A 54-Year-Old Woman With Stage 2 HER2+ Breast Cancer - Episode 4
Joyce O'Shaughnessy, MD: Neratinib is an oral pan-HER [human epidermal growth factor receptor] tyrosine kinase inhibitor. It inhibits HER1, HER2, and HER4, and because it’s inhibiting those, HER3 can’t work either. It’s basically a pan-HER inhibitor that is FDA approved in the adjuvant setting for high-risk HER2-positive breast cancers.
In the ExteNET trial, women were randomized to a year of neratinib versus a year of placebo, along with their endocrine therapy if they were ER [estrogen receptor]-positive. The results were positive in the intent-to-treat overall population. The hazard ratio for invasive disease-free survival at the 5-year mark was in the 0.73 range, about a 27% reduction in the risk of recurring with invasive breast cancer, locoregionally or metastatic. Interestingly, the benefit was much greater in the estrogen receptor-positive patients, with hazard ratios at 5 years in those patients around the 0.57 range. So now we’re at a more than 40% reduction in the risk.
Interestingly, there was a cohort of patients who had received preoperative chemotherapy and trastuzumab, and they did not have a pathologic complete response. Their physicians were interested in enrolling them in a trial because they were high risk. They finished up their year of trastuzumab and were randomized to neratinib versus placebo. That was a very positive trial, particularly in the ER-positive patients, where it was about a 40% reduction in risk in patients in the preoperative setting.
This patient is very similar to that. She still had residual disease. She had the benefit of switching over to the T-DM1 [trastuzumab emtansine]. Because she received preoperative trastuzumab and pertuzumabpertuzumab was not part of the standard of care at the time the ExteNET trial was done—and because she still had residual disease, we know that the trastuzumab and pertuzumab were not perfectly effective for her. We also know that she will benefit if she switches over to T-DM1 [trastuzumab emtansine], which she did, but we also know from the KATHERINE trial that there’s still residual risk.
We want to utilize what we have. Neratinib works very differently than the antibodies. The T-DM1 [trastuzumab emtansine] delivers the cytotoxic agent, the pertuzumab, trastuzumab interrupts HER2 signaling and stimulates ADCC [antibody-dependent cell-mediated cytotoxicity], an immune response. But nothing is getting at the tyrosine kinase end of signaling, so it works very differently. We know there’s preclinical synergy between inhibition of the estrogen receptor and inhibition of the HER family. If you inhibit just the estrogen receptor, you will upregulate the expression of the HER family, which of course could lead to recurrence, and vice versa. If you just use neratinib, you will upregulate the estrogen receptor. So of course, combined blockade is highly synergistic preclinically.
In the patients who received preoperative therapy, had residual disease, and went on to receive neratinib who were estrogen receptor-positive, at 5 years it was an absolute benefit of 7.4%. It was even higher in patients whose HER2 was centrally confirmed to be positive, even higher. We’re looking at 8% absolute gain. I believe that neratinib is highly likely to be non-cross-resistant with pertuzumab and with the T-DM1 [trastuzumab emtansine]. I actually think it’s very important for patients to have the opportunity if they’re high risk and still have 10% or more residual risk of recurrence at some point, we should do everything we can to reduce that risk.
In the ExteNET trial, no doubt the patients whose breast cancer was estrogen receptor-positive had the greatest benefit from combined ER and pan-HER inhibition with neratinib. In the ER-negative group, if you look at the patients who started the neratinib within a year of finishing their adjuvant trastuzumab and particularly within 6 months of finishing their adjuvant trastuzumab, which of course is what we would do, there would be no reason to wait. For those patients, there’s a separation of the curve, and the curve stays apart. It’s about a 2.5% absolute benefit with the neratinib. So it can be beneficial as well to high-risk ER-negative patients, and I wouldn’t hesitate to do that because the curves do pull apart in patients who started the neratinib soon after finishing up their year of trastuzumab.
Transcript edited for clarity.
Case: A 54-Year-Old Woman With Stage 2HER2+ Breast Cancer
Treatment and Follow-Up