Phase II prospective open label study of neoadjuvant pertuzumab, trastuzumab, and nab-paclitaxel in patients with HER-2 positive advanced breast cancer.
Authors: Lavasani Sayeh Moazami , Yost Susan Elaine , Frankel Paul Henry , Ruel Christopher , Murga Mireya , Tang Aileen , Martinez Norma , Kruper Laura , Tumyan Lusine , Schmolze Dan , Menghi Francesca , Liu Edison T. , Yeon Christina Haeyoung , Yuan Yuan , Waisman James Ross , Somlo George , Mortimer Joanne E. 
Published: June 2021

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Background: HER2 overexpression occurs in 20-25% of breast cancers (BC) and is associated with poor prognosis. The addition of trastuzumab (trast) to chemotherapy significantly improves disease-free (DFS) and overall survival (OS) in the adjuvant setting. Pertuzumab (pert) inhibits ligand-activated signaling and in combination with trast has synergistic inhibition of BC cells overexpressing HER2. In the neoadjuvant therapy (NT) setting, the combination of trast, pert, and docetaxel can improve the pCR rate. PCR may predict for improved DFS and OS. De-escalation with weekly paclitaxel combined with trast and pert appeared to be safe and efficacious but requires steroid premedication, whereas nab-paclitaxel (nab) does not require steroid premedication. To decrease treatment-associated toxicity in patients with HER2+ BC, we utilized a non-anthracycline regimen with pert, trast, and nab as NT. The objectives of this study were to evaluate the safety and efficacy of pert added to trast and nab in HER2+ locally advanced BC (LABC) to determine the pCR, as well as DFS and OS. Methods: A total of 45 patients with biopsy-confirmed HER2+ LABC or inflammatory BC were enrolled from 2013-2017, and were treated with 6 cycles of neoadjuvant pert (840 mg loading dose, then 420 mg IV day 1 every 21 days), weekly trast (4 mg/kg loading dose, then 2 mg/kg), and weekly nab (100 mg/m2 IV). Patient characteristics, including age, race, menopausal status, grade, stage, and prior surgery and radiation were recorded. Median treatment cycles determined, and events (AE) were identified for each arm. PCR rate, DFS and OS were calculated. Results: Median age was 56 (31-78) years. 1/45 (2%) was stage I, 30/45 (67%) were stage II, 14/45 (31%) were stage III. pCR rate was 29/45 (64.4%). The initial primary tumor size was similar in pCR and non-pCR patients (mean 4.1 cm vs. 3.2 cm, respectively). Median follow-up was 36.1 months (95% CI [27.1, 41.8]). Median treatment cycles completed was 6 (1-6). A total of 4/45 (9%) patients had >1 cycle delayed, and 32/45 (71%) patients had >1 cycle modified. For the patients achieving pCR, the DFS (95% CI) at 3 years was 85.9% (66.7%, 94.4%) and for those without pCR, it was 87.5% (58.6%, 96.7%). OS was not reached (95% CI [NR, NR]). Grade 3 AEs (> 2 patients) included 7/45 (16%) of patients with hypertension; 4/45 (9%) with anemia; and 2/45 (4%) with diarrhea, ALT, fatigue, or rash. Conclusions: This anthracycline-free regimen which included nab achieved great pCR rate of 64.4% in HER2+ BC patients with fewer treatment-related toxicities. The pCR rate is comparable with docetaxel, carboplatin, trast, and pert (TCHP) therapy in NT setting, but without the treatment-associated toxicities. This suggests we may be able to safely avoid anthracyclines and carboplatin for NT in HER2+ BC patients. The improved pCR did not translate into DFS benefit. Clinical trial information: NCT01730833.