Immuno-oncology therapies activate the body's own immune system to fight tumors – and they represent a new era in cancer treatment. Through a strategic alliance, Merck KGaA, Darmstadt, Germany, and Pfizer are combining their strengths in order to quickly capture the potential of this promising research area.

The immune system is the body's defense force. It recognizes and fights bacteria, viruses and other foreign organisms that invade the human body. However, in this form of biological warfare, cancer cells have long been formidable enemies the body has struggled to defend itself against. After a cancer diagnosis, physicians traditionally focus on attacking the tumor using classic methods such as radiation, chemotherapy or surgery. Now, along with other potentially promising treatments, immuno-oncology is opening up new prospects in cancer therapy because it harnesses the body's own immune system to fight tumor cells. Innovative immunotherapies could enhance the prospects for patients’ survival in different forms of cancer, and therefore represent a promising opportunity for research-based pharmaceutical companies such as Merck KGaA, Darmstadt, Germany.

Joining forces to fight cancer

The ace that our company has in its hands is tiny, but a potential game-changer in the fight against cancer. Its anti-programmed death-ligand (anti-PD-L1) antibody (the proposed international non-proprietary name is ‛avelumab’) could be the basis for development of a new type of cancer drug. Our view is shared by the international pharmaceutical company Pfizer, so experts from both companies got together on this basis, with far-reaching consequences. In the spirit of the concept ‛Together we are stronger’, in November 2014 this culminated in the announcement that our company and Pfizer had formed an alliance to pursue what they see as a joint objective: developing anti-cancer strategies based on a shared understanding of the important biological role of checkpoint inhibitors, a move widely regarded as an exciting one within the industry. Avelumab was discovered and initially developed in our laboratories, and is one of the company’s highest-priority programs.

‟The alliance with Pfizer has enabled us to quickly accelerate the clinical development program for avelumab, and we’re on track to meet several important milestones in the near term. Our efforts in immuno-oncology and R&D more broadly remain centered on making a meaningful difference in the lives of patients around the world,” says Luciano Rossetti, Head of Global Research and Development within our Biopharma business. From our viewpoint, the alliance is also financially worthwhile: as part of the agreement, Pfizer has paid our company US$ 850 million in order to jointly develop and commercialize the anti-PD-L1 antibody. The two companies will share the costs and revenues, apart from a potential bonus for us. If certain milestones are achieved, we are eligible to receive an additional total amount of up to US$ 2 billion from Pfizer. Another outcome of the deal is the move by both companies to co-market Pfizer's cancer drug Xalkori® in the United States and in further key markets. As a result, our company has built up its own U.S. oncology sales force, which it previously did not have and which, ultimately, could be used to market avelumab and other cancer drugs. Through this alliance, we are is thereby also gaining faster access to the U.S. oncology market – the world's largest. In addition, both companies willbe further developing a potential therapy of Pfizer’s with an almost identical designation: anti-PD-1.

A camouflaged attack

So why are scientists excited about anti-PD-L1 antibodies? In order to explain the relatively complex functions of anti-PD-L1 and anti-PD-1, we need to consider the purpose of the immune system. Its capability as a successful defense against invaders that cause disease (pathogens) depends on a collective effort by organs, tissues and the immune cells, commonly known as white blood cells. Immune cells first scan the tissue for any sign of injury, infection and general malfunction, including signs of uncontrolled cell division that could potentially form a malignant tumor. T-cells (so-called because they mature in the thymus) comprise a key subtype of immune cells that are able to recognize and eliminate hostile attacks by pathogens, in concert with other immune cells. Microorganisms have specific structures on their cell surface, called antigens, which T-cells are able to recognize using very specific receptors, and stimulate the destruction of the pathogens. The memory of this specific antigen is then retained by the immune system to prevent a repeat infection. This process is highly effective at eliminating pathogenic invaders, but it can also damage local tissues – the reason for the hot, red, painful area associated with inflammation. Once the infection has been resolved, local tissues release so-called ‟checkpoint-inhibitor” molecules, such as PD-L1, which act to switch off the T-cell response. Unfortunately, cancer cells exploit this mechanism – they cleverly camouflage themselves using the PD-L1 and other inhibitors. The consequences are disastrous: They are no longer recognized as enemies by the immune cells.

The power of antibodies

It is at this precise point where the antibodies anti-PD-L1 and anti-PD-1 come in. Their job is to turn off the mechanism that masks the spread of cancer cells. Avelumab is a molecule that binds to the PD-L1 used by cancer cells to camouflage themselves and is believed to serve as a giant red flag to the immune system, encouraging a multifaceted cell-mediated offensive against the cancer cells.

Avelumab has not yet been approved. Nevertheless, the extensive clinical development program is making tremendous progress (see interview). In the words of Kevin Chin, Executive Medical Director Immuno-Oncology at our company: ‟Our early clinical safety and efficacy data for avelumab point to encouraging therapeutic benefit for patients across multiple types of cancer. We look forward to seeing the full potential of this therapy unfold.” Moreover, the professional medical community is also following the research activities of Merck KGaA, Darmstadt, Germany, and Pfizer with close interest, and with optimism. Dr. Mary ‟Nora” L. Disis, Professor, Department of Medicine, Division of Oncology, University of Washington, says, ‟The response to avelumab in patients with previously treated, recurrent or refractory ovarian cancer has been promising. The data presented at ASCO 2015 are the most exciting I’ve seen in ovarian cancer for this patient population in the last ten years.” Avelumab could well emerge as a leading and significant addition to the pharmacological armory in the war against cancer.

“The data presented at ASCO 2015 are the most exciting I’ve seen in ovarian cancer for this patient population in the last ten years.”

Dr. Mary “Nora” L. Disis, Professor, Department of Medicine, Division of Oncology, University of Washington

“We’re combining our resources and expertise”

Interview with Andrew Schiermeier, Head of our alliance with Pfizer

What are the key strategic drivers of the alliance with Pfizer?

Andrew Schiermeier: We are combining our resources and expertise because we share a vision of making a real difference to patients with cancer. Our focus is on jointly investigating avelumab* in different cancer indications: We will explore its potential as a single agent and in various combinations with our collective portfolio of approved and investigational oncology therapies. The alliance enables the companies to quickly move into the first wave of potential immuno-oncology-based monotherapy treatment regimens and to potentially take a leadership position in the next wave of immuno-oncology combination therapies.

Andrew Schiermeier, General Manager of our Immuno-Oncology Alliance with Pfizer and Head of Global Oncology at Merck KGaA, Darmstadt, Germany.

Where does the main potential of immuno-oncology and specifically of avelumab lie?

Andrew Schiermeier: Cancer immunotherapies work by harnessing the body’s own immune system to attack a tumor, either by restoring or boosting an immune response to a malignant tumor. Avelumab is thought to enable the activation of T-cells and the adaptive immune system, while leaving other PD-1 interactions intact. Early data also suggest avelumab may possess unique features, including the possible engagement of the innate immune system. Through clinical trials, we want to identify whether this effect may benefit patients.

What are the biggest challenges in the clinical development program of avelumab?

Andrew Schiermeier: With the JAVELIN program, we aim to evaluate the potential for PD-L1 inhibition with avelumab to treat multiple types of cancer. With more than 1,500 patients treated to date, it is among the largest exploratory study programs in immuno-oncology. In 2015, more than 20 clinical programs were initiated, six of which are pivotal trials. Avelumab is currently being studied in over 15 tumor types.

What is the current status and when do you expect the market launch of avelumab?

Andrew Schiermeier: By the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO), the JAVELIN program is expected to include up to 25 trials studying avelumab as a single-agent and combination therapy. We expect the first potential market launch in 2017, with the alliance working toward at least one additional launch per year until 2022.

* Avelumab is the proposed International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody (previously known as MSB0010718C).