Stan Collender takes a work call while receiving an infusion of the immunotherapy drug pembrolizumab from Karen Haeck, RN, at Seattle Cancer Care Alliance on April 18, 2016. Collender is taking part in a national trial of the drug, led by Fred Hutch investigators, for patients with advanced Merkel cell carcinoma, a rare skin cancer.
Photo by Robert Hood / Fred Hutch News Service
He 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
Actually there wasn’t a systemic way to treat this — at least nothing
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
«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
The study, which was years in the making, was conducted at eight sites nationwide through the Fred
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 (
Pembrolizumab is a type of drug known as a checkpoint inhibitor, which blocks signals from cancer cells that can shut down
«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
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
The researchers calculated that more than
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.
‘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
«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
«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
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
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
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 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
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
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
«We’ve got this ‘glass
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
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.»
Source: http://www.fredhutch.org/en/news/center-news/2016/04/pembrolizumab-merkel-cell-carcinoma.html
