It was a small trial, just 18 rectal cancer patients, all of whom took the same drug. But the results were astonishing. The cancer vanished in every single patient, undetectable by physical exam, endoscopy, PET scans or MRI scans.
The patients had faced gruelling treatments: chemotherapy, radiation and, possibly, life-altering surgery that could result in bowel, urinary and sexual dysfunction. Some would need colostomy bags.
They entered the study thinking that afterwards, they would have to undergo those procedures because no one really expected their tumours to disappear.
But they got a surprise. No further treatment was necessary.
Dr Luis Diaz Jr of Memorial Sloan Kettering Cancer Centre, Manhattan, author of a paper published in the New England Journal of Medicine describing the results, which were sponsored by drug company GlaxoSmithKline, said he knew of no other study in which a treatment completely obliterated a cancer in every patient.
“I believe this is the first time this has happened in the history of cancer,” Diaz said.
Dr Alan Venook, a colorectal cancer specialist at the University of California, San Francisco, who was not involved with the study, said: “A complete remission in every single patient is unheard-of.”
“There were a lot of happy tears,” said Dr Andrea Cercek, an oncologist at Memorial Sloan Kettering Cancer Centre and a co-author of the paper.
Another surprise was that none of the patients had clinically significant complications.
On average, one in five patients have some sort of adverse reaction to drugs like the one the patients took, dostarlimab, known as checkpoint inhibitors. The medication was given every three weeks for six months and cost about $11,000 per dose. It unmasks cancer cells, allowing the immune system to identify and destroy them.
While most adverse reactions are easily managed, as many as 3% to 5% of patients who take checkpoint inhibitors have more severe complications that can result in muscle weakness and difficulty swallowing and chewing.
The absence of significant side effects, Venook said, means “either they did not treat enough patients or, somehow, these cancers are just plain different”.
The inspiration for the rectal cancer study came from a clinical trial Diaz led in 2017 funded by drugmaker Merck. It involved 86 people with metastatic cancer that originated in various parts of their bodies. But the cancers all shared a gene mutation that prevented cells from repairing damage to DNA. These mutations occur in 4% of all cancer patients.
Patients in that trial took a Merck checkpoint inhibitor, pembrolizumab, for up to two years. Tumours shrank or stabilised in about one-third to one-half of the patients, and they lived longer. Tumours vanished in 10% of the trial’s participants.
Cercek and Diaz then wondered what would happen if the drug was used much earlier in the course of disease, before the cancer had a chance to spread.
They settled on a study of patients with locally advanced rectal cancer, tumours that had spread in the rectum and sometimes to the lymph nodes but not to other organs. Cercek noticed chemotherapy was not helping a portion of patients who had the same mutations that affected the patients in the 2017 trial. Instead of shrinking during treatment, their rectal tumours grew.
Cercek and Diaz reasoned that immunotherapy with a checkpoint inhibitor might allow such patients to avoid chemotherapy, radiation and surgery.
Diaz asked companies that made checkpoint inhibitors if they would sponsor a small trial. They turned him down, saying it was too risky. He and Cercek wanted to give the drug to patients who could be cured with standard treatments. What the researchers were proposing might end up allowing the cancers to grow beyond the point where they could be cured.
Finally, a small biotechnology firm, Tesaro, agreed to sponsor the study. Tesaro was bought by GlaxoSmithKline, and Diaz said he had to remind the larger company that they were doing the study.
Their first patient was Sascha Roth, 38. A runner, she first noticed some rectal bleeding in 2019 but otherwise felt fine.
During a sigmoidoscopy, she recalled, her gastroenterologist said, “Oh no. I was not expecting this.” He had found a tumour.
The next day, the doctor told her he had had the tumour biopsied and that it was cancer.
She was scheduled for chemotherapy at Georgetown University, but a friend insisted she first see Dr Philip Paty at Memorial Sloan Kettering. Paty told her he was almost certain her cancer included the mutation that made it unlikely to respond well to chemotherapy. It turned out, though, that Roth was eligible to enter the clinical trial. If she had started chemotherapy, she would not have been.
Not expecting a complete response to dostarlimab, she planned to move to New York for radiation, chemotherapy and possibly surgery after the trial ended. To preserve her fertility after the expected radiation treatment, she had her ovaries removed and put back under her ribs.
After the trial, Cercek gave her the news. “We looked at your scans,” she said. “There is absolutely no cancer.”
She did not need any further treatment. Two years later, she still does not have a trace of cancer.
Study details
PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer
Andrea Cercek, Melissa Lumish, Jenna Sinopoli, Jill Weiss, Jinru Shia, Michelle Lamendola-Essel, Imane El Dika, Neil Segal, Marina Shcherba, Ryan Sugarman, Zsofia Stadler, Rona Yaeger, et al.
Published in The New England Journal of Medicine on 5 June 2022
Abstract
Background
Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesised that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer.
Methods
We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.
Results
A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumour on magnetic resonance imaging, F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.
Conclusions
Mismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response.
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