Four women had an extremely rare, aggressive and fatal type of ovarian cancer. There was no standard treatment. All four women, who lived in different countries, asked their doctors to try new immunotherapy drugs that had revolutionized the treatment of cancer. But all four of them were told that drugs were out of the question and that they wouldn’t work against ovarian cancer.
But it turns out their doctors were wrong.
According to The New York Times, the women managed to get immunotherapy and their cancers went into remission. These stories have confused scientists, who are trying to figure out why the drugs worked when they should not have. If they can figure out how this happened, they may may open the door to new treatments for a wide variety of other cancers thought not to respond to immunotherapy.
Though four women certainly don’t constitute a clinical trial, “It is the exceptions that give you the best insights,” said Drew M. Pardoll, MD, PhD, who directs the Bloomberg-Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Medical Institute in Baltimore, according to The Times. The idea behind immunotherapy is to get rid of a molecular shield that some tumors use to avoid an attack by the body’s white blood cells. Immunotherapy drugs attack that shield and pierce it, allowing the immune system to recognize and destroy tumor cells.
The new immunotherapy drugs have not always worked against many common cancers. At cutting-edge centers like Johns Hopkins and MD Anderson in Houston, researchers are looking for more answers as to why.
The recent mind-boggling success of immunotherapy with checkpoint inhibitors and CAR T-cell therapy has ushered in a clinical dilemma in the oncology wards of hospitals and medical centers across the country.
What follows is an account, factually accurate but with real names withheld, of the typical dilemma faced by patients and their doctors. It usually arises when a diagnosis of stage IV metastatic cancer leaves patients desperate for immunotherapy but clashing with treatment guidelines and a doctor’s decision to employ only palliative care.
Scenario #1: Five years ago, 60-year-old Tom was diagnosed with stage IV melanoma. At the time, checkpoint inhibitors like Keytruda (Keytruda/Merck) were experimental for the most part. Tom’s melanoma had spread from his head to his lungs. He was given 11 months to live but his oncologist advised that he seek to enroll in a clinical trial testing Keytruda. He got into the trial but didn’t obtain sufficiently positive results early enough to justify exposure to potentially dangerous and even fatal side effects.
So, after months of treatment, he found himself back at square one. Ironically, however, the oncologist heading the failed trial suggested Tom seek treatment from an oncologist at another local hospital that wasn’t a designated site for the clinical trial.
Tom’s new oncologist put him back on Keytruda. And guess what? Five years after his original, very poor prognosis, the melanoma on the top of his head had vanished; the lesion at the bottom of his head had all but disappeared, and the tumors in his lungs had shrunk by two-thirds. He’s back to where he can play nine holes of golf and his cancer, in his words, “has been neutralized.”
Scenario #2: 55-years-old Mike was recently diagnosed with stage IV metastatic gastric cancer. His cancer has been genetically profiled and his oncologist told him there were “no actionable mutations,” meaning there would not be treatment with immunotherapy.
Instead, he is on a first-line chemotherapy called 5-FU. Surgery has been ruled out because of the extent of the cancer’s spread within his abdomen. As a result, Mike feels very much like he is on palliative care only, as the overall 2-year survival rate for his particular gastric cancer is just 4%. This means, of course, that 96% of patients in a similar status don’t live that long.
One of Mike’s friends with a background in medical research suggested he get the tumor screening report and see for himself what were its conclusions. On the very first page of the report, under “Biomarker Highlights,” the tumor specimen tested “Positive for PD-L1,” a biomarker closely associated with the best potential responses for immunotherapy with checkpoint inhibitors such as Keytruda.
Again, on page 1 of the report, under “Therapies with Potential Benefit,” Keytruda is the first indication. Understandably, Mike interpreted this to mean that the screening lab is telling any oncologist reading the report that in the lab’s opinion, Keytruda is Mike’s most promising potential therapy. And yet Mike’s oncologist had told him he didn’t qualify for that or any other immunotherapy.
Mike was stunned. He gave the tumor report to his friend and asked him to analyze it. His friend noticed that the report cited two footnotes, #28 and #29, as references for the recommendation for Keytruda in Mike’s particular situation. Footnote #28 references the 2017 study, “KEYNOTE-059: Efficacy and safety of pembrolizumab (Keytruda) alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal cancer.” Here was one of the key conclusions:
In patients like Mike with advanced stomach adenocarcinoma:
“pembrolizumab monotherapy showed promising antitumor activity …in previously untreated patients with PD-L1–positive tumors.”
The National Cancer Institute also addressed the KEYNOTE-059 trial, focusing on the 148 patients who had tumors that expressed PD-L1. NCI’s report noted that many of the partial and complete responses seen in these patients persisted for long periods, ranging from just a few months to more than a year.
“The responses really are quite robust and far longer than you would see with any cytotoxic chemotherapy agent,” said the lead investigator of Keynote-059, Charles Fuchs, MD, MP, director of the Yale Cancer Center. The results confirm suggestions from earlier studies that Keytruda, “…is clearly active in patients with gastric cancer,” Fuchs added.
In other words, Mike was a perfect candidate for immunotherapy with Keytruda.
Through a mutual friend, I introduced Mike to Tom who counseled Mike to seek another oncologist; one more amenable to treating him with immunotherapy.Steve's Take: With #immunotherapy get the information you need to explore alternatives, and perhaps choose one that runs counter to your doctor’s treatment. Easier said than done; I know from experience. Click To Tweet
The caveat is that drugs such as Keytruda have side effects ranging from a mild rash to a catastrophic immune response that not only kills cancer cells but healthy tissue in vital organs. In some cases, treatment actually kills the patient. Oh, and they are expensive. Checkpoint inhibitors like Keytruda have a list price of $150,000 a year.
Mike is an ultra-marathoner. He’s also a happily married family man. His thinking is that he doesn’t want to wait until he’s too weak from chemotherapy to undertake immunotherapy, which could potentially buy him more time. He is more than willing to accept the risk of potential side effects as opposed to being on palliative care, with little prospect of surviving to his 60th birthday.
Tom and Mike are illustrative of the need to self-advocate in this new era of wonder drugs and “personalized medicine,” especially with cancer. My take is, you never want to believe that your doctor has given up on you, but sometimes they don’t tell you what your true prospects of survival are. You can be on palliative care but not know it.
It’s my observation with both Tom and Mike that the best approach when one has been labeled “terminal,” is the most direct one, meaning ask the tough questions. Like, how much time have I got.
It’s only then that you might get the information you need to explore alternatives, and perhaps choose one that runs counter to your doctor’s treatment. Easier said than done; I know from experience. But with time otherwise running out, often in a matter of weeks, be direct. You are entitled to the truth, and you will get it.