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Top Takeaways from ASCO: HER-2–positive breast cancer
A TKI comes with expected adverse effects; combination therapy with pertuzumab in NEOSPHERE, MARIANNE, brings mixed results.
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CHICAGO — From 5 days of research presented at ASCO 2015, several trials investigating treatment specifically for HER-2–positive breast cancers stood out. Here key opinion leaders offer their Top Takeaways on the research they feel has the potential to impact daily practice.
Results from ExteNET
Arlene Chan, MD, of the Breast Cancer Research Centre of the Western Australia and Curtin University in Perth, Australia, presented findings on the use of oral neratinib (PB272, Puma Biotechnology) (240 mg daily) in women with stage 1 to 3c early HER-2–positive breast cancer who had received trastuzumab (Herceptin, Genentech) 1 to 2 years prior to the analysis.
“We’ve been using trastuzumab, which is the most exciting targeted therapy in HER-2–positive breast cancer, and we have data from the last 10 to 15 years from large, randomized studies showing that trastuzumab improves OS and DFS by about 30% and 50%, respectively,” Jame Abraham, MD, director of the breast oncology program and professor of medicine at Cleveland Clinic, told Healio.com.
ExeNET sought to possibly build on these already impressive results with the addition of neratinib, a tyrosine kinase inhibitor, Abraham said.
William J. Gradishar
The pill is most widely known from a phase II trial in HER-2-treated patients who had previously received lapatinib (Tykerb, Novartis) and trastuzumab, according to William J. Gradishar, MD, FACP, professor of medicine in the division of hematology and medical oncology, Northwestern University Feinberg School of Medicine, and breast cancer section editor for HemOnc Today.
Only a fraction of patients responded; diarrhea was a major side effect in patients.
In the current study, 2-year invasive DFS served as the primary outcome measure. Secondary endpoints included DFS plus ductal carcinoma in situ (DCIS), distant DFS, central nervous system incidence and patient-reported outcomes.
“The trial reports an improvement in DFS favoring the addition of neratinib,” Gradishar said. Patients who received the drug demonstrated an improved 2-year invasive DFS rate compared with patients assigned placebo (93.9% vs. 91.6%; HR = 0.67; 95% CI, 0.50-0.91), which translated into an absolute benefit of 2.3%.
“This is a really promising result showing that in high-risk HER-2–positive patients, in addition to trastuzumab, potentially there may be other options,” Abraham said.
Diarrhea was still the most frequently reported adverse event associated with neratinib (grade 3 or grade 4, 40%). Gradishar noted the researchers’ claim that this can be managed with aggressive loperamide.
“This may change practice, but we’re going to have to take a wait-and-see attitude about that one, mainly because of the side effects,” said Adam M. Brufsky, MD, PhD, FACP, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center, University of Pittsburgh, and HemOnc Today editorial board member. “We can deal with them, but it’s going to be an interesting next year or so as we figure out what to do.”
NeoSphere 5-year analysis
Luca Gianni, MD, a medical oncologist at the San Raffaele Hospital in Milan, Italy, and colleagues evaluated four cycles of neoadjuvant docetaxel and/or trastuzumab and/or pertuzumab (Perjeta, Genetech), followed by surgery and adjuvant chemotherapy plus conventional trastuzumab in women with locally advanced, inflammatory or early HER-2–positive breast cancer.
“We’ve been using pertuzumab in HER-2-positive locally advanced breast cancer in the neoadjuvant setting based upon the NeoSphere and TRYPHAENA data, which actually showed a substantial increase in complete pathological response,” Abraham said. “Based on meta-analysis published by Dr. Patricia Cortazar, we know that increased pathological response would translate into a survival, but we didn’t have clear prospective data in HER-2 positive patients.”
Jame Abraham
The researchers calculated DFS and PFS at 3 years. For DFS, the rates were 88% with pertuzumab and trastuzumab, and 84% with pertuzumab and docetaxel. For PFS, the rates were 81% and 82%, respectively.
Abraham said the reasons for giving adjuvant chemotherapy to HER-2–positive patients, especially for small tumors is often debated in the tumor boards, and these results bring more clarity to the conversation.
“Now we can say that giving a neo-adjuvant pertuzumab, in addition to trastuzumab and chemotherapy, will improve disease free survival based upon this data,” Abraham said. “This is extremely important data, and it supports our hypothesis that the pathological response correlates with survival and is meaningful to discuss with our patients.”
Primary results from MARIANNE
With trastuzumab emtansine (T-DM1) alone or with pertuzumab, taxane and docetaxel pointing toward positive survival outcomes in patients with HER-2–positive metastatic breast cancer in earlier studies, and the combination of T-DM1 and pertuzumab found to inhibit tumor cell line proliferation in vitro, Paul Anthony Ellis, MD, of Guy’s Hospital and Sarah Cannon Research Institute, London, U.K., and colleagues set out to study the regimens further.
The researchers randomized patients with HER-2–positive progressive and locally recurrent advanced breast cancer or untreated metastatic breast cancer to three arms — chemotherapy with taxane-trastuzumab, T-DM1 alone, or T-DM1 in combination with pertuzumab — with PFS as the primary endpoint.
Adam M. Brufsky
“In the trial, T-DM1 was found to be equivalent to docetaxel-trastuzumab, and adding pertuzumab to T-DM1 did not result in any increased PFS benefits,” Brufsky said.
In the third of patients who had prior trastuzumab, it was interesting to see a 5-month improvement in PFS between the T-DM1 and the docetaxel-trastuzumab arms, and that T-DM1 with pertuzumab had an advantage over T-DM1 alone, Brufsky said. But the results were not significant because the population was a subset.
“I’m not sure what physicians are going to do with all that data,” Brufsky said. “We’re going to have to think long and hard about the results of that trial going forward,”
T-DM1 or T-DM1 with pertuzumab were found to be non-inferior, meaning they could be considered alternatives to taxane plus trastuzumab, Gradishar, told Healio.com. But it doesn’t clearly show the agents should be used a first-line therapy for most patients.
“The MARIANNE trial was disappointing, and contrary to what I’m sure many people thought it would show,” Gradishar said. “The other implication is that TDM-1 is being evaluated in other trials including in the adjuvant setting, and this is probably going to have some impact on the design of those.”
References:
Chan AB, et al. Abstract 508.
Ellis PA, et al. Abstract 507.
Gianni L, et al. Abstract 505.
All presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: Abraham, Brufsky and Gradishar report no relevant financial disclosures.