[Editors Note – The following is a guest post from @B4UConsent, a real life patient with tremendous insight into drug development from both the patient and the clinical trial management perspectives. Follow her blog and on Twitter.]
Puma Biotech (PBYI) announced last week that their neratinib NDA was accepted for review [http://www.pumabiotechnology.com/pr20160920.html] by the FDA, raising the odds that someday soon, breast cancer patients who have almost no risk of disease recurrence will continue to have almost no risk of disease recurrence, all while gaining all the pleasures of unavoidable diarrhea and a risk of “fecal incontinence.” Sleep easy, my fellow HER2-positives, but don’t forget to dose up the Imodium first.
You read that right. I have HER2-positive metastatic breast cancer. I’ve received every anti-HER2 agent on the market and completed multiple lines of cytotoxic chemotherapy. I’ve lost my hair. I’ve tried everything. And I wouldn’t take neratinib. Why bother? It’s a snore of a TKI (PD-1/PD-L1s are becoming old news, and investors are supposed to get amped about a TKI?) that perpetuates fear mongering to patients who don’t understand recurrence risk, it de-prioritizes QOL, and it indulges a wasteful healthcare system where anything other than gross inferiority must equate clinical benefit. But who’s going to prescribe this? Who’s going to take it?
The neratinib NDA is based on the ExteNET trial, a phase III design that randomized 2800 subjects to a year of neratinib or placebo. The drug is proposed as an “extended-adjuvant” treatment, initiated after the completion of the SOC year of Herceptin. A newly-diagnosed HER2-positive patient is looking at roughly 13-18 months of treatment with surgery and adjuvant chemo and Herceptin; as these patients will have experienced countless miseries over the preceding months, but not yet debilitating diarrhea, they will be in a hurry to sign up for more treatment. Because ExteNET demonstrated that neratinib increases invasive disease free survival (DFS) from 91.6% in the placebo arm to … wait for it … 93.9% in the neratinib arm. That is two percent. (For real reductions in recurrence risk, my money is on the addition of Perjeta to adjuvant Herceptin, which is currently being evaluated in the APHINITY trial.) And at five years [http://www.onclive.com/web-exclusives/neratinib-benefit-in-breast-cancer-sustained-in-5year-extenet-analysis], DFS in the neratinib arm was 90.4%, compared with 87.9% in the placebo arm. Is 2% worth the trouble? Ask a neratinib patient. She’s had a lot of time to think about it. In the bathroom. Where she was living for a year.
Nearly everyone enrolled in ExteNET (95.4% of subjects) experienced diarrhea, which is par for the course for a TKI, but, uniquely, 39.9% of neratinib subjects experienced a diarrhea event with a grade of 3 or higher. This means that there were a handful of ExteNET subjects who benefited from neratinib, but all 2800 suffered the side effects. Those of you who are enjoying your breakfast right now, look away: grade 3 diarrhea is defined as an “increase of greater than 7 stools/day over baseline, incontinence”. If that doesn’t sound so bad, consider what it would be like to go into the office with fecal incontinence. Or pretend you want to take a walk. Or leave your house. At some point in the next year. (I know what you’re thinking: where do I sign up?) Further, one patient had grade 4 diarrhea, defined as “life-threatening consequences including extremely low blood pressure as a result of severe dehydration.” To recap, there is a risk of “life-threatening” side effects when, per the 92% DFS rate at two years, the cancer itself is not life-threatening.
As these AEs raise concerns regarding both needless death and patient compliance (read: no one is going to refill this thing in a real-world setting), subsequent protocols introduced loperamide (Imodium) prophylaxis – starting at 16 mg per day – for subjects receiving neratinib. Additional analyses found that loperamide prophylaxis reduced the grade 3+ diarrhea incidence to about 16%, with 60% of all subjects reporting some diarrhea. A standard dose of loperamide is 4 mg, and 16 mg is, per the label, the maximum daily dose. That sounds like a lot of Imodium, but, you know, desperate times.
It doesn’t help Puma that the HER2-targeted space is a crowded one, and their strategy to go after early-stage patients is a transparent attempt to avoid the metastatic setting, where they have no chance of filling a single prescription. Roche has Herceptin (on-label in adjuvant and metastatic settings), Perjeta (which quickly earned a reputation as a wonder drug; it’s SOC for first-line metastatic treatment and in trials for adjuvant use) and Kadcyla (a novel antibody-drug conjugate prescribed in the metastatic setting that is also in trials for adjuvant use). In metastatic cases, when Perjeta and Kadcyla have failed, there is no consistent third-line treatment pathway. Any given oncologist is just as likely to recommend a trial, a targeted therapy identified from increasingly pervasive genetic testing or put a patient back on Herceptin + cytotoxic chemo (typically a taxane) than to prescribe Tykerb (lapatinib), a prior-generation neratinib. Tykerb followed Herceptin in HER2 approvals, and it has the dubious honor of teaching us that you never, ever remove Herceptin from the equation for a HER2-positive patient, lest you wish to hasten her demise.
The FDA has accepted Puma’s NDA, which, in the spirit of Everybody Gets a Trophy, gave the stock a bump. (Note to writers who cover healthcare for laymen: there is nothing about this routine regulatory activity that signals any sort of “approval.”) Neratinib is a drug no one needs or asked for, and if it does reach the market, you’d be better off doubling down on JNJ. You’d only need a handful of prescriptions to send loperamide sales through the roof.
[Editors Note – It is important to note that terms such as DFS (Disease Free Survival) does not mean “survival” in the lay sense, it merely means the absence of disease, one can have disease present and still be alive. Puma’s neratinib is only “benefiting” (and just barely) a tiny few more people already in remission, at a terrible cost to the vast majority of patients taking the drug.]