HER2+ BC: A Year in Review and Updates from SABCS - Episode 5

SABCS 2020 Updates: ExteNET and CONTROL Trials

Updated findings on the use of neratinib for HER2+ breast cancer from the 2020 SABCS Virtual Symposium.

Hatem Soliman, MD: Interesting information was presented regarding updates on the ExteNET trial, which was the adjuvant therapy using neratinib for patients with early stage HER2+ breast cancer.

Andrew Seidman, MD: ExteNET was the trial that led to FDA approval of neratinib to be administered for 1 year following a standard chemotherapy regimen, with a year of trastuzumab. It was conducted in the prepertuzumab space; the patients did not get pertuzumab. It was a large study of nearly 3000 patients. The study was remarkable because it was 1 of the first times a drug was approved for early breast cancer before it got approved for stage IV breast cancer.

With a median follow-up of a little over 8 years, thus far there has not been any emerging difference in overall survival. The hazard ratio is 0.95 in the intent-to-treat population. Based on the DFS [disease-free survival] data, the hazard ratio for the hormone receptor–positive group was 0.8, but confidence intervals overlapping 1, still with not enough events to power that subset. And there are reasons to suspect that the concurrent use of adjuvant aromatase inhibitor with this TKI [tyrosine kinase inhibitor] might offer preferential benefit in that group of patients. For the moment, it’s disappointing, but it’s still early. Ultimately, we will have to see if there’s a subset of patients—for example, higher-risk patients, hormone receptor–positive patients—who might benefit.

A descriptive analysis suggests a benefit in those patients who had residual disease after neoadjuvant chemotherapy, but we have the data from KATHERINE, which was a trial specifically designed to address that population. The other provocative finding was that there were fewer CNS [central nervous system] events in the neratinib group vs the placebo group. This observation motivates the migration of HER2 kinase inhibitors into the adjuvant and neoadjuvant space because we still have to confront that place as a sanctuary for distant metastasis.

Hatem Soliman, MD: I had a patient on KATHERINE who unfortunately had a relapse in the CNS, and she fought her disease valiantly for a number of years before dying. It was difficult because you had the sense that there was that unmet need. You hoped tyrosine kinase inhibitors, other small molecules, may be able to get into the brain parenchyma a little better and prevent relapses. Looking at some of these other subset analyses, descriptive analyses, this provides some provocative data around when we would try to escalate, but it brings us to an issue around the use of neratinib. There are updates on the CONTROL regimen and how that could improve the supportive care and tolerability of neratinib and its use.

Andrew Seidman, MD: CONTROL is a study with many cohorts, and they’re all designed to try to make neratinib more deliverable in terms of dealing with diarrhea, which can cause dose reductions, dose delay, or dose interruption. We’d already heard about several of the cohorts involving colestipol and budesonide as effective means in addition to loperamide, the gold standard in reducing diarrhea. What was reported on at San Antonio [Breast Cancer Symposium] was the dose-escalation cohorts, about 60 patients in each. The strategy was to gradually increase neratinib dose, the full dose of neratinib is 240 mg daily. In the dose-escalation 1 cohort, patients started at 120 mg, which is half the dose. After a week they added a tablet. They went up to 160 mg at week 2, and then by week 3 and beyond, they were at full dose. The second cohort did the same, but they did it at 2-week increments. This appeared to be helpful in minimizing significant diarrhea. Grade 3 diarrhea was 13.3% in the weekly dose-escalation cohort. The likelihood of discontinuation because of diarrhea was modest at 3%. The dose-escalation 2 groups, where they were waiting 2 weeks before changing, hasn’t been reported. This does compare favorably with previous data with colestipol and loperamide, and for some patients that is a reasonable approach. Start slow and then escalate, as opposed to the conventional approach of giving full dose and waiting for trouble to happen and then having to de-escalate therapy.

Hatem Soliman, MD: It’s important to take that into account because optimally managing drugs like these are critical to tolerability and compliance. The more of these strategies we can use—dose escalation, judicious use of antidiarrheals—the better it will be for patients to stay on the medication if they would benefit from it.

Transcript edited for clarity.