Pretreated HER2-positive Advanced Breast Cancer Research Articles

HERibuline: Eribulin mesylate and Trastuzumab in pretreated HER2-positive advanced breast cancer—A report of region’s practice.

e13020 Background: Until 2020, in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), the two first lines of metastatic treatment were well defined but after, many options were possible, most often combining targeted therapy plus chemotherapy. Eribulin mesylate is indicated for the treatment of patients with ABC previously treated by anthracycline and taxane regimens in the advanced setting. Here, we present the results of eribuline and trastuzumab (E/T) combination in HER2-positive ABC previously treated. Methods: Patients with HER2-positive ABC treated with the E/T combination from our region cancer institute were included in this retrospective study. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and safety. Results: Between November 2013 and July 2019, a total of 34 consecutive patients with HER2-positive ABC were included. The median number of previous lines for advanced setting was 4 (range 2-7). Patients treated by taxanes and anthracyclines represented 91% and 47% respectively; 50%, 79% and 62% were previously treated with pertuzumab, trastuzumab emtansine and lapatinib respectively. After a median follow up of 24.8 months, median PFS was 6.2 months (95% CI [3.35-7.13]) and median OS was 12.6 months (95% CI [7.13-18.56]). The ORR and CBR were 38% and 53%, respectively. No unexpected adverse event was observed. The most frequent grade 3-4 toxicity was hematologic (44.1%). Conclusions: Recently, new therapies have revolutionized the management of HER2-positive ABC and patients benefit from a prolonged overall survival associated with a maintained performance status. However, in pretreated and advanced metastatic setting, there are few scientific evidence to guide the choice of treatments. A combination of E/T could be an effective option in patients with good performance status and willing to receive treatment.

Anti-HER2 antibody inetetamab plus camrelizumab and utidelone for pretreated HER2-positive advanced breast cancer: A single-arm, multicenter, phase 2 study.

e13030 Background: Treatment options for patients with HER2-positive breast cancer after progression on two or more lines of HER2-directed therapies are scarce. Inetetamab, a novel anti-HER2 antibody, exhibits the same binding affinity to HER2 antigen and antibody-dependent cell-mediated cytotoxicity as trastuzumab. Previous studies have demonstrated the treatment potential of PD-1 inhibitor combined with HER2-targeted therapy in HER2-positive gastric or gastroesophageal junction cancer. Utidelone, a genetically engineered epothilone analogue, has shown promising efficacy in heavily pretreated metastatic breast cancer. This study aimed to investigated inetetamab plus camrelizumab (anti-PD-1 antibody) and utidelone in patients with HER2-positive recurrent or metastatic breast cancer who had progressed after at least two lines of HER2-directed therapies with trastuzumab and tyrosine kinase inhibitors (TKIs). Methods: In this phase 2 study (NCT04681287), patients received intravenous camrelizumab (200 mg once every 3 weeks), inetetamab (8 mg/kg loading dose then 6 mg/kg, day 1), and utidelone (30 mg/m2, days 1-5) until disease progression or intolerable toxicity. The primary endpoint was 3-month progression-free survival (PFS) rate according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Secondary endpoints included objective response rate (ORR), PFS, overall survival, and safety. Simon’s two-stage design was adopted for this study. Results: Between April 2021 and January 2022, a total of 27 patients were enrolled. As of January 2022, 20 patients could be analyzed. The median number of previous systemic therapies for advanced disease was three. Previous HER2-targeted therapies included trastuzumab (20 [100%]), pyrotinib (17 [85%]), lapatinib (7 [35%]), pertuzumab (3 [15%]), and margetuximab (2 [10%]). The first stage required 10 patients, and 8 of them were free from progression at 3 months. The study proceeded to the second stage for another 31 patients, and the accrual is ongoing. The 3-month PFS rate in 20 patients was 75%. The ORR was 30% (6/20); one (5%) patient achieved complete response. The most common treatment-related adverse events (TRAEs) were peripheral neuropathy (19 [98%]), capillary proliferation (19 [98%]), alopecia (18 [90%]), and fatigue (7 [35%]). Grade ≥3 TRAEs included peripheral neuropathy (2 [10%]) and rash (1 [5%]). No treatment-related treatment discontinuation or deaths occurred. Conclusions: Inetetamab plus camrelizumab and utidelone showed promising efficacy and acceptable safety profile in patients with HER2-positive advanced breast cancer after progression on at least two lines of HER2-directed therapies with trastuzumab and TKIs. Clinical trial information: NCT04681287.

Margetuximab for the treatment of HER2-positive metastatic breast cancer

ABSTRACT Introduction No specific standard treatment is currently recommended for HER2-positive advanced breast cancer (BC) patients progressing to dual HER2 blockade and to trastuzumab emtansine (TDM-1). However, several novel anti-HER2 agents are emerging and rapidly revolutionizing this setting. Among these, the FC-engineered monoclonal antibody margetuximab has recently demonstrated to slightly improve progression-free survival (PFS) compared with trastuzumab, when combined with chemotherapy for pretreated HER2-positive advanced BC. Areas covered The present review article recapitulates the clinical development of margetuximab, critically discussing its implications in the current landscape of BC treatment algorithms. Expert opinion The clinical role of Margetuximab can only be interpreted in view of the rapidly evolving treatment landscape for pretreated HER2-positive advanced BC. Indeed, the recently approved anti-HER2 agents tucatinib and trastuzumab deruxtecan currently represent appealing options for the post-TDM1 setting, while margetuximab may have a role after progression to the abovementioned agents, in case of a future approval. Regardless of its clinical uptake, it should be noted that the development of margetuximab has relevantly improved our biological understanding of HER2-positive BC, highlighting the implication of patient’s genotype in determining treatment outcomes, as well as the relevance of antibody-dependent cellular cytotoxicity (ADCC) in the context of HER2-blockade.

First-in-human phase I study of ALT-P7, a HER2-targeting antibody-drug conjugate in patients with HER2-positive advanced breast cancer.

3551 Background: ALT-P7 is an antibody-drug conjugate, in which two molecules of monomethyl auristatin E (MMAE) are site-specifically conjugated to a cysteine-containing peptide motif of trastuzumab variant. This is the first-in-human study evaluating safety and pharmacokinetics of ALT-P7 in patients with HER2-positive advanced breast cancer. Methods: This was an open label, 3+3 dose-escalation phase 1 trial. Eligible patients were with HER2-positive advanced breast cancer progressive to at least two kinds of prior anti-HER2 treatment. ALT-P7 at doses from 0.3mg/kg to 4.8mg/kg were intravenously administered once every 3 weeks. Dose limiting toxicities were evaluated over the first cycle of 21 days. Primary objective was to define the maximum tolerated dose. Results: ALT-P7 were administered in 27 patients (n=4 at 0.3mg/kg, n=3 at each of 0.6, 1.2, 2.4, 3.6, 4.2, 4.5 mg/kg, n=5 at 4.8mg/kg) between Jan 2018 and Feb 2020. The median number of previous line of systemic therapy was six, including median four prior anti-HER2 agents. The most common grade (G) 3/4 adverse event (AE) was neutropenia (n=4). The other common drug-related AEs of all grade were myalgia (n=9), fatigue (n=7), sensory neuropathy (n=6), alopecia (n=6), pruritus (n=6), and neutropenia (n=6). Dose limiting toxicities(DLTs) were observed in three patients at 4.8mg/kg (G4 febrile neutropenia, G4 thrombocytopenia, G4 hyperbilirubinemia, G3 myalgia, G4 hyponatremia). No DLTs have been observed up to 4.2mg/kg, and safety evaluation at 4.5mg/kg is currently ongoing. Toxicokinetic analysis for total antibody, drug-conjugated antibody, and free payload suggested that there were no accumulation of ALT-P7 upon repeated injection. In 22 patients with response evaluation, disease control rate at 6 weeks of ALT-P7 treatment was 77.3%(17/22) and partial response was achieved in two out of fifteen patients with measurable lesion. The median PFS at doses from 2.4 to 4.8mg/kg was 6.2 months (95% CI 2.5-9.9 months). Conclusions: ALT-P7 was well tolerated to a dose of 4.2mg/kg in heavily pretreated HER2-positive advanced breast cancer. DLTs were observed at 4.8mg/kg, and 4.5mg/kg is under evaluation. The observed clinical activity warrants further evaluation in a phase 2 trial. Clinical trial information: NCT03281824. Clinical trial information: NCT03281824 .

Eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer patients: safety and efficacy. An Italian experience.

Background:Chemotherapy plus targeted therapy is the established treatment for human epidermal growth factor receptor 2 (HER2)–overexpressing breast cancer (BC). Limited data regarding the safety and activity of the combination of eribulin and trastuzumab (E/T) in pretreated HER2-positive advanced BC (ABC) are available. The aim of this observational, retrospective, multicenter study was to examine the tolerability and the clinical activity of E/T in this setting.Methods:Patients treated with eribulin mesylate plus standard dose of trastuzumab were included. Data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were reported.Results:Between October 2012 and November 2015, 24 consecutive patients with HER2-positive ABC were included. All patients were heavily pretreated: the median number of prior chemotherapy regimens for ABC was 3 (range 2–9). The median number of cycles with E/T was 11.5 (range 2–26). The ORR was 41.7%. Median PFS was 5.4 months, median postprogression survival was 5.4 months, and median OS was 8 months. Neutropenia was the most common grade 3/4 clinical adverse event (16.7%).Conclusions:Tolerability and clinical activity of the E/T combination schedule are encouraging. The results of this study indicate that this combination might be considered for treatment of pretreated HER2 ABC.

Phase Ib dose-finding trial of lapatinib plus pegylated liposomal doxorubicin in advanced HER2-positive breast cancer

PurposeCombination of anthracyclines with trastuzumab is hampered by cardiotoxicity. Pegylated liposomal doxorubicin and lapatinib could represent a safer alternative to combination therapy.MethodsIn this phase Ib study with 3 + 3 dose escalation design, patients with HER2-positive advanced breast cancer received pegylated liposomal doxorubicin 30 mg/m2 intravenously on day 1 plus lapatinib 1250 (level 1) or 1500 (level 2) mg/day orally on days 1–21 of each 21-day cycle. The aims were to establish the maximum tolerated dose at first cycle, and the activity and safety of multiple cycles.ResultsNine patients out of 11 enrolled were evaluable: 3 at level 1 and 6 at level 2. No dose-limiting toxicities occurred at dose level 1, while 1 (grade 3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further dose-limiting toxicities. Main grade 1–2 toxicities at first cycle were leucopenia, diarrhea, elevated transaminases, mucositis. Three patients had grade 3 toxicities at subsequent cycles, including colitis, anorexia, stomatitis plus hand-foot syndrome. One partial response, 5 disease stabilizations, and 3 disease progressions were reported.ConclusionsCombination of pegylated liposomal doxorubicin and lapatinib is feasible and potentially active in pretreated HER2-positive advanced breast cancer patients.Trial registrationNCT02131506 (ClinicalTrials.gov identifier).

Abstract P5-15-11: Eribulin should be a candidate strategy in combination with pertuzumab plus trastuzumab for taxane pretreated HER2 positive advance breast cancer

Abstract Background: Pertuzumab (P) improves clinical outcome when combined with docetaxel and trastuzumab (T). The efficacy of continuing multiple anti-HER2 therapy including P and/or T after initial progression is unclear. Eribulin mesylate (ERI) is able to overcome taxane (TAX) resistance advanced breast cancer (ABC). The objective of this study is to investigate the efficacy and safety of ERI plus P and T for both TAX and T pretreated HER2-positive ABC. Methods: This is a single institute, open-label, single-arm, Phase II study with pharmacokinetics (PK) of ERI (UMIN000012375). The initial dose of P is 840 mg, followed by 420 mg q3w; the initial dose of T 8 mg/kg, followed by 6 mg/kg q3w; ERI is administered at 1.4 mg on Days 1 and 8 of each cycle, q3w. Dose reductions of ERI (to 1.1 and 0.7 mg/m2) were permitted to manage any toxicity (more than grade 3). Patients (Pts) must have previous treatment with both TAX and T. The primary endpoint is assessed overall response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), safety, and PK of ERI. Left ventricular ejection function (LVEF) was evaluated before and end of this study. Results: Thirty Pts were enrolled. Median age at baseline was 57 years. Half of Pts had endocrine positive. All Pts were treated with TAX and T. Twenty-one Pts were treated with anthracycline-based treatment (70%). Median number of previous chemotherapy was 4 (2-5). Pts had multiple metastases, 40% with bone, 36.7% with lung, 20% with liver, and 10% with brain. Pts received a median number of 8 cycles of ERI (mean dose 1.2 ± 0.19 mg/sqm), 8 cycles of both P and T. Total number of 27 Pts needed to reduce dose of ERI because of adverse events (AEs) especially grade 3 neutropenia. The ORR (CR+PR) was 34.8% (95% CI 16.4-57.3, n=23) with median PFS of 42.6 weeks (95% CI 20.3-51.9, n=30). Clinical benefit rate (CR+PR+≥6 month SD) was 60.9% (95% CI 16.4-57.3%). T-DM1 pretreated affected poor outcome than the other factors (p=0.0011). The most common grade 3/4 AEs were neutropenia in 20 Pts (66.7%) without febrile neutropenia. Grade 1/2 AEs were fatigue in 24 Pts (80%), anorexia in 23 Pts (76.7%), anemia in 22 Pts (73.3%), diarrhea in 20 Pts (66.7%), peripheral neuropathy in 16 Pts (53.3%), and hand-foot syndrome in 12 Pts (43.3%). Baseline LVEF was 67%. One Pt had asymptomatic LVEF decrease (below an absolute value of 55%). Otherwise, there was no overall decrease in mean LVEF from baseline. Nine points (pre-dose, end of infusion, 0.5, 1, 2, 4, 24, 72, and 168 h after ERI) of PK analyses were evaluated in 6 Pts, and 3 point (pre-dose, end of infusion, and 168 h after ERI) in 10 Pts. PK parameters of ERI were as follows; Maximum plasma concentration (Cmax) was 375.96 (257.6-531.8) ng/ml, terminal half-life was 36.807 (31.90-40.80) h, total clearance was 1.945 (1.15-3.15) L/h/m2. Cmax of ERI was not correlated with neutrophil count (R2=0.2338, n=16). Conclusions: The combination of ERI plus P and T was well tolerated; no new safety signals ware observed. PK parameter of ERI were as same as previous reports when combined with both P and T. ERI might be a one of strategy in combination with P plus T for TAX pretreated HER2 positive ABC. Citation Format: Araki K, Fukada I, Kobayashi K, Takahashi S, Ito Y. Eribulin should be a candidate strategy in combination with pertuzumab plus trastuzumab for taxane pretreated HER2 positive advance breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-11.

247P - Safety and efficacy of eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer (ABC) patients. An Italian multicenter experience

247P - Safety and efficacy of eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer (ABC) patients. An Italian multicenter experience

Eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer (ABC) patients: Results on safety and efficacy—An Italian multicenter experience.

e12087Background: Chemotherapy (CT) plus targeted therapy is the established treatment for HER2 overexpressing breast cancer (BC) patients (pts). The debate about anti-HER2 combination beyond standard therapies is still unresolved. Limited data regarding the safety and activity of the combination of eribulin and trastuzumab (E/T) in pretreated HER2-positive advanced breast cancer (ABC) are available. The aim of this observational, retrospective, multicenter study was to examine the tolerability and the clinical activity of eribulin plus trastuzumab in this setting. Methods: Pts treated with eribulin mesylate (1.23 mg/m2 administered via intravenous infusion on Days 1 and 8 each 21-day cycle) plus standard dose of trastuzumab (16 pts received 3-week schedule: 8 mg/kg load, 6 mg/kg q 3 weeks; 3 pts received weekly schedule: 4 mg/kg load, 2 mg/kg q week) were included. Data on overall response rate (ORR), progression free survival (PFS), post-progression survival (PPS), overall survival (OS) and safety were ...

Real-life effectiveness of T-DM1 in heavily pretreated HER2-positive advanced breast cancer patients: An Italian observational study.

e12019Background: T-DM1 showed remarkable activity in metastatic (m) HER-2 positive breast cancer (BC) and it recently was approved for clinical use in patients (pts) who previously failed trastuzumab and taxanes. The impact of drug prescription in real life compared with the findings reported in clinical trials exerting a strict accrual criteria has been rarely assessed. We investigated use and effectiveness of T-DM1 in daily practice. Methods: We included all pts with HER2-positive mBC, diagnosed in 12 Italian oncology hospitals between 2013 and 2015. Our aim was to assess the actual use of T-DM1 in HER2 positive mBC pts and its efficacy in clinical practice. Results: The data of 119 pts were retrospectively collected. The median age was 49 years (28-78), visceral metastases were present in 91 pts (77%) and brain metastases in 44 (37%). It is noteworthy that 29 pts (24%) received T-DM1 as second-line, 42 (35%) as third-line, and 43 (36%) as fourth- or further-line option. Moreover, 4 pts had TDM-1 as fi...

Patient-reported outcomes (PROs) from TH3RESA, a phase 3 study of trastuzumab emtansine (T-DM1) versus treatment of physician’s choice (TPC) in patients with pretreated HER2-positive advanced breast cancer.

153 Background: Progression-free survival and objective response rate were significantly improved with T-DM1 vs TPC in TH3RESA. The impact of treatment on quality of life is a key aspect in determining treatment value. Here we present the PRO results from the TH3RESA study. Methods: Patients were randomized 2:1 to T-DM1 (3.6 mg/kg every 21 days) or TPC. Patients were asked to complete the EORTC QLQ-C30 (a 30-item questionnaire assessing symptom bother, functioning and health status) and the EORTC QLQ-BM22 (a 22-item survey evaluating pain from bone metastases) at the start of each cycle. Data from patients with a baseline and ≥1 post-baseline assessment were included; a clinically meaningful difference was defined as ≥10 points. Time to pain progression (TPP) was assessed using the Kaplan-Meier method and Cox proportional-hazards models. Results: A greater proportion of patients in the T-DM1 arm (n=297) vs. the TPC arm (n=117) experienced a clinically meaningful improvement in global health status (57.8% [95% CI; 52.0–63.3] vs. 47.1% [95% CI; 38.4–56.4]). The most bothersome symptoms in the T-DM1 arm as measured by the EORTC QLQ-C30 were fatigue and pain. Over the first 10 T-DM1 treatment cycles, 19–30% of patients reported being impacted “quite a bit” or “very much” by fatigue, and 16–25% by pain. Nausea/vomiting and diarrhea were perceived as more tolerable, with 1–5% and 1–4% of patients reporting “quite a bit” or “very much” impact, respectively. TTP was 2.9 months in the T-DM1 arm vs 3.6 months in the TPC arm, but was not significantly different (HR 1.12 [95% CI; 0.82–1.52], p = 0.495). Mean baseline EORTC QLQ-BM22 pain scores were similar in the T-DM1 (n = 306) and TPC arms (n = 130); (25.4 ± 23.8 [SD]) and (27.3 ± 24.4), respectively. There were no clinically meaningful changes in pain levels from baseline over time in either arm. Conclusions: For patients on T-DM1, the most impactful symptoms were fatigue and pain, while the least bothersome were diarrhea and nausea/vomiting; distribution of severity of impact was relatively stable over the first 10 cycles of treatment. TPP was similar between the T-DM1 and TPC arms. Clinical trial information: NCT01419197.

Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial

Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare trastuzumab emtansine, an antibody-drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, with treatment of physician's choice in this population of patients. This randomised, open-label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncology Group performance status 0-2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), number of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS analysis and the first interim overall survival analysis. This study is registered with ClinicalTrials.gov, number NCT01419197. From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to trastuzumab emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to trastuzumab emtansine. After a median follow-up of 7·2 months (IQR 5·0-10·1 months) in the trastuzumab emtansine group and 6·5 months (IQR 4·1-9·7) in the physician's choice group, 219 (54%) patients in the trastuzumab emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with trastuzumab emtansine compared with physician's choice (median 6·2 months [95% CI 5·59-6·87] vs 3·3 months [2·89-4·14]; stratified hazard ratio [HR] 0·528 [0·422-0·661]; p<0·0001). Interim overall survival analysis showed a trend favouring trastuzumab emtansine (stratified HR 0·552 [95% CI 0·369-0·826]; p=0·0034), but the stopping boundary was not crossed. A lower incidence of grade 3 or worse adverse events was reported with trastuzumab emtansine than with physician's choice (130 events [32%] in 403 patients vs 80 events [43%] in 184 patients). Neutropenia (ten [2%] vs 29 [16%]), diarrhoea (three [<1%] vs eight [4%]), and febrile neutropenia (one [<1%] vs seven [4%]) were grade 3 or worse adverse events that were more common in the physician's choice group than in the trastuzumab emtansine group. Thrombocytopenia (19 [5%] vs three [2%]) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group. 74 (18%) patients in the trastuzumab emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. Trastuzumab emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received trastuzumab and lapatinib. Genentech.

A case of metastatic breast cancer successfully treated with lapatinib plus capecitabine therapy

Lapatinib is a dual tyrosine-kinase inhibitor which targets both human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) tyrosine kinases [1]. It has the advantage of being administered orally. Lapatinib showed promising results both in trastuzumab-naive and in pretreated HER2-positive advanced breast cancer [2–5]. It has been shown that lapatinib plus capecitabine is superior to capecitabine alone in HER2positive advanced breast cancer patients previously treated with anthracycline, taxane and trastuzumab [6]. Herein, we describe a case of metastatic breast cancer patient who had resistance to trastuzumab and showed a clinically complete response to lapatinib with capecitabine therapy.