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Negligible Benefit Of Nerlynx, A New Breast Cancer Drug, Calls For Caution

This article is more than 6 years old.

Early last summer I received an email with this subject line: “Global HER2-positive breast cancer market to approach $10 billion in 2025, says GlobalData.” The body of the message, labeled as NEWS RELEASE, opened with a statement about the growing “market“ for HER2+ breast cancer that’s set to rise “at a compound annual growth rate of 4.4%” through 2025. This summary information, based on data for 8 countries, linked to a fuller report provided by the consulting firm, here.

I am hardly naïve about the business of health care. At some level, I appreciate the role of investors in supporting biotech and pharma companies that develop new and better medicines. Yet seeing these figures, billions of dollars to be made off of women’s bodies gone awry—HER2+ breast cancer as a business opportunity—in stark terms, and apart from any pretense of considerations about health as you’d see in a medical journal or even in a pharmaceutical ad, jarred my sense of propriety about oncology news and data.

Days later, the FDA approved a new pill, Nerlynx, as adjuvant (extra) therapy of early-stage, HER2 positive (HER2+) breast cancer. Neratinib (Puma Biotechnology) may be prescribed to lower the risk of recurrence, after surgery and a year of Herceptin plus other treatments including chemo, and in some cases hormone-blocking agents, for stage 1, 2 or 3 HER2+ tumors. In the randomized ExteNET trial, detailed in this 2016 publication, a year of neratinib, after a year of Herceptin and chemo, very slightly increased invasive disease-free survival (iDFS).

How slightly? As reported in the FDA’s July 2017 post and supplemental data, with just 2 years of follow-up, 94.2% of women randomized to receive neratinib did not experience an invasive recurrence or death, vs. 91.9% of those on the placebo. That sliver of benefit observed in the study’s primary endpoint, iDFS, 2.3%, was statistically significant. But it’s not a clinically meaningful difference, among other reasons because 2 years is too early to assess a drug’s capacity to reduce recurrences after early-stage breast cancer, even in HER2+ cases.

I considered writing on Nerlynx in July (2017). Generally, I had concerns about the potential for widespread overtreatment of women with small, HER2+ breast tumors. The NEJM had just published a paper on another drug, Perjeta, as adjuvant therapy for HER2+ breast cancer. Those data, discussed at the ASCO meeting in June, showing a similarly slim benefit in disease-free survival at around 3 years of follow-up, met with appropriate skepticism. Weeks ago, the FDA granted priority review for this indication of Perjeta (Genentech).

Upon its approval, analysts estimated Nerlynx would sell for over $10,000 per month. Today I checked GoodRx.com, and the going price seems to be around $12,000 for a month’s supply. I was also concerned about neratinib’s toxicity. (see below). I was puzzled by the fact that all 2840 patients in the ExteNET trial enrolled between July 2009 and October 2011, but as of July 2017, the median published follow-up was only 2 years.

This week, The Lancet Oncology published an update of the neratinib trial with a median follow-up of 5 years. The results are not obviously better than what was previously reported: 90.2% of patients who received neratinib remained alive and invasive breast cancer-free, compared to 87.7% in the placebo group. In absolute terms, the recurrence rates were low all-around. As detailed in the paper’s Table 3 and text, of 1420 patients in each ExteNET arm, only 91 (6.4 %) of those assigned to neratinib, and 111 (7.8%) developed distant invasive (metastatic) disease.

In sum, distant recurrences occurred in fewer than 10% of patients taking either the placebo or neratinib as adjuvant treatment after HER2+ breast cancer, with 5 years of follow-up. The observed difference in metastatic recurrence was only 1.4%. It’s worth noting that nearly a third of patients in this trial, 31-32%, had small (T1) tumors; almost 1 in 4 (24%) had no nodal involvement. It’s possible (and likely) that recurrences would be greater in patients with Stage 3 disease. It would be useful to see that data prospectively analyzed, to see if Nerlynx reduces recurrences in patients at higher risk for relapse.

The question for patients with early-stage HER2+ breast cancer is if it’s worth taking a treatment (Nerlynx) that lowers the risk of distant recurrence by less than 2% at 5 years, and which has not yet been studied over the long term. The option of taking Nerlynx should be weighed in context of standard treatment (surgery, with or without radiation, and Herceptin plus chemotherapy) for early-stage HER2+ disease, and, for tumors that are also estrogen receptor positive (ER+), hormone blocking agents.

Another disappointing aspect of the results, as demonstrated in Figure 2 of the paper and described in the text, is that the main benefit (reduced invasive recurrence) occurred in women with hormone-sensitive, HER2+ cancers. There was no improvement seen in women with hormone receptor negative tumors (Fig 2C): the rates of invasive disease-free survival for those patients were 89.8% and 88.9%. (The curves are so tight that it’s not clear from the figure which is for placebo vs. neratinib). So if you’re considering a Nerlynx prescription for adjuvant therapy of ER negative, HER2+ disease, you might want to be aware that it doesn’t seem to help.

A strength of the ExteNET trial is its size, including 2840 women with operable (non-metastatic, Stage 1, 2 or 3 HER2+ breast cancer) in 80 countries and, in some ways, its straightforwardness: it involves only two study arms: neratinib and placebo. All participants had received neo-adjuvant (pre-surgical) or adjuvant chemotherapy in addition to Herceptin prior to randomization. Some also received radiation after lumpectomy; many were and are also taking endocrine treatment for estrogen-receptor (ER) positive disease. The study received support from 3 companies: Wyeth, Pfizer, and Puma Biotechnology. 

Overall survival is not the main endpoint of this trial. But it seems reasonable, and would be reassuring, to see some information about survival trends, now that it’s 6 years after the study closed enrollment. I contacted Puma about this issue, and received the following answers from Puma’s CEO, Alan Auerbach, by email: “Overall survival is being monitored by the Independent Data Monitoring Committee (IDMC). Data regarding overall survival is not expected until at least 2020.”

Because neratinib carries a high risk of adverse events, with grade 3 toxicity affecting approximately half of patients in the neratinib arm (Table 4), I asked about the possibility that deaths could be higher with neratinib arm of the study. Here is Auerbach’s response, by email: “overall survival is being monitored by the Independent Data Monitoring Committee. If the IDMC found that neratinib was leading to a negative impact on overall survival they would have already communicated that to the company. There has been no communication from the IDMC that neratinib is causing a negative impact on survival.”

The latest report indicates Grade 3 diarrhea affected 40% of patients taking neratinib in the ExteNET trial, vs. 2% in the placebo arm. Here’s what the FDA wrote about the side effects, last July:

“Common side effects of Nerlynx include diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, swollen and sore mouth (stomatitis), decreased appetite, muscle spasms, indigestion (dyspepsia), liver damage (AST or ALT enzyme increase), nail disorder, dry skin, abdominal swelling (distention), weight loss and urinary tract infection.”

The FDA acknowledged this frequent toxicity, and in its July notice of Nerlynx approval, advised prescription of anti-diarrheal agents during the first 8 weeks of treatment, along with fluids and salt if needed: “Patients should be given loperamide for the first 56 days of treatment with Nerlynx and as needed thereafter to help manage diarrhea. Additional antidiarrheals, fluids and electrolytes should also be given as clinically indicated to help manage diarrhea.”

Now you may be wondering, why am I so concerned about side effects of a breast cancer drug? Many times, I’ve argued that toxic agents may be worth trying for people living with metastatic disease, even if those medicines haven’t yet been shown to extend life, because they can improve the quality of life, or slow a tumor’s growth and serve as a bridge, keeping a tumor in check, until a new drug is available. If you’ve got a terminal disease, trying an experimental agent that’s manufactured by a reputable company may be a very reasonable thing to do.

But here’s the thing. Nerlynx is approved to prevent cancer’s recurrence in patients who are, already, taking a lot of treatment—surgery, Herceptin, chemo, and in many cases hormone blockers—to reduce the probability of that (recurrence) happening. The threshold for prescription of adjuvant treatment should be higher, and data to support its use, clearer. When you’re giving a medication to prevent recurrence after cancer, the only things to measure—apart from toxicity, which is significant, and costs—are recurrences and survival. In the case of Nerlynx, the recurrence data are borderline, and survival data are lacking.

Yet there is a real need for better treatment of HER2+ breast cancer. The American Cancer Society estimates there will be over 252,000 new invasive cases this year. So this information, and need, applies to tens of thousands of new U.S. patients every year. HER2+ tumors tend to be aggressive and, in the absence of adjuvant therapy, recur early and not infrequently in the brain. For patients who fear recurrence, understandably perhaps the best prevention—to avoid feeling “used” by pharma, or oncologists—is to know your options, and to ask hard questions of your physicians, about the likely benefit in your case, and to invest in research, for better and less toxic remedies.

Despite my reservations, I wouldn’t write off Nerlynx entirely. It’s an interesting drug that may prove helpful in treating some cancers. It’s said to irreversibly block cell growth signals not only through HER2, but in “cousin molecules” like HER1 and HER 4. Of the Human Epidermal growth factor Receptor proteins in cancer cells, HER2 is the most studied. HER2 is amplified and implicated in 15-20% of breast cancers. Abnormal HER2 has been found in smaller fractions of colon and lung cancers, and occasionally in other tumors.

Today the ClinicalTrials.gov website indicates that Neratinib (also known as HKI-272) is being tried in 4 dozen trials of various solid malignancies, and in combinations with other agents. My enthusiasm for neratinib, which is not strong and mainly theoretical, has to do with its potential use at lower and less toxic doses, in combination with medications that could, in principle, potentiate its activity in otherwise hard-to-treat cancer types.

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