When a new form of cancer treatment known as cancer immunotherapy first hit the spotlight, it came with a big promise.
In the case of Jimmy Carter, the treatment led the former president to a cancer-free life in his 90s. But other patients haven’t had the same kind of response.
Unlike chemotherapy, which involves administering powerful drugs that kill both cancerous and healthy cells (most of which can repair themselves), immunotherapies are designed to help the immune system identify and knock out just the cancerous cells. Immunotherapy can come with its own set of side effects in which the unleashed immune system goes after healthy parts of the body.
And a majority of patients don’t respond to the treatment. For example, roughly 30% of metastatic melanoma patients using an immunotherapy called Keytruda — the same one Carter used — respond completely. That’s better than the average response rate of chemotherapy treatments on their own in cases of metastatic melanoma, though most patients still aren’t responding.
It’s led researchers to look at how combinations of these immunotherapies (often called I-O) might be able to boost those responses. And in some cases, it’s worked — but not nearly all.
“I think we all have seen the activity of combining I-O with I-O, with CTLA4 plus PD-1, where there’s a toxicity penalty,” Pfizer’s senior vice president and head of immuno-oncology, early development and translational oncology Chris Boshoff said during a discussion with reporters in May at Pfizer’s New York office.
Yervoy and Opdivo, the treatments that inhibit the protein receptors CTLA4 and PD-1, respectively, have been approved in combination to treat melanoma and a form of kidney cancer. But the combination also increases the toxicity, or amount of harm done to the body because of the treatment.
And so far, that’s the only immunotherapy-immunotherapy combination that’s had a big success. “Beyond that, there’s actually currently very little I-O, I-O that’s showing meaningful benefit,” Boshoff said.
For example, cancer drugmaker Incyte said in April that a key trial combining its cancer immunotherapy drug with a blockbuster drug from Merck failed in a late-stage trial, news that sent Incyte’s stock tumbling. The trial was looking to see if combining two drugs — Merck’s Keytruda, also a PD-1 checkpoint inhibitor, and Incyte’s IDO1 inhibitor — that both essentially take the brake off the immune system to go after the cancer cells in people with metastatic melanoma could work even better than Merck’s drug alone.
The immunotherapy-immunotherapy combination strategy hasn’t worked yet for Pfizer, either. The company didn’t hit a key marker in an early trial that was evaluating its approved immunotherapy, Bavencio, and one of its experimental immunotherapies that’s meant to accelerate the immune response.
So Pfizer’s paying more attention to a different approach: combining immunotherapies with some of their targeted cancer treatments, with the hope that the one-two-punch might get more promising results.
Trying other cancer drug combinations
Targeted cancer therapies work by locking onto a particular molecule to keep cancer from spreading. They also differ from chemotherapy, which works by killing all fast-dividing cells.
While their primary purpose is to block cancer progression, early research suggests that these targeted therapies might manipulate the body’s immune response. Ideally this means that targeted cancer drugs could make the body better at responding to immunotherapy.
Take PARP inhibitors, a class of drugs that block a particular enzyme that’s used by our cells to repair DNA so that tumors can’t survive. In certain kinds of cancer that repair system is broken which allows cancer cells to thrive — so blocking it is critical.
These PARP inhibitors tend to work well in cancers that have a BRCA mutation, such as breast cancer. Those tend to have more mutations present in the tumor as well as T-cells, a key part of the body’s immune system that are able to respond to the cancer, Boshoff said.
“It happens that those tumors that respond to PARP inhibitors are also cancers that could benefit from an immune checkpoint blocker,” Boshoff said.
And the introduction of the PARP inhibitor could have an effect on how the body’s immune system responds to the cancerous cells. “Separately PARP inhibitors themselves appear, pre-clinically at least, to activate immune response,” he said.
Pfizer is exploring how a combination of its PARP inhibitor talazoparib and its immunotherapy Bavencio work in clinical trials. The company is also conducting trials to see how its other targeted cancer drugs work in combination with immunotherapy, including Xtandi for prostate cancer, Ibrance in breast cancer, and Inlyta in kidney cancer.
‘It’s a journey’
At the same time, companies like Bristol-Myers Squibb are working on figuring out if there are some cancer patients that might respond better than others to immunotherapy-based combinations. For example, that might mean patients with more mutations in their tumors, known as called tumor mutation burden. The idea is that the more mutations a tumor has, the more likely the immune system will be able to recognize and go after it.
“It’s a journey. What you’re seeing today is the tip of the iceberg,” Dr. Fouad Namouni, oncology development head at BMS, told Business Insider in April. “More work is needed to better understand this disease and continue to bring combinations like Opdivo and Yervoy to patients. But not every patient’s the right patient in our case.”
Because there’s still so much we don’t know about cancer immunotherapy and why some people have great responses and others don’t, Pfizer also hasn’t given up on its combination immunotherapy trials, including one that combines three different immunotherapies that go after PD-1, OX-40, and 4-1BB.
But after what Pfizer’s learned over the past few years, it might mean focusing on certain subsets of patients that respond the best to the combinations.
“It gives us a clue as to possible precision approaches to optimize the activity of OX-40 and 4-1BB” Pfizer’s senior vice president and group head of oncology research and development Bob Abraham said.
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