Immunotherapies have revolutionised oncology. Their ability to target tumours and enhance the immune response has had a dramatic impact on the prognosis of some cancer patients. But not for all patients. Over the past decade it has become clear that some people with cancer respond better than others. Quite why there is this variation is the focus of a considerable number of studies.
Likewise, some patients who initially benefit from immunotherapies go on to become resistant. Again the underlying reasons for this are a subject of intense research. One potential solution to both issues is to use combination immunotherapies, which consist of two or more drugs with distinct therapeutic targets.
Combined effort
According to Dr Stefan Zimmermann from the European Society for Medical Oncology (ESMO), an increasing number of clinical trials are examining combination immunotherapies.
“A recent review of the current landscape of clinical research in cancer immunotherapy counted more than 3,000 trials enrolling patients, including more than 1,000 trials evaluating combinations with anti-PD-L1 antibodies, and encompassing about 1,000 different clinical-stage substances.”
He added: “Combining therapeutic compounds is the first logical step towards better results, namely higher rates of patients responding to treatment, with deeper and more sustained responses. Harnessing the synergy between individual substances is one way to overcome known mechanisms of resistance to single agents.”
This view is shared by Professor Charles Swanton, Cancer Research UK’s chief clinician, who said the idea is that the combined therapies will enhance each other’s beneficial effects.
“The hope is that combination approaches will see additive or synergistic benefit over monotherapy studies. We hope to capitalise further on the effects of single agent anti-PD-1/PD-L1 and anti-CTLA-4 monotherapy trials and see even greater survival benefits for patients.”
Efforts to prevent resistance are also driving interest in combination therapies, said Matthew Galsky, MD, professor of medicine, haematology and medical oncology, Mount Sinai Hospital in New York.
“There are a variety of strategies attempting to overcome intrinsic resistance to a PD-1/PD-L1 blockade, [and] the rationale for any individual combination is usually based on the proposed mechanism by which that combination might overcome resistance.”
Clinical challenges All clinical trials are complex irrespective of the type of drug being tested. Demonstrating that a candidate molecule is safe and effective can only be achieved if all other variables are understood and controlled.
The complexity of the research increases significantly when multiple molecules are being assessed. This is true whether the drugs involved are immunotherapies or traditional small molecule medicines, according to Galsky.
“The considerations are really quite similar, with the exception that the adverse event profile and the kinetics of developing adverse events, tend to be a bit different with immunotherapy combinations versus other multidrug regimens.” The key challenge is developing a protocol that can determine whether the combined immunotherapeutic regimen is having a therapeutic effect rather than just one of the therapies, he said.
“It has become quite common to do single arm combination trials and view those results in the context of historical controls – this has led the field down the wrong path at least a few times.
“Ideally,” he continued, “any time a single agent is being compared with a combination, there should be randomisation. However, to complicate matters a bit, the best endpoints for such trials with immunotherapy are not well defined.”
Disease complexity
The vast majority of immunotherapies are being developed to treat cancers, which is a challenge for developers as cancer trials are notoriously difficult.
Cancers by their very nature are unique. The huge range of potential causes of the abnormal cell division that characterises cancer mean that every tumour is different.
This is a major headache for companies testing combination immunotherapies, said Charles Swanton.
“The problem is that the biology of the tumour microenvironment is complex and our understanding of the appropriate targets and the cell types they are expressed upon is limited.”
The recent failed phase 3 trial of a combination of MSD’s monoclonal antibody Keytruda (pembrolizumab) and InCyte Corporation’s epacadostat in metastatic melanoma is a case in point he says.
The research was halted early after it became clear the combination therapy did not meet the primary endpoint of improving progression-free survival in the overall population compared to Keytruda alone.
“This [the Keytruda-epacadostat result] should incentivise studies driven by a detailed understanding of the tumour microenvironment, the cell types in that microenvironment, the immune checkpoint receptors they express, and when they express them during the course of disease. He added: “A more detailed understanding of the nature of immune suppressive cell types in a tumour, the immune checkpoint proteins they express, and how to target them using combinatorial approaches, may guide the more rational design of clinical trials to improve immune surveillance and tumour control.”
Understanding why the combination failed relies upon having a clear and detailed understanding of the constituent drugs’ molecular targets on the tumour and how they interact. Achieving this level of understanding is a significant challenge, said Stefan Zimmermann.
“Drug development is outpacing our capacity to develop biomarkers due to the complexity of the cancer immune response. Furthermore, there are unique difficulties with the dynamic properties of the tumour environment and its heterogeneity, compounded by the mind-boggling variety of new substances with ever-more diverse mechanisms of action.”
Adverse events and autoimmunity
Another major challenge for all immunotherapy studies, including combined immunotherapy trials, is the increased potential for autoimmunity. All immunotherapies, as the name suggests, mediate their therapeutic benefits via interactions with both the target molecule – usually a protein expressed on the surface of a tumour – and the patient’s immune system. While the latter interaction is core to how immunotherapies fight disease, it is potentially one of their major drawbacks. The immune system is hugely complex and understanding, stimulating or suppressing its components is perhaps modern medicine’s greatest challenge. For example, it is becoming clear that via their interaction with the immune system, some immunotherapies can increase the risk that the immune system may target normal tissue.
The risk of autoimmune responses or toxicities, and indeed all adverse events, is greater for combination therapies than for monotherapies. This has shaped industry development strategies, said Stefan Zimmermann.
“For better or worse, currently the overwhelming majority of trials build their combinations on very tolerable anti-PD-L1 monoclonal antibodies backbone,” he said, adding that this has reduced the range of potential therapies being developed.
“Despite their remarkable activity in a variety of cancers, they only benefit a minority of patients, and combinations are one way forward. As combinations are inherently limited by their compounded toxicity, and because the mechanisms underlying resistance are so diverse, progress is more and more conditioned by correct identification of the patient population for which the drugs will work.”
Economics
Developers willing to take on the additional challenges of trialling a combination immunotherapy need to keep pricing in mind.
Analysis by the Institute of Clinical Oncology – an association of the US Association of Community Cancer Centers – indicates that the average mono-immunotherapy is $150,000 a year. This contrasts with the approved ipilimumab-nivolumab combination therapy, which costs $256,000 a year, according to the researchers.
Whether higher prices are an incentive to take a combination of immunotherapies into clinical development or likely to make drug companies think twice is a point of debate. Clearly, the potential for higher revenues is attractive. However, given the current focus on pharmaceutical prices and accusations of opportunism, some developers may opt not to trial combinations if their price tag is going to be in the hundreds of thousands of dollars.
In an ideal world, the fact that combination immunotherapies are more effective in more patients that monotherapies would drive their development. However, drug development is seldom only about the patients.