PracticeUpdate Oncology February 2019

EDITOR’S PICKS 13

Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual HER2 Blockade for HER2-Positive Breast Cancer The Lancet Oncology

Take-home message • This open-label phase III trial evaluated the effect on pathologic complete response of neoadjuvant trastuzumab/pertuzumab alongside 5-FUepirubicin/cyclophospha- mide followed by paclitaxel/carboplatin compared with neoadjuvant trastuzumab/ pertuzumab followed by paclitaxel/ carboplatin with no addition of anthracyclines in patients with stage II/III HER2+ breast cancer. • Pathologic complete response rates were similar between the anthracycline and non-anthracycline groups, and febrile neutropenia was more common in the anth- racycline group. Neil Majithia MD T he TRAIN-2 trial compared an anthracycline-containing regimen with an all tax- ane/ carboplatin regimen with trastuzumab and pertuzumab as neoadjuvant chemotherapy (NACT) in HER2+ early stage breast cancer. No difference in pCR rates were noted, but there was more toxicity in the form of febrile neutropenia in the anthracycline group, leading investigators to endorse the non-anthracycline regimen as an alternative to standard anthracycline-containing regimens. The most striking finding was the extremely high pCR rate in both arms: 67% to 68% overall. Moreover, looking at subgroups, the pCR rate was 84% to 89% in the ER−/PR− group and 51% to 55% in the ER+/PR+ group. These percentages are, to my knowledge, the highest reported in a clinical trial, especially in a large, multicenter phase III study. TRAIN-2 raises the question of routinely doing more NACT cycles with dual anti- HER2 therapy if higher percentage of pCR is the goal. All patients in this trial had nine cycles of therapy, with symmetry between the duration of treatment and total dose of trastuzumab and pertuzumab. Alternatively, the results are supportive of continuing trastuzumab and pertuzumab routinely in the adjuvant setting after shorter (typically, 4–6 cycles) of anti-HER2 therapy with NACT as is commonly given in the US. The trials results also support substituting paclitaxel for docetaxel as an alternative, non–anthracycline based chemotherapy regimen to be coupled with pertuzumab and trastuzumab for HER2+ tumors in the neoadjuvant setting. COMMENT By Lee S. Schwartzberg MD, FACP

who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the inten- tion-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. FINDINGS Between Dec 9, 2013, and Jan 14, 2016, 438patientswereenrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the pri- mary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19months (IQR 16-23 months). A pathological complete response was recorded in 141 (67%, 95%CI 60-73) of 212 patients in the anthracycline group and in 140 (68%, 61-74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anth- racycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses therewere 220patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutrope- nia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p<0·0001). Symptomatic left ventricu- lar systolic dysfunction was rare in both groups (two [1%] of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related. INTERPRETATION In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutrope- nia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treat- ment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results. Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual HER2 Blockade for HER2-Positive Breast Cancer (TRAIN-2): A Multicentre, Open-Label, Ran- domised, Phase 3 Trial. Lancet Oncol 2018 Nov 06;[EPub Ahead of Print], MS van Ramshorst, A van der Voort, ED van Werkhoven, et al. www.practiceupdate.com/c/76015

Abstract BACKGROUND The optimal chemotherapy back- bone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracy- clines would improve pathological complete response compared with a carboplatin-tax- ane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab. METHODS The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II-III HER2-positive breast cancer. Patients were ran- domly allocated using central randomisation software (1:1 ratio) with minimisation without a

random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m 2 ), epirubicin (90 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) every 3 weeks for three cycles followed by pacl- itaxel (80 mg/m 2 on days 1 and 8) and carboplatin (area under the concentration-time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hos- pital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients

VOL. 3 • NO. 1 • 2019