Haematology+Oncology_News

H aematology & O ncology N ews • Vol. 9 • No. 1 • 2016 10 CONFERENCE COVERAGE

Neratinib shows consistent breast cancer benefit at 3 years

The 3-year outcomes were most robust in patients who began neratinib less than 1 year after completing trastuzumab and who were hormone receptor-positive. That is the scenario where delayed adjuvant neratinib might prove beneficial in clinical practice.

reduce the frequency and severity of diarrhoea. Another ExteNET follow-up is planned at the 5-year mark. Audience members asked how the United States Food and DrugAdmin- istration’s approval of pertuzumab with indications for neoadjuvant treat- ment of HER2-positive breast cancer as well as for metastatic disease will change the prospects for neratinib. Dr Chan replied that, like other medical oncologists, she’s eagerly awaiting the results of the APHINITY trial, which is testing adjuvant pertuzumab versus pla- cebo on top of chemotherapy plus trastuzumab in women with HER2- positive disease. “I would suspect that even if APHINITY is positive, there will be patients who will still have a risk of relapse, so we still won’t be curing all HER2-positive patients,” she said, adding that a new clinical trial would be required in order to establish that neratinib is of benefit in such individuals. implications for women with oestro- gen receptor-positive versus triple- negative disease, based on both their likelihood of pathologic complete response (pCR)and the prognostic impact of that response. “I put it to you that really what this tells us is if we have a triple- negative patient who doesn’t achieve pCR after good neoadjuvant therapy, this [capecitabine] is probably a reasonable option, even though it’s quite toxic, and certainly should be explored further,” he said. “I’m not sure I would go home and treat my ER-positive patients who don’t get a pCR with capecitabine based on this study.” In the trial, the 2-year disease-free survival rate – the trial’s primary end- point – was 82.8% with capecitabine and 74.0% without it. The estimated 5-year rates were 74.1% and 67.7%, respectively (hazard ratio, 0.70; P = 0.005). Furthermore, the 2-year overall sur- vival rate was 94% with capecitabine and 89.2% without it. The estimated 5-year rates were 89.2% and 83.9%, respectively (HR, 0.60; P < 0.01). Patients in the capecitabine arm were more likely to experience grade 3 or worse neutropenia (7% vs 2%) and diarrhoea (3% vs < 1%). And 11% developed grade 3 hand-foot syndrome. However, these toxicities weremanage- able, according to the investigators. Dr Toi disclosed that he receives a re- search grant fromChugai Pharmaceuti- cal Company. The trial was supported by a grant from Specified Nonprofit Corporation – Advanced Clinical Re- search Organization (ACRO) and other donations to the Japan Breast Cancer Research Group.

robust in patients who began neratin- ib less than 1 year after completing trastuzumab and who were hormone receptor-positive. In this subgroup, the 3-year invasive disease-free sur- vival rate was 93.3% with neratinib versus 88.6% with placebo. That, Dr Chan said, is the scenario where de- layed adjuvant neratinib might prove beneficial in clinical practice. Patients with hormone receptor- negative disease didn’t benefit from neratinib. Forty percent of patients on ner- atinib developed grade 3 diarrhoea, the agent’s major side effect and one that is a class effect with the tyros- ine kinase inhibitors. Most cases occurred within the first 30 days of treatment and lasted for a median of 5 days, with 1.4% of neratinib- treated patients being hospitalised for this complication. Dr Chan noted that the study protocol precluded prophylaxis with loperamide during the first month of neratinib, which has been shown by other investigators to markedly “The balance of benefit and toxicity would favour the use of capecitabine in [this] post-neoadjuvant chemo- therapy situation, but prediction for therapeutic benefit needs to be in- vestigated further,” Dr Toi concluded. “The cost-effectiveness analysis will be carried out soon,” he added. Press briefing moderator Dr Virgin- ia Kaklamani, codirector of the San Antonio Breast Cancer Symposium, as well as professor of medicine in the division of haematology/oncology at the University of Texas, San Antonio, and leader of the Breast Cancer Pro- gram, Cancer Therapy & Research Centre there, wondered if the results are practice-changing. “On Monday morning, when I see a patient who has residual disease after neoadjuvant chemotherapy, what do I tell her?” she asked. “I think we need to take care of the reimbursement issue,” Dr Toi replied, referring to the current lack of the United States Food and Drug Ad- ministration approval of capecitabine for this indication. “But personally, I would like to consider this treatment.” In the session where the findings were presented, some attendees expressed skepticism about the ob- served benefit of capecitabine, given previous studies. This benefit may have been due in part to the fact that in CREATE-X, capecitabine was given largely be- cause it does not have cross-resist- ance with anthracyclines and taxanes, Dr Toi speculated. Attendee Dr Steven Vogl, an on- cologist at the Montefiore Medical Centre in New York, proposed that the findings may have different

BY BRUCE JANCIN Frontline Medical News T he investigational oral tyrosine kinase inhibitor neratinib showed continued benefit in terms of re- duced invasive disease-free survival at 3 years of follow-up in women with early-stage HER2-positive breast cancer in the randomised, double- blind ExteNET trial, DrArlene Chan reported at the San Antonio Breast Cancer Symposium. The 3-year analysis was not prespecified. It was performed be- cause she and her coinvestigators were concerned that the previously reported benefit seen at 2 years might be lost with longer follow-up, as has occurred with trastuzumab in the landmark HERA (HERcep- tin Adjuvant) trial. Reassuringly, however, the absolute 2.3% benefit for neratinib compared to placebo seen at 2 years in ExteNET was maintained at 3 years in the up- dated analysis, where the absolute difference remained essentially

the well-established observation that relapse occurs in up to 26% of trastuzumab-treated patients at 8-plus years of follow-up. The study hypothesis is that neratinib, a tyrosine kinase inhibitor of HER1, –2, and –4, will prevent or delay dis- ease recurrence because it attacks the cancer through a mechanism of action different from that of trastuzumab. At 2 years of follow-up post neratinib, the invasive disease-free survival rate was 93.9% with active therapy and 91.6% with placebo, as previously reported by Dr Chan. At 3 years in the roughly 85% of patients who remained in the study, which changed sponsors in the interim, the rates were 92% and 89.9%. The 3-year outcomes were most

unchanged at 2.1%, according to Dr Chan, vice chair of the Breast Cancer Research Centre of Western Australia in Perth. Moreover, most patients have reached the 4-year mark in follow- up, where the invasive disease-free survival benefit has remained sig- nificant in favour of neratinib at 90.5% versus 88.6% with placebo, she added. ExteNET was a large international trial of 2,840 women with stage II- IIIc HER2-positive breast cancer with node-positive disease who were randomised to oral neratinib at 240 mg/day or placebo for 1 year beginning an average of 4.4 months after completing adjuvant chemo- therapy and 1 year of trastuzumab. The impetus for ExteNET was

CREATE-X – Capecitabine is efficacious against residual HER2-negative breast cancer BY SUSAN LONDON Frontline Medical News A djuvant capecitabine improves outcomes in women with HER2- negative breast cancer who still who historically haven’t fared well on this drug.

Can aspirin prevent breast cancer? BY BRUCE JANCIN Frontline Medical News A large randomised controlled trial of aspirin for breast cancer prevention is warranted in light of new evidence that aspirin use shows a strong independent inverse relationship with mammographic breast density, Dr Marie E. Wood declared at the SanAntonio Breast Cancer Symposium. Breast density, she noted, is well accepted as a modifiable risk factor for both oestrogen receptor-negative (ER–) and oestrogren receptor-positive (ER+) breast cancer. “Aspirin could be a promising breast cancer prevention therapy. It is cheap, safe, well tolerated, and there is strong biologic and epidemiologic evidence for a prevention effect for both ER– and ER+ breast cancers,” said Dr Wood, professor of medicine and director of the familial cancer program at the University of Vermont in Burlington. There is an unmet need for better chemoprevention agents for breast cancer. The current ones, such as tamoxifen and raloxifene, don’t prevent ER– breast cancer. Plus, they have substantial side effects leading to low utilisation for primary prevention, she continued. Dr Wood presented a retrospective study of 26,000 women that demonstrated a dose-response relationship between aspirin use and lower mammographic breast density. The relationship was stronger in women under age 60 years and inAfricanAmericans. That’s an important finding because those two groups are at increased risk for developing ER– breast cancer. She and her coinvestigators reviewed the electronic medical records of 26,000 women in 36 primary care and ob.gyn. practices. All had undergone routine screening mammography during 2012-2013 and had an office visit in the prior year that included gathering a confirmed list of medications. The study group included 5111 aspirin users and 20,889 nonusers. After performing logistic regression analysis to adjust for differences between the two groups in terms of age, ethnicity, and body mass index, the investiga- tors examined the association between aspirin use and BI-RADS (Breast Imaging Reporting and Data System) breast density. The prevalence of low-risk, entirely fatty breasts was 9.6% in aspirin nonusers, compared with 16.9% in aspirin users, while extremely dense breasts were present in 5.1% of nonusers versus just 1.6% of aspirin users, Dr Wood reported. Women taking aspirin at 300 mg/day or less were 16% less likely to have mammographically dense breasts – that is, BIRADS 3 or 4 – than were aspirin nonusers. Women on more than 300 mg/day were 38% less likely to have dense breasts than nonusers. Previous clinical trials looking at aspirin for breast cancer prevention have had design flaws that compromised the findings. Moreover, the several prior studies examining a link between aspirin use and mam- mographic breast density either lumped all NSAIDs together or were limited by small sample size, according to the oncologist. As a next step in this project, Dr Wood and her coinvestigators plan to examine duration of aspirin use and its relationship to mammographic breast density in this study population.

have invasive disease after neoadju- vant chemotherapy, according to find- ings of the CREATE-X trial reported at the San Antonio Breast Cancer Symposium. “Patients with pathologic residual invasive disease after neoadjuvant chemotherapy have a higher risk for relapse,” said presenting author Dr Masakazu Toi, a professor at Kyoto University Hospital in Japan, and founder and senior director of the Japan Breast Cancer Research Group (JBCRG). But “it is unclear whether postoperative systemic chemotherapy following neoadjuvant chemotherapy is able to prolong survival.” The phase III trial was conducted among 910 patients with early breast cancer in Japan and Korea who still had positive nodes or didn’t achieve a pathologic complete response after receipt of neoadjuvant chemotherapy that included an anthracycline, a tax- ane, or both. They were randomised to open-label adjuvant capecitabine or no capecitabine, in addition to standard therapy. Results of a preplanned 2-year in- terim analysis, reported in a session and related press briefing, showed that the risk of disease-free survival events was 30% lower and the risk of death was 40% lower among women given capecitabine than among coun- terparts not given the drug, prompting early stopping of the trial. The disease-free survival results were similar in subgroup analyses. In particular, benefit was similar in patients with triple-negative disease,