Written by:
Senior Director, Oncology Bioscience,
AstraZeneca
Vice President, Head of Oncology Discovery, AstraZeneca
As cancer evolves, its complexity and heterogeneity increases along with its ability to develop resistance to cancer treatments. To bring benefit to patients and achieve long-term survival, it’s important we treat cancer early and find multimodal ways to target its vulnerabilities. At AstraZeneca, our diverse portfolio of medicines is designed with this in mind, with a focus on combinations which challenge drug resistance, and have the potential to elicit deeper, more durable responses.
Why use combination therapy in cancer?
Monotherapy – killing cancer cells with a single pharmaceutical agent – plays a key role in cancer treatment, bringing benefit to many patients. However, there’s more we can do to tackle challenges that persist in the clinic, such as drug resistance and unwanted side effects of treatment.
Combining two or more agents to target aspects of cancer growth and survival has emerged as a key opportunity for driving progress – by developing treatment regimens which target independent molecular pathways, cancer combination therapy aims to:
- Address complexity: Each tumour is unique in its genetic, epigenetic and proteomic detail, and cells within a single tumour are heterogeneous and often respond to treatment differently. Cancer combination therapies that target subsets of cancer cells, offer a nuanced approach to targeting complex tumour biology.
- Overcome resistance: A strategic combination of medicines can hinder the tumours’ ability to develop resistance, and potentially enhance patient outcomes.
- Enhance treatment response: Combination therapy has the potential to enhance cancer cell death, and lead to deeper and more durable responses compared to monotherapy.
While we have seen some real success with cancer combination therapies to date, this has often been slow and linear, by addition of a new cancer medicine to an established cancer treatment. At AstraZeneca, we follow the science to inform our approach to combinations, with a diverse portfolio designed to attack cancer from multiple angles.
Thinking beyond synergy for cancer combination therapy
The concept of synergy – clinical activity of two agents exceeding addition of their individual effects – has long been a major driver in the design of cancer combination therapies. While it has powerful therapeutic potential, there can also be challenges navigating developing these regimens, such as unwanted side effects that can result from synergistic biology. Further, reliance on synergistic mechanisms can also lead to unexpected vulnerabilities to drug-resistance, such as reduced durability of treatment. For example, our research published in Blood Cancer Discovery1 investigated the role of synergy in the development of resistance to combination therapy in human leukaemia cell lines. The study revealed for the first time an experimental relationship between synergy and an increased likelihood of developing tumour resistance, an effect put forward by previous studies2-5, and suggests cancer combination therapies that depend primarily on synergy may have less durable responses.
We’re now beginning to ask bold questions to challenge convention in oncology, to address the emergence of resistance to treatment, and tackle the side effects which often make dosing cancer combinations at the intended dose difficult. By attacking cancer from multiple angles, and with multiple modalities, more meaningful clinical outcomes may be achieved through combinations. Our oncology portfolio is designed to deliver on this strategy, including precision medicines such as: antibody drug conjugates (ADCs), small molecule inhibitors targeting diverse mechanisms of tumour biology, and immune-oncology agents. Combinations of these agents have the potential to allow targeting multiple disease drivers simultaneously, maximising desired therapeutic effect and minimising potential for drug resistance.
As we look for new ways to move the needle for patients, we’re thinking strategically and following the science to enable these multimodal combinations which can be scheduled to target more than one aspect of complex cancer biology, with the goal to achieve deeper, and more durable responses.
By focusing on a strong scientific rationale, we’re thinking beyond synergy in developing strategic cancer combination therapies. Our goal is to engage more than one target and hinder the tumours’ ability to develop resistance by eliciting deeper and more durable responses.
Finding strategic combinations in the precision medicine era
As we broaden our view beyond synergy in thinking about oncology combinations, we need an approach to guide us through their prioritisation and development.
To address this, our combination discovery efforts focus on finding agents which will work at the right dose, in the right patients, and with an acceptable safety profile, with the overall aim to attack a tumour from multiple angles and drive deeper responses in the clinic.
We are now using model systems which capture the heterogeneity of tumours better, such as patient derived xenografts and organoids, to help define our combinations strategies. By enhancing our preclinical and translational understanding of underlying disease mechanisms and biomarkers, better predicting combination tolerability and identifying the right dose schedules - we are answering critical questions which help us deliver combination therapies in the clinic.
Our research, published in Cancer Discovery,6 illustrates how large-scale combination screens can be mined differently to prioritise targeted combinations most likely to benefit specific patient populations. Rather than focusing on the combinations which elicited the broadest and highest “synergy scores”, we took a holistic approach to prioritising combinations: looking for those that not only demonstrate activity above monotherapy, but also exhibit selectivity for specific cancer types and genetic backgrounds. With this approach, we were able to successfully identify and validate novel combination hypotheses, while simultaneously optimising clinical translatability. One of the ways in which we achieved this was by using multi-omics data, which identified emergent biomarkers that can predict unique responses to combination treatments.
Our novel experimental and analytical approach is one of the largest published combination screens to date and will also help future artificial intelligence approaches to identify new cancer combinations for therapies and biomarkers of response.
By taking a precision medicine approach, our innovative framework takes us a step closer to designing combination therapies based on each patient's unique response potential. It provides valuable insights early in drug development and allows us to test how different modalities work together, ultimately increasing the chances of improved outcomes for patients.
In developing novel combination therapies, it’s important to focus on how they will benefit patients. We prioritise combinations which attack a tumour from multiple angles, demonstrate selectivity for specific cancer types, and present a more favourable activity and safety profile than existing monotherapies. We want to be confident that for any given combination, the sum is greater than its parts and we understand how to best develop it from the outset.
Unlocking the full potential of combination therapy: cancer treatment development
In the past, oncologists have had great success with building combination therapies step-by-step, adding active new therapies to existing treatments. Technological advances are now allowing unprecedented insights into cancer, enabling us to accelerate this process, designing and evaluating innovative cancer combination therapies much faster, and with much greater precision.
It’s important we continue to challenge convention, leverage model systems which reflect the complexity of cancer, and seek to improve our understanding of mechanisms of resistance. By doing so, we have the potential to develop smarter combination strategies and attack cancer from multiple angles – bringing us a step closer to one day eliminating cancer as a cause of death.
