With the right molecular signal, a cancer drug works in every patient


SAscha Roth was in her late 30s and feeling great. Then she noticed some bleeding when she used the bathroom. She went to see a gastroenterologist, who diagnosed her with rectal cancer. Her doctor, she recalled, “was as shocked as I was.”

A friend who had had colon cancer insisted Roth see her surgeon at Memorial Sloan Kettering Cancer Center. That led to her becoming patient no. 1 in a study that is a striking example of the importance of efforts to test cancer drugs in earlier stages of disease.

As part of the study, Roth received the cancer drug Jemperli, made by GSK. The treatment made her cancer shrink until it was undetectable — what doctors call a complete response. It did the same for the 13 other participants in the clinical trial, all of whom, like Roth, had locally advanced rectal cancer. So far, all of them have been spared radiation, chemotherapy, and disfiguring surgery that often involves the removal of the rectum.

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The results are unprecedented and well beyond what the doctors conducting the study expected.

“What’s really remarkable is this is the first time I know of in solid tumor oncology where we’ve had a 100% complete response, and we’ve completely omitted the normal standard of care,” said Luis Diaz, head of the division of solid tumor oncology at Memorial Sloan Kettering and one of the doctors who designed the study.

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Sasha Roth Courtesy Sascha Roth

Results from the trial were presented Sunday at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine.

All of the patients in the study had a rare genetic signature in their tumors, known as mismatch repair deficiency. This means that cells are not as able to repair errors in DNA, a process that can lead to cancer. Eight of the 12 patients described in the New England Journal paper, including Roth, had Lynch syndrome, a genetic condition that causes mismatch repair and carries a much higher risk of colon cancer; Roth believes the condition may be why her father developed brain cancer, which killed him.

Immunotherapy drugs such as Jemperli or Merck’s Keytruda are thought to work against such cancer because all those changes in DNA make it easier for the immune system to learn to recognize and attack a tumor.

The study’s approach built on previous work by Diaz, who pioneered the development of Keytruda, to treat patients with mismatch repair deficiency. In May 2017, the Food and Drug Administration granted accelerated approval to Keytruda as a treatment for patients whose tumors had spread beyond their original location and tested positive for mismatch repair deficiency.

That was a historic moment, the first time the FDA granted an approval to use a drug to treat cancer based entirely on a genetic difference with no regard for where in the body the cancer originated. It meant doctors would treat the tumors as mismatch repair deficient cancer, not rectal, breast, or colon cancer.

But Diaz had been looking for a way to test moving Keytruda or a drug like it, known as a checkpoint inhibitor, in patients whose cancer had not spread. In late 2017, he joined Memorial Sloan Kettering as head of solid tumor research, and had his first meeting with Andrea Cercek, now co-director of Memorial Sloan Kettering’s center for young onset colorectal and gastrointestinal cancers.

“You know that our patients, once they have cancer even the lucky ones who survive, live with that forever,” Cercek told STAT. “They live with the toxicity and the sequela of the treatment to some degree.”

In that first meeting, Cercek remembers, she told Diaz she wanted to study immunotherapy in mismatch repair patients. She wanted to spare them radiation, chemo, and surgery. More than that, she had noticed that it seemed these patients were doing worse than others on chemotherapy. “Write it,” he said, telling her to design the trial.

Diaz said that he shopped the study around to drugmakers, but had little interest until he talked to the top executives at a small biotechnology firm called Tesaro, Lonnie Moulder and Mary Lynne Hedley.

For drugmakers like Merck, mismatch repair deficiency may have seemed a curiosity. It was large indications such as melanoma and lung cancer that were making drugs like Keytruda among the world’s bestsellers.

But Moulder had a history of finding small niches for drugs that allowed them to compete with much larger companies. Tesaro funded the study. Later on, it was purchased by GSK, which was interested in a different medicine the company had developed. When Jemperli was approved, it was the seventh such immunotherapy drug, known as a PD-1 inhibitor.

For the patients in the Memorial Sloan Kettering study, including Roth, it was plenty effective. Initially, when Cercek enrolled her in the trial, Roth had expected to move to the New York area for radiation and chemotherapy that would follow her treatment. She had surgery to move her ovaries in order to protect them from the radiation. But her cancer became undetectable, and the Memorial Sloan Kettering doctors decided to change the study so that they would not require radiation, chemotherapy, or surgery. Just six months of immunotherapy treatment was enough by itself.

Outside experts say that the study is still too small to change the way patients with mismatch repair deficiency are treated. “These results are cause for great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Hanna K. Sanoff, an oncologist at the Lineberger Comprehensive Cancer Center at the University of North Carolina, wrote in a New England Journal editorial accompanying the study.

One worry is that although so far none of the tumors has come back, they could. Perhaps eliminating chemotherapy, radiation, and surgery is a step too far. But all those treatments, Diaz points out, come with significant downsides.

“To get these kinds of responses and still consider doing standard of care or doing radiation, in my mind I don’t think that’s appropriate,” said Cercek. She agrees that longer follow-up is needed, but also notes that it is incredibly unlikely to get 14 complete responses in a row. If a patient’s cancer does come back, radiation and surgery are still options.

Hesham Abdullah, GSK’s global head of oncology development, said in a statement that the company plans “to further expand the clinical study in this neoadjuvant setting.”

Cercek said that she has been moved by watching patients recover, and seeing many of them in basically the same health as they were when they were diagnosed.

“There’s absolutely nothing more rewarding than this,” she said.



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