• Researchers seek clues in those who respond better to new drug
  • ‘It’s a piece of the puzzle,’ professor Padmanee Sharma says

Mark Perkins considers himself a poster child for the new generation of cancer drugs that harness the patient’s immune system to attack sick cells. Two years after trying Merck & Co.’s Keytruda -- and almost four years after receiving a prognosis of as little as six months left to live -- he is cancer free.

The 56-year-old grandfather’s case is more than a success story for a new class of treatments that have fewer side effects than standard chemotherapy. It’s also at the frontier of what could possibly lead to a new approach to treating cancer, if it turns out that patients who, like Perkins, have many more mutations in their tumors than the average have a better chance of responding to immunotherapy.

Drugs like Keytruda, known as checkpoint inhibitors, have produced dramatic responses in some advanced cancer patients, but doctors still don’t understand why only about 20 percent gain long-term survival. Researchers say looking at the mutation load for answers makes scientific sense, because these drugs work by taking the brakes off the immune system’s killer T-cells, unleashing them to go after cancerous cells. In theory, the more mutations a cancer has, the more foreign it will appear to the newly enhanced immune cells.

“It’s a piece of the puzzle, we need to put all the pieces together to figure out which patients will respond,” said Padmanee Sharma, professor of genitourinary medical oncology and immunology at the University of Texas MD Anderson Cancer Center in Houston. Having more mutations is “like the lottery, if you buy 300 tickets you have a higher chance of winning than if you have just one.”

New Regimen

Cancer is caused by changes in the DNA that make cells grow and multiply out of control. While all cancers are caused by genetic mutations, doctors only recently started to study the subset of patients who have a high number of mutations. If further studies confirm they respond well to immunotherapy, doctors could define new treatment regimens, says Alexandra Snyder, an oncologist at Memorial Sloan Kettering’s Cancer Center in New York.

“So we could say, ‘if you’re in the top percentage of mutation burden, you should go to treatment X, if you’re in the middle, you should use X plus Y,’” she said.

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Until recently, researchers had focused on patients who have high levels of a protein called PD-L1, which is related to the marker targeted by the checkpoint inhibitors. Yet doctors were baffled to find some patients with low levels of PD-L1 who still respond to the drugs. Factoring in mutation levels could open up opportunities for patients who had so far not been considered for immunotherapy drugs like Keytruda or Bristol-Myers Squibb Co.’s Yervoy and Opdivo.

That would include patients like Perkins, who was diagnosed in August 2012 with cancer of the duodenum, part of the small intestine -- a form of cancer Keytruda isn’t approved for. Perkins went through several rounds of chemotherapy before a new doctor noticed that earlier genetic tests showed he had micro-satellite instability -- known as MSI, a sign of extremely high mutational burden in tumors. He enrolled Perkins in a trial by Luis Diaz, an associate professor of oncology at Johns Hopkins Medicine.

Diaz first surmised that mutations might play a role in why certain patients responded to checkpoint inhibitors around 2010. He initially had a hard time finding a drugmaker to participate in a study, until Merck agreed to supply Keytruda for a trial and a cancer fundraising organization, Swim Across America, provided funding.

High Mutational Loads

In the two-year study that started in 2013, Diaz found that 60 percent of patients with MSI responded to checkpoint-inhibitor therapy. That compares with the 20 percent to 30 percent of skin and lung cancer patients -- two types of cancer Keytruda is approved for -- who typically respond, he said. Diaz estimates that about 4 percent of patients with metastatic cancers have high mutational burdens and could benefit from using checkpoint-inhibitors drugs, equating to almost 24,000 people in the U.S.

While testing for MSI can easily be done when doctors collect tissue samples to study other markers, it’s not done regularly -- something that Diaz hopes will eventually become routine.

Perkins started on Keytruda in July 2014 and since three months after starting the drug, there has been no evidence of cancer in various exams of his gastrointestinal tract.

“None of us knows whether we’ll have tomorrow, but clearly I’m in the physical condition now and showing now that it’s likely if I don’t get something else or a recurrence, there’s a great likelihood that I’ll live another 20 or 30 years, or more possibly,” Perkins said.

‘Cried a Little’

Some studies suggest environmental factors can cause more mutations than average in patients: melanoma patients who have had lots of exposure to the sun, for instance, or lung cancer patients who were smokers. It’s too early to generalize that patients whose cancer was driven by lifestyle factors will fare better with checkpoint inhibitors. But patients like Nancy Pinkston, a 67-year-old retiree in Dallas, may help find the answer.

In January, Pinkston discovered a lump under her arm when showering. She was diagnosed with melanoma, which had spread to her lymph nodes.

“I’m sure it comes from the sun,” she said. “When I was a kid, I didn’t know about sunblock.”

Her oncologist suggested that she enroll in a trial testing Bristol’s Opdivo, which had only been approved for a more advanced form of melanoma than she had. When the treatments were done in May, Pinkston went for a scheduled surgery.

“There was no cancer, just dead cells,” Pinkston recalled the surgeon telling her. “I cried a little and she cried a little and we hugged.”

The trial, which is ongoing, will retrospectively analyze the patients’ mutational load and other biological makers, to see if there is a correlation with responses.

Pfizer Drug Cocktail

In the meantime, drugmakers are moving ahead to capitalize on the findings. Pfizer Inc. plans to combine a checkpoint inhibitor with two drugs in development that stimulate the immune system. The goal is to assess whether the three-drug cocktail works on a variety of tumor types for patients with a high mutational burden.

Pfizer hypothesizes that by adding drugs that stimulate the immune system, the combination will help the “survival” of immune cells, which typically “get exhausted after a while,” said Chris Boshoff, head of the company’s immuno-oncology program.

Regulators are also paying attention. The U.S. Food and Drug Administration’s acting director of the Oncology Center of Excellence, Richard Pazdur, said the mutational-load findings are a significant discovery.

“I look at it from a patient’s point of view,” he said, recalling data from refractory bile duct cancer patients. “It was a small number of patients, but it was a very high number of patients that had a response, and I was thinking ‘Everybody who has this disease should get tested for what their MSI status is.’”

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