ALK-positive NSCLC—patient’s story opens eyes

That was the state of affairs one week later, when Dr. Tubbs looked at the results of Hiznay’s Abbott Molecular Vysis ALK Break Apart FISH assay (the companion diagnostic test to crizotinib) and realized something wonderful: Unlike almost all non-small-cell lung cancers, Hiznay’s expressed a rearrangement of the ALK gene. “This is a fairly rare event,” Dr. Tubbs says in his understated way. “I remember having the desire to tell the clinician as soon as possible, because Nate [Dr. Pennell] had let us know that this patient was really sick. The fact that I was able to give news that led to very specific therapy was exhilarating. That doesn’t happen too often in pathology.”

It took some time for the still very ill Hiznay to understand just how good the news was. “I remember I was still pretty out of it, but I realized it was good because the doctors who came in all had very excited smiles,” he says. “I remember the doctor who took care of me in the ICU said, ‘Congratulations. You’re a mutant.’ But I didn’t grasp right away how important it was.”

Because the FDA had just approved crizotinib on Aug. 26—the same day Hiznay received his diagnosis—the Cleveland Clinic had none of it on hand. A supply was shipped overnight, and Hiznay took his first dose on Sept. 10, becoming the Cleveland Clinic’s first patient to take it outside of a clinical trial. One week later, he was well enough to leave the ICU for the solid tumor oncology floor. “And on Sept. 21, I was discharged, and I walked out on my own without any oxygen,” he says. Two months later, a CT scan revealed no trace of cancer: “That was finally when I was really starting to feel well.” Since then, crizotinib has been demonstrated to be superior to standard chemotherapy in patients with previously treated, advanced non–small-cell lung cancer with ALK rearrangement (Shaw AT, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368:2385–2394).

As good as he felt during his crizotinib treatment, Hiznay knew his tumor was likely to develop resistance to the drug. “I don’t think anyone ever said it out loud to me, but I knew it was a possibility,” he says. “That worry was definitely always there.” Unfortunately, that fear became a reality in May 2012, when a biopsy of a swelling in his neck showed the cancer had returned.

Again a powerful drug was brought in to beat it back, this time an investigational compound from Novartis called LDK378, a second-generation ALK inhibitor that works in a similar manner as crizotinib. “It inhibits the ALK protein much more strongly than crizotinib,” Dr. Pennell says. “It’s very promising for patients for whom crizotinib has stopped working.” An 80 percent response rate for LDK378 in patients whose disease had progressed after treatment with crizotinib has been reported (Shaw A, et al. Results of a first-in-human phase I study of the ALK inhibitor LDK378 in advanced malignancies. Abstract No. 4400. 2012 European Society for Medical Oncology Annual Meeting, Vienna, Austria). At CAP TODAY press time, the first regulatory filing for LDK378 was expected to take place by early next year.

Hiznay received treatment with LDK378 through a clinical trial based at the University of Colorado Hospital, Aurora. As with crizotinib, he experienced quick and dramatic improvement. “I look forward to LDK378 getting on the market because it has even better results than crizotinib does for patients,” he says. But for him, those results didn’t hold. Seven months after the clinical trial, a PET scan showed his cancer was becoming resistant to LDK378.

“That is the reality of these new agents,” Dr. Tubbs says. “The tumors learn to circumvent the action of the drug through other pathways. That’s why there’s intense research right now into understanding those mechanisms of resistance and developing ways to account for that resistance and circumvent it. The good thing is that there’s new information coming out literally every week about acquired resistance and the mechanisms for potential therapeutic approaches.”

Now that LDK378 is no longer efficacious against Hiznay’s cancer, traditional intravenous chemotherapy seems to be doing the job. He began chemotherapy with bevacizumab, carboplatin, and pemetrexed last November, and in March a PET/CT scan showed that the cancer had again had a complete treatment response. Now on maintenance therapy, Hiznay hopes, of course, that the cancer won’t return—but if it does, he says that yet more treatment possibilities remain. “I’ve never had targeted radiation therapy, so that would be an option,” he says. A second round of crizotinib, in the hopes that the tumor has lost its resistance to that drug, is another possibility.

In the meantime, inspired by his own experience as a cancer patient, Hiznay has left medical school and enrolled in the Cleveland Clinic’s molecular medicine PhD program, where he’s studying the role of molecular genetics in cancer. “I kind of view myself as the poster boy,” he says. By remarkable coincidence, one of his classmates, Hannah Picariello, worked on a clinical trial for crizotinib a few years ago. The two put together a presentation about Hiznay’s experience, “It’s Personal Now: the Future of Medical Research,” which Dr. Tubbs invited them to give to the Clinic’s molecular pathology department in May.

For listeners, the talk was a rare chance to hear firsthand how critical their work is. “There was a lot of emotion in the room from the people who do the testing,” Dr. Tubbs recalls. “It’s eye-opening whenever laboratory personnel hear patients discuss their illness, because we get so isolated in the laboratory. It’s probably something we need to be more exposed to, so we never forget there’s a patient who’s going to receive the result that we are generating. We can never forget how important that is to them and their families.”

Then, too, Dr. Tubbs himself found special meaning in Hiznay and Picariello’s presentation. “Because I’ve had melanoma and prostate cancer, I had a perspective on his illness that I might not have had three years ago,” he says.

For the moment, Hiznay is concentrating on his studies, undergoing maintenance chemotherapy every three weeks and CT scans every six weeks, and staying optimistic in his belief that the development of new treatment options will outpace his cancer. “It’s very much a rapidly evolving treatment world,” he says firmly. “You just have to stay ahead of the curve.”

Anne Ford is a writer in Evanston, Ill.