Pertuzumab

About: Pertuzumab is a research topic. Over the lifetime, 1453 publications have been published within this topic receiving 73219 citations. The topic is also known as: 2C4 Antibody & MOAB 2C4.

Abstract P2-16-10: Safety of pertuzumab plus trastuzumab plus vinorelbine for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer

Abstract: Background: HER2 overexpression or amplification, occuring in ∼15-20% of breast cancers (BC), is associated with a poor prognosis. Trastuzumab (T) and pertuzumab (P) are humanized monoclonal antibodies that bind to different HER2 epitopes, inhibiting HER2 signaling. It was previously shown that first-line (1L) treatment of patients (pts) with HER2-positive metastatic breast cancer (MBC) with vinorelbine (V)+T had similar efficacy to docetaxel+T, but with fewer adverse events (AEs) (HERNATA). In a recent study, P+T+docetaxel significantly improved progression-free survival (PFS) and overall survival (OS) compared with T+docetaxel in pts with HER2-positive 1L MBC (CLEOPATRA). The objective of the VELVET study is to investigate the efficacy and safety of P+T+V for 1L treatment of HER2-positive MBC. Methods: This is a multicenter, open-label, single-arm, two-cohort, Phase II study. The recruitment target is 105 pts per cohort. Pts in Cohort 1 receive P+T+V as separate infusions. Pts in Cohort 2 receive P+T from a single infusion bag followed by V. The initial dose of P is 840 mg, followed by 420 mg q3w; the initial dose of T is 8 mg/kg, followed by 6 mg/kg q3w; V is administered at 25 mg/m2 in Cycle 1, followed by 30-35 mg/m2, on Days 1 and 8 of each cycle, q3w. Pts must have HER2-positive MBC or locally advanced BC (LABC) and a baseline left ventricular ejection fraction (LVEF) of ≥55%. Previous treatment with systemic nonhormonal anticancer therapy in the metastatic setting is not allowed. The primary endpoint is independently assessed overall response rate. Secondary endpoints include PFS, OS, and safety. Results: Interim safety data are presented for Cohort 1; 106 pts were enrolled. Median age at screening was 56 years. Median interval between initial BC diagnosis and enrollment was 2.6 years. 33% of pts had Stage IV BC at initial BC diagnosis. At diagnosis of advanced disease, 13% and 87% of pts had LABC and MBC, respectively. 54% of pts had previously received chemotherapy, including taxane (38%) and anthracycline (36%). 41% had prior T exposure. A median of 6 cycles of P, T, and V was received at the time of this analysis. An AE overview is shown in the table. Grade ≥3 neutropenia/febrile neutropenia was experienced by 8% of pts in Cycle 1 and by 14% of pts in Cycle 2; this proportion decreased during subsequent cycles. There was no overall decrease in mean LVEF from baseline. Conclusions: The combination of P+T+V was well tolerated; no new safety signals were observed. The incidences of grade ≥3 neutropenia, febrile neutropenia, and leukopenia were lower than those previously observed in pts with HER2-positive MBC treated with 1L P+T+docetaxel in CLEOPATRA or those treated with T+V in HERNATA; however, it should be noted that the treatment period in these two studies was longer. Efficacy data for Cohorts 1 and 2 will be reported at the end of the study. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-10.

Abstract OT3-01-01: HERMIONE: A phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with chemotherapy of physician's choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1)

Abstract: Background: Although HER2-targeted therapies such as pertuzumab and T-DM1 have improved patient outcomes, treatment resistance typically occurs. MM-302 is a HER2-targeted liposomal doxorubicin in development by Merrimack Pharmaceuticals. In a Phase 1 study, patients with HER2-positive metastatic breast cancer (MBC) were treated with MM-302 alone and in combination with trastuzumab with or without cyclophosphamide. MM-302 had an acceptable safety profile and promising efficacy was observed in patients not previously exposed to an anthracycline. Trial design: HERMIONE (NCT02213744) is a randomized Phase 2, two-arm, open-label trial designed to evaluate if MM-302 can address an unmet medical need in patients with anthracycline naive, trastuzumab-, pertuzumab- and T-DM1-pretreated HER2-positive locally advanced breast cancer (LABC)/MBC. Patients are randomized 1:1 to receive MM-302 (30mg/m2, Q3W) plus trastuzumab (6mg/kg, Q3W) or chemotherapy of physician9s choice (vinorelbine, capecitabine, or gemcitabine) plus trastuzumab (6mg/kg, Q3W). Eligibility criteria: Centrally confirmed HER2-positive LABC/MBC, no prior anthracycline exposure, prior trastuzumab in any setting, prior pertuzumab and T-DM1 in the LABC/MBC setting, unlimited prior lines of therapy, ECOG 0-1 and LVEF ≥50%. CNS metastases are permitted if stable and without symptoms or steroids for 4 weeks. Specific aims: The primary endpoint is independently assessed progression free survival (PFS). Secondary endpoints include investigator assessed PFS, overall survival, response rate, safety and patient related outcomes. Statistics: 250 patients will be enrolled to observe 191 PFS events for 90% power to detect a Hazard Ratio of 0.625. The MM-302 arm will be compared to the control arm on the primary endpoint of PFS using a stratified log-rank test at one-sided 0.025 level. Accrual status: First patient in was December 2014 and enrollment is expected to be complete in late 2016. Sites are open in the US, Canada and Western Europe and are currently enrolling patients. Citation Format: Miller K, Cortes J, Hurvitz SA, Krop IE, Tripathy D, Verma S, Riahi K, Reynolds JG, Wickham T, Molnar I, Yardley DA. HERMIONE: A phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with chemotherapy of physician9s choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-01.

Abstract OT2-07-02: Trastuzumab deruxtecan (DS-8201a) vs investigator's choice of treatment in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received T-DM1: A randomized, phase 3 study

Abstract: Background: There is no uniform standard of care for HER2-positive breast cancer (BC) after disease progression on ado-trastuzumab emtansine (T-DM1). DS-8201a is a novel HER2-targeted antibody-drug conjugate (ADC) with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a drug-to-antibody ratio of 7 to 8. It is designed with the goal of improving critical attributes of an ADC. In an ongoing phase 1 trial, DS-8201a showed promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed objective response rate [ORR] of 54.5%; April 2018 data cutoff; Iwata et al, ASCO 2018). Based on preliminary results from the phase 1 trial, DS-8201a received FDA breakthrough therapy and fast track designations for metastatic BC that progressed after prior treatment with T-DM1. The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC whose disease progressed on or after T-DM1 (NCT03523585, DESTINY-BREAST02). Approximately 600 subjects will be randomized (2:1) to DS-8201a or investigator9s choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine). Randomization is stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. DS-8201a (5.4 mg/kg) will be administered IV once every 3 weeks. Progression free survival (PFS) based on blinded, independent central review using RECIST v1.1 criteria is primary efficacy endpoint; overall survival (OS) is the key secondary endpoint. Other secondary efficacy endpoints are ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health-related quality of life will also be measured. The primary analysis for PFS will occur when approximately 372 PFS events have been observed; providing 90% power to detect a hazard ratio of 0.70 in PFS (a 43% improvement in median PFS from 3.3 months with investigator9s choice to 4.7 months with DS-8201a) with a 1-sided alpha of 0.025. An interim OS analysis is planned at the time of the PFS analysis. Final OS analysis will occur when approximately 428 OS events have been observed. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 160 sites including in North and South America, Europe, and Asia. For further information on this trial, contact Fabrice Andre at FABRICE.ANDRE@gustaveroussy.fr or visit clinicaltrials.gov. Citation Format: Andre F, Shahidi J, Lee C, Wang K, Krop IE. Trastuzumab deruxtecan (DS-8201a) vs investigator9s choice of treatment in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received T-DM1: A randomized, phase 3 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-02.

Should trastuzumab be administered concomitantly with anthracycline in women with early, HER2-positive breast cancer?

Abstract: Clinical targeting of the human epidermal growth factor receptor 2 (HER2) has dramatically improved the outlook of a subset of about 15% of breast cancers carrying HER2 gene amplification and/ or HER2 protein overexpression. Since the initial experiences with the anti-HER2 monoclonal antibody trastuzumab, it was clear that combination with conventional chemotherapy was required to exploit the full potential of HER2-targeting. However, prohibitive rates of cardiac toxicity were observed when trastuzumab was given concurrently with anthracyclines, which are compounds that have played a pivotal role in the treatment of breast cancer for decades. While most of the anti-HER2 programs have been designed as to avoid concomitance with anthracyclines, high rates of pathological complete remission were obtained in carefully selected patients with operable breasts cancer receiving concomitant trastuzumab and anthracycline in the preoperative setting. A recently published randomized study compared directly the current standard of sequential anthracycline followed by concomitant taxane and trastuzumab with a reversed sequence of taxanes followed by anthracyclines with trastuzumab administered concurrently with the whole program as neoadjuvant treatment for patients with early, operable breast cancer. The practical question asked by this study was whether a potential increase in the efficacy of trastuzumab based regimens could be worth the risk of giving it in concomitance with anthracyclines. This editorial will review the background of this study and discuss the impact of its results on the current clinical practice and on future research in the field.