AstraZeneca's Oncology Goal: Separate Efficacy And Toxicity
By Ed Miseta, Chief Editor, Clinical Leader
Matthew Ellis, SVP of Early Oncology R&D for AstraZeneca, is helping lead the charge in what he calls the company's oncology revolution. Early Oncology refers to everything at AstraZeneca dealing with the treatment of cancer prior to Phase 3 trials. Ellis deals with the complicated process of going from the discovery of a potential therapeutic target or mechanism to the discovery and development of potential medicines, the triage of those medicines, and working out the right risk-benefit profile so they can be administered to humans.
Ellis had been in academia his entire life until March 2022, when he opted to move to the pharma side of the house. He made the move at the age of 62.
“People have asked what led me to make the switch at that point in my life,” he says. “I felt the ambition of AstraZeneca matched my own regarding the development of treatments for patients. Working for a pharma company allows me to achieve more than I could if I'd stayed in academia. It suddenly seemed like the right thing to do. Amazing developments are being made in how we approach cancer, and I wanted to be part of it.”
“We must make treatments more effective and with better safety profiles for patients,” states Ellis.
An Improved Treatment
Ellis notes the discovery process is lined with bottlenecks, which makes oncology drug development so difficult. Still, he notes medicines being developed today have made great progress and no longer resemble chemotherapy treatments of the past. The focus today is on precision medicine, which entails carefully selecting patients who are administered a well-engineered therapeutic. He hopes that process will lead to greater effectiveness and fewer side effects.
One example Ellis cites is work being done with PARP (poly adenosine diphosphate-ribose polymerase) inhibitors. PARP inhibitors are drugs given to patients with a particular form of cancer that arises because of a defect in specific DNA repair pathways. When cells divide, they must replicate their genetic information. When there are errors in replicating that genetic information, the mistakes remain uncorrected. The mistakes become mutations and can eventually lead to cancer.
“The result can be serious hereditary breast or ovarian cancer that arises when the patients are in their thirties, forties, or fifties,” says Ellis. “In men, it can result in prostate cancer. The defects that cause these cancers also makes them sensitive to inhibition of other DNA repair pathways. Researchers have found that by inhibiting an enzyme, you could get those tumors to regress.”
The PARP inhibitors resulting from that research are now a standard of care for patients. They are given to treat these patients and are even given to prevent the recurrence of the cancer. But the problem with PARP inhibitors, like all medicines, is they have side effects. There has been a lot of interest in editing some of those side effects out of the treatment, and researchers have found the side effects may result because they're non-selective. They inhibit two enzymes known as PARP1 and PARP2. PARP2 is potentially responsible for the majority of the side effects.
The good news is that PARP2 is not thought to be required for the drug’s effectiveness. AstraZeneca has recently announced new clinical data for a PARP1 selective drug which is potent with markedly reduced side effects.
A Novel Use Of Antibodies
A second example Ellis cites are antibody drug conjugates. When a patient receives a chemotherapy treatment, it is taken as a pill or injected into their arm. The chemo goes through their entire body, and can cause unpleasant side effects such as hair loss, neuropathy, and bone marrow problems. The revolution taking place with those treatments involves taking the chemotherapy and attaching it to an antibody. Known as an antibody drug conjugate, they can deliver the chemotherapy to the tumor cells by recognizing and interacting with something selectively expressed by cancer cells. The cancer cell internalizes the antibody drug conjugate, and the chemotherapy is released inside it.
“You can imagine the endless variants of that type of treatment,” says Ellis. “We can create many different antibodies and chemotherapies. One of the products that has regulatory approval and has made it to patients can target HER2 (human epidermal growth factor receptor 2) breast cancer. It is the result of combining the chemotherapy and the antibody, and the treatment has worked with impressive results.”
The next wave of antibody drug conjugates now being developed includes those that target TROP2, a transmembrane protein widely expressed in various cancers, including non-small cell lung cancer. Those clinical trials are progressing rapidly.
Another class of drug is called a bispecific antibody. Usually, an antibody sees one antigen. But a bispecific antibody can be designed to see two immune checkpoint proteins, which can prevent cancer cells from being recognized by the immune system. Bispecific antibodies can combine, targeting two of these immune checkpoint proteins, including PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4).
“The result is a more effective drug with reduced toxicity,” states Ellis. “The toxicity reduction is due to the way it is manufactured. CTLA-4 antibodies can cause undesired immune-related side effects and can only be given in small amounts. However, by making a bispecific antibody that also binds to PD-1, which is only expressed on ‘active’ immune cells, CTLA-4 is preferentially inhibited on immune cells that actively target cancer. We can bring together the antibody inhibition on the tumor cell while leaving normal cells less exposed to the toxic side effects.”
The Search For Cancer Drivers
A final part of AstraZeneca’s focus is on cell engineering. CAR-T cells are used when engineering a cytotoxic T-cell to recognize cancer. AstraZeneca is investing in this approach with the aim of extending the potential of CAR-T beyond hematological cancers by engineering T cells to overcome current challenges of cell therapies in the treatment of solid tumors, for example, to enable penetration of the tumor microenvironment that poses a physical barrier.
AstraZeneca is hoping newer treatments can help patients with any type of cancer. Ellis has been an oncologist for nearly three decades and believes cancer is a syndrome, not a diagnosis.
“If a patient has lung cancer, what's the driver for that type of lung cancer?” he asks. “Not every lung cancer is due to smoking, and non-smoking lung cancers behave very differently than smoking-induced lung cancers. The same is true with breast and colon cancer. Each patient’s cancer can have a subtly different cause. This is important since pharma companies can develop drugs that attack those causes.”
HER2 targeting was traditionally all about breast cancer. However, with deeper disease understanding we now know that some stomach cancers also express HER2 and can be targeted with those same HER2 drugs. Companies can now reposition a drug initially designed to treat a subset of breast cancers for a subset of gastric cancers. There are subsets of HER2-activated tumors in many different sites around the body.
“Categorizing cancers based on their mutations instead of their location creates a larger population of patients,” says Ellis. “Some of these studies are now called basket trials, which can be tumor site-of-origin agnostic. What matters is they have a common mutation or mechanism. The PARP inhibitors are good examples of that. Some women with hereditary cancer will get ovarian or breast cancer. Some will get both. Men might get prostate or pancreatic cancer. The same fundamental mechanism drives all these cancers, so they all respond to the same class of drugs.”
More Successful Phase 3 Trials
If these new oncology drugs are successful, they are expected to have a meaningful impact on Phase 3 trials. They may lead to more successful trials that are shorter in duration and may simplify the patient recruitment process.
“My goal in early oncology is for AstraZeneca to have more successful Phase 3 trials,” states Ellis. “To achieve that goal, improved safety profiles will play an important role. If we get the drug right and it is well tolerated, we know the patient will stay on the drug. That is essential for them to benefit from it. Second, if you properly define the patient population, you can expect big therapeutic effects. That means your trials can be smaller. Finally, I think you can conduct trials that include patients with tumors arising in different organ sites. It doesn't matter if the patient has breast, ovarian, prostate, or pancreatic cancer. You can stratify those factors in the trial, but the trial doesn't start off looking at the organ site. It starts with the mechanism. I think that will result in more rapid clinical trial accrual, smaller clinical trials, and a greater anticipated benefit.”
One of the challenges with clinical trials is that they take too long and cost too much. If pharma can reduce or eliminate Phase 3 failures, while conducting more efficient and effective trials with fewer patients, that would address both issues.
“I believe we also have to adopt 21st-century diagnostic platforms,” adds Ellis. “We need to sequence the DNA and RNA of tumors. We must also sequence proteins and understand how they are altered. This is a field called proteogenomics, and it can lead to a better diagnosis for patients. The more we know about a cancer, the better we can find the right drug for that cancer. We must use all we have learned to drive predictive medicine algorithms that match patients to the right therapy. Let’s assume that pharma companies are developing 30 antibody drug conjugates. How do we determine which patients get which antibody drug conjugate? We are going to have a matrix and will need to measure many things simultaneously and efficiently. If we can do that, we can choose the right medicine for each patient and potentially eliminate conventional chemotherapy. Wouldn't that be great?”