First Therapeutic Approved for Rare Skin Cancer

Imagine being told you had a rare and exceedingly deadly cancer ― and, if that wasn’t bad enough, that there was not a single drug approved to treat your disease.

Tom Judd doesn’t have to imagine. He’s lived through it. After being diagnosed in 2013 with the skin cancer Merkel cell carcinoma, Judd’s cancer jumped from his face throughout his body, growing until it interfered dangerously with organ function. By early 2015, the cancer that some of his doctors had never heard of had nearly killed him despite surgery, radiation and chemotherapy.

But almost two years ago, Judd received his first of many infusions of a new immunotherapy drug called avelumab on a clinical trial, and today over 90 percent of his tumor mass has disappeared. And as of Thursday, the devastating lack of options patients like him face at diagnosis has lessened, too: Because of the data from this clinical trial, avelumab (brand name Bavencio) has become the first systemic therapy approved by the U.S. Food and Drug Administration for Merkel cell carcinoma, and the first treatment of any kind approved for metastatic MCC. This is also the first approval the immunotherapy drug has notched from the federal agency — for any disease.

“I’m so happy that I get to have quality of life. It’s huge,” said Judd, 66. “If it all went sour tomorrow, I’ve had a couple of years past the lowest point of my life where I am getting to live a happy life ― truly. I can ride bikes, I can go on hikes, I can play in my garden. I can love my grandkid. It’s a wonderful time.”

The Phase 2 trial included 88 patients like Judd who had metastatic MCC that had come back despite at least one round of chemotherapy or other treatments used off-label. Including Judd, 28 of those patients’ tumors shrank or disappeared in response to avelumab, and 23 of those 28 people have not seen their cancers grow again in the average of 10 months since they started treatment, according to the team’s most recent published data. In contrast, the typical patient with metastatic MCC has only a five percent chance of surviving without disease progression one year after starting chemo.

Metastasis is common in MCC ― the cancer spreads in about a third of patients. The federal agency has granted avelumab (pronounced a-VELL-oo-mab) a broad approval, for use in any adult or adolescent patient with metastatic MCC.

The approval as a first- and second-line therapy “is a really big deal,” said MCC expert Dr. Paul Nghiem of the University of Washington and Fred Hutchinson Cancer Research Center, who was a senior investigator on the avelumab trial. Nghiem’s team conducted foundational work on the role of immune cells in MCC that paved the way for immunotherapy trials in the disease, including a trial he leads of another immunotherapy drug as a first-line therapy in advanced MCC.

The avelumab trial, called JAVELIN Merkel 200, is led by principal investigator Dr. Howard Kaufman of the Rutgers Cancer Institute of New Jersey and funded by industry. One of its 35 sites worldwide is the Fred Hutch/University of Washington Comprehensive Cancer Consortium. Kaufman will present updated data from the trial on April 3 at the annual meeting of the American Association of Cancer Research.

In comparison to the near-zero survival rates otherwise expected in patients like those on the trial, the team’s most recent calculations, presented by Kaufman at a scientific meeting in February, project that about a third of patients on the trial are on track to survive more than a year and a half ― and counting ― without their disease progressing.

 “That’s an unheard-of number,” Nghiem said. These patients “had no hope at all of surviving, because they had failed chemotherapy already, and that really is a grim situation: immune-suppressed, and the cancer is angry and becomes resistant to additional chemotherapy.”

The researchers are now extending the avelumab trial to patients who have never received chemotherapy. Nghiem and colleagues at Fred Hutch are also studying avelumab in combination with a T-cell therapy for MCC, and they plan to present their first results from that trial later this year.

Nghiem is hopeful that such combination approaches will help to extend the success that researchers have seen with immunotherapy drugs, known as checkpoint inhibitors, in some Merkel cell carcinoma patients.

He noted that the avelumab trial tested the drug in “a worst-case scenario” ― in patients whose immune systems were suppressed as a result of chemo ― and the FDA’s broad approval means that real-world data will likely look better as patients are treated on the drug before receiving chemotherapy. But there’s still room for improvement, he said.

"Just use the best drug first, that’s clear now," Nghiem said. "But even when you do that, only a little more than half of patients will have a good response that lasts. We need to make that better.”

‘Just try and hold out a little longer’

In October 2012, while wintering in another state with family, Judd got a pimple-like bump on his face. He had already been treated for less-dangerous skin cancers, so the bump wasn’t a red flag. He got it burned off the next spring after he got back home to Idaho.

It kept coming back, and the doctors kept burning it off. Something wasn’t right, so Judd’s doctors biopsied it. It was Merkel cell carcinoma.

With his diagnosis, Judd became a member of a nightmarishly exclusive club: Only 2,000 Americans a year are diagnosed with MCC. In contrast, according to the American Cancer Society, more than 250,000 are diagnosed with breast cancer; 135,000 are diagnosed with colorectal cancer; and 87,000 are diagnosed with melanoma, which is often called the most deadly form of skin cancer. But MCC’s death rate is three times higher than melanoma’s.

Judd, a Vietnam veteran, underwent surgery and radiation at the VA, and a follow-up scan of his chest and above showed that his tumors were gone.

But Judd and his wife, Karen Judd, had consulted with Nghiem, whom they had discovered online. Nghiem recommended a full-body scan because of this cancer’s tendency to jump around.

And at Judd’s next scan, in May 2014, there it was: A large tumor in his abdomen. Suddenly, Judd had stage IV cancer.

Judd, Karen and Nghiem agreed that Judd should try to enroll in a clinical trial of an immunotherapy drug for MCC, but a trial was not yet available. So Judd started on chemo to buy more time. Meanwhile, he and Karen shut down the family landscaping business and moved from Idaho to Oregon to be closer to family.

“At that point, I decided, well, if my life is going to be this short, I want to go live next to my daughter and my granddaughter and my son-in-law,” Judd said.

In December, Judd’s skin and eyes turned yellow with jaundice ― the cancer had spread to his pancreas and was blocking his bile duct. Because of the effects of the blockage on his blood chemistry, Judd was no longer qualified for the avelumab trial, which, by then, had opened in Seattle.

His weight was dropping, he was tortured by unbearable itching and Karen began to call family and friends to tell them to come say goodbye.

“Tom is a very optimistic, positive person, and this was the first time he told me he didn’t know if he could go on,” remembered Karen, Judd’s wife of 37 years. “I was heartbroken. I told him to just try and hold on a little longer.”

Judd’s medical team tried one big shot of radiation to his pancreas to try to beat back the tumor enough to restore the flow through the bile duct, as one last chance for him to qualify for the trial.

It worked. On March 30, 2015, Judd received his first infusion of avelumab.

But by that point, Judd had developed many more tumors throughout his body, including in his kidneys, lungs, heart and liver.

‘I’m the luckiest man on this Earth’

Avelumab works by blocking a molecule on cancer cells called PD-L1 that triggers an off-switch on patients’ immune cells. Blocking PD-L1 allows the immune system to rev back up and kill off tumors.

The drug was developed and commercialized through a partnership between the drug companies EMD Serono Inc./Merck KGaA and Pfizer Inc., which jointly funded the trial. Last fall, based on data the team published at the time, the drug received special review status at the FDA, three times over: breakthrough therapy and priority review status, plus an orphan drug designation ― all designed to speed or promote the development of promising drugs that are desperately needed by patients with few other options.

Several drugs that interfere in immune off-switch mechanisms like the PD-1 pathway ― checkpoint inhibitors ― are already approved by the FDA for other cancers. Last year, Nghiem and colleagues published data from their MCC immunotherapy trial using a checkpoint inhibitor known as pembrolizumab (Keytruda) as a first-line therapy. The trial’s demonstration of durable benefit to half the patients who took it led to pembrolizumab’s inclusion in published treatment guidelines for MCC, insurance coverage and widespread use ― but no FDA approval, at least not yet.

To the investigators’ knowledge, the avelumab study is the largest-ever trial in metastatic MCC. Judd was among seven patients treated at the Fred Hutch/University of Washington Cancer Consortium by Nghiem and study site leader Dr. Shailender Bhatia; the other patients were treated at sites scattered across North America, Europe, Australia and Asia.

Among 28 of 88 patients whose tumors responded to the drug, most of the tumors shrank by over 30 percent — and eight of these patients’ tumors completely disappeared. An additional nine patients saw their tumors stop growing.

Both Judd and Karen vividly remember his first scan, six weeks after starting the experimental treatment.

All of the doctors involved in Judd’s care on the trial, with their assistants and coordinators in tow, came in to the clinic room where Judd and Karen waited for his results. This was either really good news, or really bad news, they thought, watching the parade of medical professionals cramming into the exam room. Judd was gripped with anxiety.

It was good news: Over one-third of his cancer, throughout his body, had disappeared.

“I was about in tears,” Judd recalled during a recent interview at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner. Like Judd, most patients who responded to the drug did so very quickly.

For the past two years, which saw his cancer almost reduced to nothing, Judd and his wife have driven up to SCCA every two weeks for him to receive a two-hour infusion of the drug, followed by two hours of observation.

Judd says he hasn’t experienced any side effects of note. He’s gained his weight back, and he has plenty of energy to run after his 4-year-old granddaughter when he and Karen babysit once or twice a week. This is similar to the experiences of most of his counterparts on the trial, who reported relatively mild side effects ― typically fatigue and flu-like symptoms.

This stands in stark contrast to what is common in chemo: In the mostly elderly patients with metastatic MCC, chemotherapy often causes toxic organ damage and even death. Chemotherapy is widely used off-label in advanced MCC, as it was in Judd’s case, even though there is no evidence that it extends survival. It beats back most patients’ cancers for a while but the cancer nearly always comes back in months, more aggressive than before.

Judd says that he feels “very lucky” to “live in this time and in this area that this can even happen,”

“It does make me live for today a little bit more than ever, and know that when I wake up and I’m feeling good, I’m the luckiest man on this Earth and I better enjoy it,” he said.