Background: The addition of trastuzumab (H) to pre-operative chemotherapy in H+BC increases the rate of pathological complete remission (pCR). H causes cardiac toxicity, especially when given with anthracyclines (Anth). TCH is a widely used adjuvant regimen with decreased cardiac toxiciy. We reported that TCH produces pCR in 40% of non-randomised pts with H+BC. Lapatinib is an alternative HER2 antagonist, which produces responses following trastuzumab failure, and which has been reported to augment H activity in combination. We studied the non-Anth regimens TCH v TCL v TCHL in pts with H+BC. The primary objective of this study was pCR. Secondary endpoints were toxicity and translational.
Methods: Eligibility criteria included: primary BC, HER-2 +, node + disease (histologically or cytologically confirmed) or node-negative with >T1, normal left ventricle ejection fraction, no active/uncontrolled cardiovascular disease, normal organ and marrow function. Treatment consisted of 6 cycles of D (75mg/m2) + C (AUC 6) q3 weekly and H (8 mg/kg on cycle 1 day 1 and 6 mg/kg q3weekly thereafter for one year) ± L (1000mg OD) for up to 1 week before surgery. A sample size of 36 evaluable pts is required to detect an absolute 25% difference in the pCR rate between the hypothesised 65% pCR rate vs the historical-control pCR rate of 40%.
Results: Following presentation of NCIC MA31 we decided to suspend accrual on our TCL arm.78 female pts were accrued to TCH/TCHL in 11 ICORG sites between 12/2010- 06/2013. Of 40 patients accrued to TCHL, only 18 pts completed 6 cycles. 17pts came off study early due to toxicity, 3 pts after cycle 3, 2 pts after cycle 2, 12pts after cycle 1. (1 patient was also registered but never started). Of 38 pts accrued to the TCH arm,33 pts completed 6 cycles,2 pts completed 5 cycles and 2 pts w/d after cycle 1. 3 TCHL & 1 TCH pt still remain on Rx. 2 pts have not yet had surgery. 52 SAEs occurred on study, 49 involving hospital admission, & 3 of medical significance. The most frequent SAEs were diarrhoea (10), febrile neutropenia (4), nausea (4), neutropenic sepsis (3), dehydration (2), wound infection (2), vomiting (2) neutropenia (2) decreased haemoglobin (2), GI perforation (1). There was 1 fatality on the TCH arm due to Neutropenic sepsis and typhlitis. One TCHL pt suffered GI perforation at cycle 1. pCR rates were 48% (16/33) for the TCH arm and 44% (7/16) for the TCHL arm. Translational studies are underway.
Conclusions: TCH containing treatment produces a high rate of pCR. TCHL will not produce a statistically higher rate of pCR in this sample. The addition of lapatinib to TCH results in substantial GI toxicity. TCHL appears to be less tolerable than other active chemotherapy +H+L regimens such as that used in Neo-ALLTO. ICORG is currently leading an international study of paclitaxel+H +/- L in metastatic BC.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-25.