Merck & Co.’s approval from the US Food and Drug Administration (FDA) of Keytruda (pembrolizumab), a drug to treat melanoma, is a key development not only for Merck, but for the industry as other companies seek to advance immunotherapies in the oncology market.

Immunotherapies represent one area with much promise in the oncology market, with anti-programmed death-1 (PD-1) antibodies and anti-programmed death-ligand 1 (PD-L1) antibodies a key area of focus. The recent US approval of Merck & Co.’s Keytruda (pembrolizumab) highlights a growing list of immunotherapies, which include drug candidates from other companies, such as Bristol-Myers Squibb, Roche, and AstraZeneca.

Assessing the market and its potential
Immunotherapy agents, such as 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. 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 US Food and Drug Administration (FDA) approved the first checkpoint molecule inhibitor, Bristol-Myers Squibb’s 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.

Earlier this month, Merck & Co. received FDA approval for Keytruda (pembrolizumab) for treating advanced or unresectable melanoma, making it, the first anti-PD-1 therapy approved in the United States. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, Keytruda releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. Keytruda is intended for use following treatment with ipilimumab. For melanoma patients whose tumors express a gene mutation called BRAF V600, Keytruda is intended for use after treatment with ipilimumab and a BRAF inhibitor, a therapy that blocks activity of BRAF gene mutations.

Pembrolizumab is a pivotal drug in Merck’s strategy. In June, the company filed for marketing approval in the European Union, and additional regulatory filings in other countries outside of Europe are planned by the end of 2014. Merck is also evaluating the drug for other cancer indications as both a monotherapy and in combination with other anticancer drugs. Pembrolizumab is being evaluated across more than 30 types of cancers as both 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, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide.

Merck has formed several collaborations to advance pembrolizumab. In May 2014, Dako, an Agilent Technologies company, formed a collaboration with Merck & Co. 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.

In February 2014, Pfizer and Merck & Co. 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 pembrolizumab 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.

Other companies advance immuno-oncology drug candidates
Bristol-Myers Squibb. Bristol-Myers Squibb is advancing its PD-1 immune checkpoint inhibitor, nivolumab. In July 2014, Bristol-Myers Squibb and Ono Pharmaceutical Co. received manufacturing and marketing approval in Japan for nivolumab, marketed as Opdivo, as a treatment of patients with unresectable melanoma, making it the first PD-1 immune checkpoint inhibitor to receive regulatory approval on a global basis.

In August 2014, Bristol-Myers Squibb partnered with Celgene to evaluate a combination therapy of Bristol-Myers Squibb’s nivolumab and Celgene’s nab technology-based chemotherapy Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin-bound), in a Phase I study. Multiple tumor types will be explored in the study, including HER-2 negative metastatic breast cancer, pancreatic cancer, and non-small cell lung cancer (NSCLC). The study, which is expected to begin in the fourth quarter of 2014, will be conducted by Celgene. By combining an immunotherapy (nivolumab) with a standard chemotherapy (Abraxane), the companies will explore whether these two agents may lead to an enhanced anti-tumor response compared to either agent alone.

Nivolumab being is studied in multiple tumor types consisting of more than 35 trials as both 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 NSCLC, melanoma, renal cell carcinoma (RCC), head and neck cancer, glioblastoma and non-Hodgkin lymphoma. In 2013, the FDA granted fast track designation for nivolumab in NSCLC, melanoma and RCC. In May 2014, the FDA granted nivolumab breakthrough therapy designation for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab.

Incyte Corporation and Bristol-Myers Squibb also formed a clinical trial collaboration earlier this year 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, NSCLC, 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 NSCLC, metastatic melanoma, ovarian, colorectal, and squamous cell head and neck cancers.

Roche. 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: with its cancer drug Avastin (bevacizumab) and chemotherapy for solid tumors; with Avastin for renal cell cancer; with Tarceva (erlotinib) for NSCLC with EGFR-activating mutations; with Zelboraf (vemurafenib) for metastatic melanoma; and with cobimetinib in locally advanced or metastatic solid tumors.

AstraZeneca. AstraZeneca is advancing its anti-PD-L1 immune checkpoint inhibitor, MEDI-4736. In July 2014, AstraZeneca entered into a clinical study collaboration with Kyowa Hakko Kirin for a Phase I/Ib immuno-oncology study that will evaluate the safety and efficacy of two separate combinations of three investigational compounds in multiple solid tumors. The study will evaluate AstraZeneca’s anti-PD-L1 antibody, MEDI4736, in combination with Kyowa Hakko Kirin’s anti-CCR4 antibody, mogamulizumab, and AstraZeneca’s anti-CTLA-4 antibody, tremelimumab, in combination with mogamulizumab. Under the agreement, AstraZeneca and Kyowa Hakko Kirin will co-fund the study, which will be conducted by Kyowa Hakko Kirin. The Phase I part of the study is expected to establish a recommended dose regimen, and the Phase Ib study will assess the safety and efficacy of the two combinations. Results from these studies will determine the future clinical development of the combinations.

Also in July 2014, MedImmune, the biologics arm of AstraZeneca, partnered with Advaxis, Inc., a US-based biotechnology company developing cancer immunotherapies, for a Phase I/II immunotherapy study to evaluate the safety and efficacy of AstraZeneca’s MEDI4736, in combination with Advaxis’ lead cancer immunotherapy vaccine, ADXS-HPV, as a treatment for patients with advanced, recurrent, or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer. Under the agreement, MedImmune and Advaxis will evaluate the combination as a treatment for HPV-associated cervical cancer and squamous cell carcinoma of the head and neck. The Phase I part of the trial is expected to establish a recommended dose regimen of MEDI4736 with ADXS-HPV, and the Phase II portion will assess the safety and efficacy of the combination. The study will be funded and conducted by Advaxis. Results from the study will be used to determine whether further clinical development of this combination is warranted. Under the terms of the deal, MedImmune has a non-exclusive relationship with respect to HPV-driven tumor types and right of negotiation for future development of combinations involving MEDI4736 and ADXS-HPV.

In May 2014, AstraZeneca initiated a Phase III clinical trial for MEDI-4736 to evaluate the drug to treat locally advanced, unresectable non-small cell lung cancer. Also, in  May 2014, Incyte formed a clinical collaboration with Medimmune 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.

Merck KGaA. In July 2014, MorphoSys AG, a provider of human antibody technologies, and Merck Serono, the biopharmaceutical division of Merck KGaA, signed an agreement to discover and develop therapeutic antibodies against undisclosed immune checkpoints. MorphoSys will apply its proprietary Ylanthia antibody phage library and technology platform to identify antibodies against targets of interest. Merck Serono will be fully responsible for execution of development from Phase I onwards. MorphoSys will co-fund research and development costs with the option to opt-out at predefined stages. MorphoSys will be eligible to receive development and commercial milestone payments, and in addition, tiered royalties on product sales that will reflect the extent of MorphoSys co-funding. Merck Serono will have sole responsibility for commercializing of any resulting products. Merck Serono’s immuno-oncology pipeline assets currently investigated in clinical trials span from Phase I to Phase III for the treatment of different cancer types, including tecemotide, a MUC1 antigen-specific cancer immunotherapy, two immunocytokines NHS-IL2 (MSB0010445) and NHS-IL12 (MSB0010360), and the monoclonal antibody anti-PD-L1 (MSB0010718C). Its pre-clinical pipeline is focuses on three innovation clusters: therapeutic cancer vaccines, cancer stem cells, and tumor immunotolerance.

Novartis. 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.