First, the cancer was on the bridge of his nose. Surgery took care of that. Then, there was a tumor under his jaw: more surgery, plus eight weeks of radiation. A few months later, a routine scan caught another in his brain. More surgery and radiation. Several months more, and two tumors popped up under the skin of his chest.
He had had enough. Stan Collender had refused to acknowledge that the grim statistics of his rare skin cancer, Merkel cell carcinoma, were relevant to him; but now his usually boundless optimism was starting to falter.
“There’s gotta be some systemic way to treat this. Because all we’re doing is playing Whack-A-Mole: We’re waiting for things to pop up and then we’re going after them. This is not acceptable,” the PR exec and Beltway pundit remembers telling his Washington, D.C., doctor.
Actually, there wasn’t a systemic way to treat this — at least nothing FDA-approved. Collender, now 65, is one of the 2,000 Americans who are diagnosed each year with Merkel cell carcinoma (MCC), which kills one of every three people who develop it. Once the cancer spreads widely, or metastasizes, survival rates plummet, and patients are typically treated with chemotherapies used off-label.
Instead, Collender followed a tip from his doctor and — guided by both hope and desperation — flew across the country to Seattle to join a new trial of the immunotherapy drug pembrolizumab, led by Dr. Paul Nghiem, head of the Division of Dermatology at the University of Washington.
Nghiem, who is also an affiliate investigator at Fred Hutchinson Cancer Research Center, and his colleagues released on Tuesday their latest results from the trial, which experts in the field say are helping to transform the way this disease is treated. In this small study in 26 participants, just over half the patients with advanced cancers saw their tumors shrink or disappear after receiving the immune-boosting drug as a first-line systemic therapy. More notable to Nghiem is that the results of treatment seem, so far, to be lasting longer on average than what is typically seen with chemotherapy.
“The claim to fame on this is not that it works a whole lot better than chemo upfront. That’s not the case. It’s pretty comparable,” Nghiem said. However, “it’s probably less toxic in the short term, it’s not immune-suppressive, and among the people who respond [in this trial], the vast majority stay in response. It’s really looking pretty different.”
The study, which was years in the making, was conducted at eight sites nationwide through the Fred Hutch-based Cancer Immunotherapy Trials Network, in partnership with the National Cancer Institute, which sponsored the trial, the NCI’s Cancer Therapy Evaluation Program, and drugmaker Merck.
The trial network is led by Dr. Martin (Mac) Cheever of Fred Hutch and UW, who was “pleasantly surprised and quite thrilled,” he said, by the high number of patients whose immune systems revved up to fight this unusually aggressive cancer after taking the drug, at rates not seen in trials of single immunotherapy agents in other advanced cancers.
“It’s quite remarkable that one agent that unleashes T cells that are already in the body can have such a profound effect in many of the patients,” Cheever said. However, he cautioned that data are still being collected on just how long these participants’ immune systems will manage to keep their cancers in check.
“We don’t yet know how durable these responses are, but our presumption is that they will be quite durable in some patients,” he said.
The investigators presented the results of the Phase 2 trial at the annual meeting of the American Association for Cancer Research in New Orleans. The data were published simultaneously in The New England Journal of Medicine.
This research is “highly anticipated” in the MCC field, said expert Dr. Manisha Thakuria, director of the Merkel Cell Carcinoma Clinic at the Dana Farber/Brigham and Women’s Cancer Center, who was not involved in this trial.
“We’re excited that we can use this class of medications in Merkel cell patients — which I think we’ve all suspected for a long time — but finally this is the data we’ve been waiting to see,” she said.
Unleashing immune cells against cancer
Collender was one of 26 people with advanced MCC who received pembrolizumab (also known by the trade name Keytruda) on this trial starting in early 2015. They all had either metastatic (far-flung) or locally recurrent cancers that could not be treated with surgery or radiation therapy. None of them had previously received chemotherapy, which suppresses the immune response.
Pembrolizumab is a type of drug known as a checkpoint inhibitor, which blocks signals from cancer cells that can shut down MCC-targeting T cells. Instead, it allows these immune cells to stay activated and kill tumors. And in MCC, research has shown, the immune system seems to be key.
“Paul Nghiem, who’s one of the world’s experts in Merkel cell cancer, has shown T cells play a role in prognosis of patients,” Cheever said. “Because of Paul’s work, we wanted to try anti-PD1 [the type of checkpoint inhibitor pembrolizumab is] — an agent known to unleash existent T cells that are already there, but [which] have not expanded to the extent necessary to get at the cancer.”
On the study, participants received infusions of pembrolizumab every three weeks. Similar to what has been seen in chemotherapy for this disease, around half (56 percent) of the patients’ cancers responded to the drug. However, of the 14 patients in the trial who had confirmed responses to pembrolizumab, 12 still had tumor regressions between two to 10 months later, when the scientists analyzed their data for publication.
Furthermore, the therapy triggered anti-cancer immune responses in participants with two very different types of MCC — one type caused by the Merkel cell polyomavirus, the other caused by extensive DNA damage from UV light exposure.
The researchers calculated that more than two-thirds of patients on the trial would have at least six months after treatment without their disease progressing. In contrast, previous research has shown that chemotherapy only keeps this cancer at bay for an average of three months; by 10 months after starting chemotherapy, over 90 percent of patients will have had their disease return, typically more aggressive than before.
Nghiem sees these results as “some light coming in” to this challenging disease.
“It’s just happy for patients who have this admittedly uncommon disease — finally resources came together to do a trial that’s finally showing hope,” Nghiem said.
Collender, one of these patients, is now about a year out from his first infusion.
He remembers being “a total basket case” before his first scan on the trial, on July 21, 2015, to see the effects of the treatment. And for good reason: “If this didn’t work there wasn’t anything else,” he said. While he suspected that the tumors on his chest might have shrunk, the big worry was whether any more tumors had shown up in his brain.
He still has the text sent him by the trial’s Seattle site leader Dr. Shailender Bhatia, about an hour before his official appointment to review the scan: “Your scan results look FANTASTIC!” Bhatia texted. (He added a smiley-face emoji for emphasis.)
‘The field changed overnight’
Last September, Nghiem presented preliminary data from the trial showing potential benefit of pembrolizumab in MCC, and “the field changed overnight,” he said.
The preliminary data made it easier for MCC patients to access this and similar drugs off-label, he said, and it generated increased interest among multiple pharmaceutical companies to study checkpoint inhibitors in this cancer.
“It’s just been an amazing transition to watch — from desperately trying to get even the tiniest little pharma to pay a tiny bit of attention and do some tiny little thing, to now,” Nghiem said. “It’s not going to be a struggle anymore: There’s going to be trials, there’s already hope, and we can build on the 50 percent of people who benefit.”
Nghiem said that for many years, he has tried to avoid using chemotherapy to treat his MCC patients, except in specific circumstances, due to its immune-suppressing effects. He envisions the results of this trial changing how other physicians use it, too.
“Chemo is not going away, but in my opinion I think it’s going to be used in a more appropriate setting,” such as palliation, he said. “I think immune therapy will be Plan A. I do think that’s the case, unless there’s some contraindication” — such as when a patient must take immune-suppressing drugs because of a transplanted organ.
A Merck spokeswoman declined to comment on any plans for pursuing FDA approval of pembrolizumab in MCC. Another checkpoint inhibitor with a related mechanism of action, called avelumab (developed by Merck KGaA and Pfizer), has received special designations from the FDA for accelerated development in MCC based on the preliminary results of a trial in patients who had previously been treated with chemotherapy.
‘They are doing great’
Collender is one of 14 trial participants who continues to receive the drug on the trial because his cancer is still responding. He was in Seattle over the past few days to see his team at Seattle Cancer Care Alliance, Fred Hutch’s patient-care arm, the local site of this trial.
After additional trial sites came online, Collender could have switched to a site within driving distance of his home in McLean, Virginia. But he was so impressed with his Seattle team, he said, that he continued his grueling schedule of regular cross-country flights: Every three weeks, he flies to Seattle Sunday night, then has bloodwork at 8 a.m. Monday morning, followed by a meeting with the doctor and pembrolizumab infusion through his chest port.
During infusions he often holds conference calls with his clients or gives radio interviews about his area of expertise — federal budget issues — all while the people he speaks to remain unaware of what is going on on his end of the line. Then, he hops on the 2 p.m. flight back to D.C., where he works over the plane’s WiFi.
“It’s like a full day in the office,” he said, with satisfaction.
The only side effect from treatment Collender has really noticed is some minor gastrointestinal issues that he can control with over-the-counter meds. He’s continued his aggressive workout routine — he boasts of doing two hour-long spin classes in a row — throughout treatment.
Collender’s experience on pembrolizumab — feeling pretty good — is fairly common among the 10 trial participants Bhatia has cared for at the Seattle site, the medical oncologist and UW professor said.
“They are doing great, their quality of life is excellent,” Bhatia said. At the advanced stage of this disease, the goal of care is longer life with a maximal quality of life. So what he has seen in those receiving the trial drug is especially striking in contrast to what many patients experience on chemotherapy, including nausea, vomiting, hair loss and infectious complications due to immune suppression: “We don’t see any of that,” he said.
“It’s remarkable how well-tolerated it is in most of the patients,” Bhatia said.
Trial participants most commonly experienced fatigue after treatment, the investigators reported. Two participants each experienced one very serious adverse event — inflammation of the heart muscle or elevated liver enzymes that can be a sign of liver problems. Both of these conditions got better after the patients were taken off pembrolizumab, and — “excitingly,” Nghiem said — their immune systems still continue to control their cancers, many months after stopping the drug.
Being on pembrolizumab for a while “just tipped the scales,” Nghiem said. “And then the immune system got back to the upper hand.”
A glass half-full
The investigators are currently recruiting more patients to the trial and gathering more follow-up data on those already enrolled. But as promising as the results of this trial are so far, it is only the beginning, the investigators said.
“We’ve got this ‘glass half-full, half-empty’ thing. There’s a lot of progress from this, but half the people are not benefiting,” Nghiem said.
Researchers now have to determine a way to predict which patients are likely to benefit from the drug, Nghiem and Cheever said, and how to improve the therapy so it works as long as possible for as many patients as possible.
The investigators suggested that combining multiple types of checkpoint inhibitors, or combining a checkpoint inhibitor with radiation, could result in synergistic effects. Another possibility is to use a vaccine to train the body to mount an immune response to the cancer that then could be boosted with a checkpoint inhibitor. Nghiem is also collaborating with Dr. Aude Chapuis at Fred Hutch on strategies to treat patients with both checkpoint inhibitors and infusions of cancer-fighting T cells.
Cheever said that it makes most sense to think of pembrolizumab as the “backbone” for future treatments for MCC, rather than the final answer — especially given promising results seen in trials of combination immunotherapies for another skin cancer, melanoma.
“The data in melanoma give great hope that this type of drug that unleashes immune cells will provide the basis for even more effective therapies” in MCC, Cheever said.
Changing the odds
After his experience on this trial, Collender is now an impassioned advocate for participation in cancer clinical trials. “I am not a lab rat,” he wrote in a 2015 New York Times editorial. Instead, he sees himself as a test pilot, a research collaborator, a pioneer. Most of all, he said, he sees himself as a patient receiving expert treatment for his disease.
He joined the trial to access care he hoped would save his life. And he is living: He and his wife are looking forward to an upcoming European cycling vacation, he gets up early to work out with his personal trainer, and he continues his breakneck work schedule — squeezing in his recent visit to Seattle between business trips to Hong Kong and London.
He estimates that there was a less than 1 percent chance that all the necessary elements came together at just the right time for him to be able to get on the trial.
“If this trial started six months later, I probably wouldn’t be here right now talking to you,” he said.
“Needless to say, I’m pretty happy about it,” he added. “But what I’m really happy about is that if this continues to work for me and others as it has been, there won’t be a less than 1 percent chance of someone getting the drug who needs it.”
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Susan Keown is a staff writer at Fred Hutchinson Cancer Research Center. Before joining Fred Hutch in 2014, Susan wrote about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at skeown@fredhutch.org or follow her on Twitter at @sejkeown.
