AT ASCO 2015

CHICAGO (FRONTLINE MEDICAL NEWS) – Extending adjuvant targeted therapy for HER2-positive early breast cancer by a year with neratinib further protects against recurrence, suggest primary results of the phase III randomized ExteNET trial (Study Evaluating the Effects of Neratinib After Adjuvant Trastuzumab in Women With Early-Stage Breast Cancer).

At 2 years of follow-up, women assigned to receive neratinib, an investigational pan-HER tyrosine kinase inhibitor, had a one-third reduction in the risk of invasive breast cancer or death relative to counterparts assigned to receive placebo, with an absolute difference between groups of 2.3%, investigators reported at the annual meeting of the American Society of Clinical Oncology. Benefit was even greater among the subset whose tumor had hormone receptors.

“The ExteNET study, utilizing 12 months of neratinib therapy, is the first study … to demonstrate a significant improvement in invasive disease–free survival at 2 years. The underlying [molecular] cross-talk mechanism, which may explain the observed greater benefit in the hormone receptor–positive cohort, clearly requires further evaluation in other studies,” said Dr. Arlene Chan, a medical oncologist at the Breast Cancer Research Centre of Western Australia and Mount Medical Centre, both in Perth.

Grade 3 or 4 diarrhea was problematic, however, occurring in 40% of the neratinib group and often leading to dose reductions and discontinuations. “Studies have shown that the incidence of diarrhea can be attenuated with the use of an intensive loperamide prophylaxis regimen, and we believe that by adopting this approach, it will make this treatment far more tolerable for all our patients,” she noted.

Invited discussant Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center, New York, noted that there are factors weighing both for and against making extended therapy with neratinib a new standard of care.

“On the one hand, the absolute disease-free survival gain is real, and if you recall, these results are similar to what we saw with the 2-year data for the original adjuvant trastuzumab studies,” she elaborated. “But on the other hand, we don’t have overall survival data, and that is something we did have with the trastuzumab trials. Additionally, from a practical perspective, to which population do we apply these results? In the U.S., pertuzumab is an option for our high-risk HER2-positive patients, so would the benefit seen with neratinib persist in these pertuzumab-pretreated patients? For our lower-risk patients, stage 1 patients, for whom we have very effective taxane-based therapies, how do we justify the risks of treatment for the potential small benefits expected in this group that already does very well?”

“We await the longer follow-up and FDA deliberations to determine how and whether to offer neratinib as extended therapy to our early-stage patients,” Dr. Modi concluded. “How will these ExteNET data apply to patients who have received pertuzumab? This is an area where further clinical research could guide us forward.”

Session attendee Richard Gelber, Ph.D., of the Dana-Farber Cancer Institute, Boston, agreed with Dr. Chan that the trial’s short follow-up is a limitation. “I would hypothesize that it’s actually a fatal limitation for the results we saw today. I would consider the results nonactionable. In fact, the early results of ALTTO done at about that time showed an even larger advantage than we saw here today,” he said, referring to an adjuvant trial of lapatinib that was ultimately negative. “Similar pathway, and I would propose that the longer-term follow-up would likely prove a negative result.”

Dr. Chan replied: “I think that in terms of the absolute benefit derived from our study, we need to take it in the context that this is added upon a treatment intervention with trastuzumab, which has already provided an enormous benefit for our patients,” so it may be unreasonable to expect another large gain; furthermore, the MA.17 trial, which investigated extended adjuvant hormonal therapy, had an even smaller benefit at the 2-year mark, but eventually concluded in favor of the therapy. She added that the ExteNET trial will continue to follow patients out to 5 years.

Dr. Steven Vogl, an oncologist in the Bronx, New York, didn’t mince words about the observed toxicity, saying, “This neratinib sounds like a terrible drug. How many people were still taking it after 6 months and how many actually finished a year of the stuff?”

The relative dose intensity was 81% in the neratinib arm, compared with 98% in the placebo arm, according to Dr. Chan. Only 61% of patients in the former were able to complete the full year of planned treatment.

“Seeing an impressive response with that degree of noncompliance suggests that maybe you don’t need as much drug as you gave,” Dr. Vogl proposed.

ExteNET, sponsored by Puma Biotechnology, enrolled 2,840 women who had completed adjuvant chemotherapy and trastuzumab (Herceptin) for early breast cancer that was HER2 positive by local assessment. The women were randomized evenly to neratinib – an oral irreversible inhibitor of HER 1, 2, and 4 shown to be active in trastuzumab-pretreated patients – or placebo.

The study had a complex evolution, with several major amendments of the protocol due to new results from other trials and changes in sponsorship, Dr. Chan noted. Initially, women were required to have stage 1 to 3c disease with receipt of the last trastuzumab dose no more than 2 years earlier; later, that was modified to stage 2 to 3 disease and receipt of the last trastuzumab dose no more than 1 year earlier. Also, the duration of follow-up was temporarily shortened from 5 years to 2 years.

In intention-to-treat analyses, the 2-year rate of invasive disease–free survival was 93.9% with neratinib and 91.6% with placebo (hazard ratio, 0.67; P = .009), reported Dr. Chan, who disclosed that she has a consulting or advisory role with Pfizer, and that she is on the speakers’ bureau and is provided with travel, accommodation, and expenses by Pierre Fabre.

In some noteworthy subgroup findings, benefit was even greater among women with hormone receptor–positive disease (hazard ratio, 0.51; P = .001) or centrally confirmed HER2-positive disease (hazard ratio, 0.51; P = .002).

The neratinib group also had a significantly better rate of survival with freedom from invasive and in situ disease combined (93.9% vs. 91.0%; hazard ratio, 0.63; P = .002).

In terms of adverse events of special interest, neratinib was associated with a sharply higher rate of grade 3 or 4 diarrhea when compared to placebo (40% vs. 2%), as expected from its mechanism of action, Dr. Chan said. But rates of cardiac toxicity and interstitial lung disease did not differ between groups.