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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The first agent of this class to be approved was the HER2-specific monoclonal antibody trastuzumab (HerceptinTM) which was developed by Genentech/Roche and approved in 1998. It demonstrated a clear clinical benefit in HER2-positive breast cancer and is now widely used in this disease. However, resistance to trastuzumab occurs, so other related therapeutics have been developed to address this problem. For example, pertuzumab (PerjetaTM) is a monoclonal antibody used in combination with trastuzumab and docetaxel for the treatment of metastatic HER2-positive breast cancer. It was the first-in-class HER dimerization inhibitor that works by inhibiting the dimerization of one type of HER2 receptor with another, thus preventing them from signaling to promote cell growth and proliferation. Discovered and developed by Genentech, it was first approved by the FDA in 2012. An alternative approach by Genentech involved the conjugation of a highly cytotoxic small molecule (i.e. a “payload”) to trastuzumab via a cleavable chemical linker to form an Antibody-Drug Conjugate (ADC). First approved by the FDA in 2013, this agent, trastuzumab emtansine (KadcylaTM) delivers the highly cytotoxic tubulin-interactive emtansine payload to HER2-positive tumor cells, a strategy that can be effective in patients resistant to trastuzumab alone. Trastuzumab (HerceptinTM), pertuzumab (PerjetaTM), and trastuzumab emtansine (KadcylaTM) are described in detail in Chapter 7.
HER-2 as a Prognostic and Predictive Biomarker in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alexandra S. Zimmer, Suparna B. Wedamb, Stanley Lipkowitza
Pertuzumab is an antibody which inhibits dimerization of HER-2 with other members of the EGFR family, thus inhibiting activity of HER-2 [114–116]. Two phase II trials measured the efficacy of pertuzumab in combination with trastuzumab in patients that had HER-2 amplification in their tumors and whose tumors had progressed on trastuzumab based therapies [117, 118]. The ORR for the two studies was 16/66 (24%) and 2/11 (18%), and prolonged stable disease was noted in 17/66 (26%) and 3/11 (27%) patients for an overall clinical benefit of approximately 50%. In contrast, a phase II study that investigated the efficacy of pertuzumab in patients with HER-2 negative tumors (FISH negative and/or IHC 0, 1+ or 2+) found very low rates of clinical benefit [119]. Partial responses were seen in 2 of 78 (2.6%) patients and stable disease lasting greater than 24 weeks in 4 of 78 (5%), resulting in a clinical benefit in approximately 7.7% of patients. The data was consistent with HER-2 amplification/overexpression as a predictive biomarker although more data will be needed to assess this fully.
Breast Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Amy Case, Gwenllian Edwards, Catherine Pembroke
In more recent years, dual anti-HER2 targeted therapy, with both adjuvant trastuzumab and pertuzumab, has become the new standard of care for HER2-positive patients in the node-positive setting. Pertuzumab is a monoclonal antibody with a complementary mechanism of action to that of trastuzumab. It inhibits HER2 heterodimerization with other HER family receptors, thus inducing cell-mediated cytotoxicity. The APHINITY trial was a prospective randomized controlled trial (RCT) of 4,805 HER2-positive patients randomized to receive either placebo or pertuzumab for 1 year in addition to the standard of care (chemotherapy and trastuzumab).86 The addition of pertuzumab was found to be associated with a significantly higher invasive-disease free survival of 7.1% versus 8.7% in the placebo group, with the biggest effect seen in those with lymph-node involvement or hormone receptor–negative disease. The evidence for the impact on overall survival is awaiting maturity.
Management of breast cancer diagnosed during pregnancy: global perspectives
Published in Expert Review of Anticancer Therapy, 2022
Jyoti Bajpai, Rima Pathak, T.S. Shylasree, Hope S. Rugo
In contrast to chemotherapy, owing to its molecular weight, trastuzumab’s placental transfer is minimal during the first trimester but increases from the second trimester onwards and is associated with oligo/anhydramnios and premature delivery. Trastuzumab is not recommended during pregnancy due to substantial risks involved, however, it may be carefully discussed in special high-risk situations weighing fetal and maternal risks and benefits [36]. However, in the HERA trial, a few women who accidentally conceived while receiving trastuzumab delivered healthy neonates [31,35]. Inadvertent fetal exposure to 1 to 2 cycles of trastuzumab therapy is not a strong reason for termination of pregnancy.There is lack of data about pertuzumab and hence it should be avoided. Figure 1A shows the management algorithm.
Breast cancer treatment-related cardiovascular disturbances: advocacy for a watchful attitude in this never-ending story
Published in Expert Opinion on Drug Safety, 2022
Charlène Rivier, Benoite Mery, Elise Rowinski, Sandrine Sotton, Wafa Bouleftour, Laurent Bertoletti, Olivier Tredan, Nicolas Magne
At the beginning of the century, trastuzumab first proved efficient in early [13] and metastatic [14] HER-2 positive breast cancers. Unfortunately, it caused cardiac reversible toxicity [15] resulting in various consequences of asymptomatic decrease in cardiac function to symptomatic heart disease, as reported in meta-analyses [16,17]. Recently, pertuzumab has also emerged as a standard therapy in metastatic disease [18], with no new safety signal as regards cardiac events. In NeoSphere [19], about early breast cancer, the 5-year analysis reported a total of 5% of cardiac events (all groups combined), with only one case of grade 3 left ventricular dysfunction in the pertuzumab group. These results are correlated with those of APHINITY [20] that reported a few cardiac effects. In 2017, the long-term results of phase II TRYPHAENA [21] (223 patients included) were published. Low rates of symptomatic left ventricular systolic dysfunction were found (from 0% to 2.7% according group) as well as a LVEF decline of ≥10% from baseline to <50% (11.1% to 16%). Finally, the primary analysis of cardiac safety during the neoadjuvant period in BERENICE [22] also showed reassuring data with low rates of New York Heart Association (NYHA) class III and IV heart failure (1.5% at most) and confirmed LVEF decline (0.5–1%).
Development and validation of an LC-MS/MS method for simultaneous quantification of co-administered trastuzumab and pertuzumab
Published in mAbs, 2020
Sandor Schokker, Fabrizia Fusetti, Francesco Bonardi, Remco J. Molenaar, Ron A.A. Mathôt, Hanneke W.M. van Laarhoven
The TRAP trial was a Dutch, investigator-initiated, multicenter, Phase 2 feasibility study where trastuzumab and pertuzumab were added to neoadjuvant chemoradiation with carboplatin and paclitaxel (NCT02120911).6 The trial was approved by the institutional review board of the Amsterdam University Medical Centers and conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients provided written, voluntary informed consent prior to inclusion. In short, HER2-positive patients with resectable esophageal adenocarcinoma received paclitaxel (50 mg/m2), carboplatin (area under the curve = 2) and radiotherapy (23 × 1.8 Gy) over the course of 5 weeks. Intravenous trastuzumab was administered in a loading dose of 4 mg/kg with subsequent weekly doses of 2 mg/kg in weeks 2–6, and ultimately 6 mg/kg every 3 weeks in weeks 7–13. Intravenous pertuzumab was dosed at 840 mg every 3 weeks until week 13. Doses could be delayed, but not reduced. Surgery was performed around 14 weeks after start of neoadjuvant treatment. PK sampling was done pre-dose on days 1, 8, 15, 22, 29, 43, 64, and 85, and post-dose on days 1, 22, 43, 64, and 85. Further methods of this study have been published previously.6