (1). Anti-PD-1 inhibitors target a receptor protein known as PD-1 on the surface of activated T cells; anti-PDL-1 inhibitors target a binding partner (ligand) of PD-1, called PD-L1, which is expressed at higher than normal levels on many tumors and on cells in the tumor microenvironment. In 2011, the FDA approved the first checkpoint molecule inhibitor, Bristol-Myers Squibb Yervoy (ipilimumab), which achieved 2013 sales of $960 million, to treat advanced melanoma. Ipilimumab, however, targets a different checkpoint molecule, CTLA-4, on the surface of activated T cells.

Merck & Co. has advanced its PD-1 antibody, pembrolizumab (MK-3475), for treating advanced melanoma to FDA review. Pembrolizumab is an investigational selective, humanized monoclonal anti-PD-1 antibody designed to block the interaction of PD-1 on T-cells with its ligands, PD-L1 and PD-L2, to reactivate anti-tumor immunity. Pembrolizumab exerts dual ligand blockade of PD-1 pathway.

In May 2014, FDA accepted for review the biologics license application (BLA) for pembrolizumab. FDA granted priority review designation with a PDUFA date of October 28, 2014, and the pembrolizumab will be reviewed under FDA’s Accelerated Approval program. FDA previously granted pembrolizumab breakthrough therapy designation for advanced melanoma. If approved by FDA, pembrolizumab has the potential to be the first anti-PD-1 antibody in a new class of immune checkpoint modulators. Merck also announced it plans to file a marketing authorization application for pembrolizumab in Europe for advanced melanoma by the end of 2014. Pembrolizumab is being evaluated across more than 30 types of cancers, as a monotherapy and in combination. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to more than 24 clinical trials across 30 different tumor types, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide, including new Phase III studies in head and neck and other cancers, according to Merck.

In May 2014, Dako, an Agilent Technologies company, formed a collaboration with Merck to develop a companion diagnostic test for the analysis of the potential tumor biomarker PD-L1 to aid in the treatment of cancer. The companion diagnostic test coming out of this collaboration will be evaluated as part of the clinical development program for Merck & Co.’s investigational anti-PD-1 antibody being studied for the treatment of cancer.

Strategically, pharmaceutical companies are also evaluating PD-1 and PD-L1 not only as monotherapies but in combination with new investigational drugs as well as marketed products, often through partnerships. For example, in February 2014, Pfizer Inc. and Merck & Co., Inc., signed an agreement to explore the therapeutic potential of Merck’s  pembrolizumab, in combination with two Pfizer oncology assets. A Phase I/II clinical study will evaluate the safety and anti-cancer efficacy of pembrolizumab combined with Pfizer’s Inlyta (axitinib) in renal cell carcinoma. A separate Phase I study will evaluate the safety and tolerability of the combination of and PF-05082566 (PF-2566), Pfizer’s investigational, fully humanized monoclonal antibody that stimulates signaling through 4-1BB (CD-137), a protein involved in regulation of immune cell proliferation and survival. Pfizer will conduct the clinical studies of MK-3475 plus axitinib and pembrolizumab plus PF-2566. This agreement does not provide for any collaboration between Pfizer and Merck following the completion of the specified studies. Under a separate agreement Pfizer and Merck are currently exploring the pre-clinical combination of pembrolizumab with Pfizer’s investigational therapy palbociclib (PD-0332991). Merck is conducting these pre-clinical studies. Further studies would depend on the outcome of the ongoing pre-clinical studies as well as subsequent agreement by Merck and Pfizer.

Bristol-Myers Squibb is advancing its investigational PD-1 immune checkpoint inhibitor, nivolumab. The company is studying nivolumab in multiple tumor types consisting of more than 35 trials as a monotherapy or in combination with other therapies, in which more than 7,000 patients have been enrolled worldwide. Among these are several potentially registrational trials in non-small cell lung cancer, melanoma, and renal cell carcinoma. In 2013, the FDA granted Fast Track designation for nivolumab in these three tumor types.

Last month, Incyte Corporation and Bristol-Myers Squibb formed a clinical trial collaboration to evaluate the safety, tolerability, and preliminary efficacy of a combination regimen of Bristol-Myers Squibb’s, nivolumab, and Incyte’s oral, small-molecule indoleamine dioxygenase-1 (IDO1) inhibitor, INCB24360, in a Phase I/II study. Multiple tumor types will be explored in the study, which could potentially include melanoma, non-small cell lung, ovarian, colorectal, squamous cell carcinoma of the head and neck, and diffuse large B-cell lymphoma. The study, which is expected to begin in the fourth quarter of 2014, will be co-funded by the companies and conducted by Incyte. Bristol-Myers Squibb also formed a clinical trial collaboration with the biopharmaceutical company Celldex Therapeutics to evaluate the safety, tolerability, and preliminary efficacy of nivolumab, with varlilumab, Celldex’s CD27-targeting investigational antibody in a Phase I/II study. Multiple tumor types will be explored in the study, which could potentially include non-small cell lung cancer, metastatic melanoma, ovarian, colorectal, and squamous cell head and neck cancers.

In June 2014, FDA granted breakthrough therapy designation in bladder cancer for Roche’s investigational cancer immunotherapy MPDL3280A, a PD-1 antibody. MPDL3280A is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, MPDL3280A may enable the activation of T cells, restoring their ability to effectively detect and attack tumor cells. Roche is also evaluating MPDL3280 in combination with other cancer therapies, now in early development, including with Avastin (bevacizumab) and chemotherapy for solid tumors, with Avastin for renal cell cancer, with Tarceva (erlotinib) for non-small cell lung cancer with EGFR-activating mutations, with Zelboraf (vemurafenib) for metastatic melanoma, and with cobimetinib in locally advanced or metastatic solid tumors is ongoing.

AstraZeneca is advancing its anti-PD-L1 immune checkpoint inhibitor, MEDI-4736. In May 2014, the company initiated a Phase III clinical trial for MEDI-4736 to evaluate the drug to treat locally advanced, unresectable non-small cell lung cancer. In May 2014, Incyte formed a clinical collaboration with Medimmune, the biologics arm of AstraZeneca, for a Phase I/II oncology study to evaluate the efficacy and safety of MEDI-4736, in combination with Incyte’s INCB24360. AstraZeneca is also evaluating MEDI-4736 in combination with its investigational anti-CTLA4 monoclonal antibody tremelimumab as well as MEDI-4736 in combination with GlaxoSmithKline’s (GSK) BRAF inhibitor dabrafenib and GSK’s MEK inhibitor trametinib. AstraZeneca also is evaluating MEDI-0680 (AMP-514), an anti-PD-1 monoclonal antibody in Phase I/II development.

In 2010, the biopharmaceutical company Amplimmune Inc. formed a broad strategic alliance with GSK to further develop PD-1 targeting therapies that may be effective in the treatment of cancer and other diseases. Under that agreement, GSK obtained exclusive worldwide rights to AMP-224 as well as other potential next generation fusion proteins that target PD-1. In 2013, AstraZeneca acquired Amplimmune.

In February 2014, Novartis broadened its cancer immunotherapy research program with the acquisition of CoStim Pharmaceuticals Inc., a Cambridge, Massachusetts-based, privately held biotechnology company. With the acquisition Novartis added late-discovery stage immunotherapy programs directed to several targets, including PD-1.

Reference
1. American Cancer Society, “What is New in Cancer Immunotherapy Research,” website, accessed June 1, 2014.