Prior Trastuzumab Research Articles

102P - Multicenter phase 2 trial of varlitinib versus lapatinib in combination with capecitabine in patients with HER2+ metastatic breast cancer (MBC) who failed prior trastuzumab therapy

102P - Multicenter phase 2 trial of varlitinib versus lapatinib in combination with capecitabine in patients with HER2+ metastatic breast cancer (MBC) who failed prior trastuzumab therapy

Abstract CT013: NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC)

Abstract Background: T-DM1, an antibody-drug conjugate that delivers the maytansinoid antimicrotubule agent DM1 to antigen-expressing HER2+ cells thereby improving the therapeutic index, is FDA- approved as 2nd-line therapy in HER2+ MBC patients (pts) after prior trastuzumab (T) and a taxane. Most pts currently receive T and pertuzumab (P) as neoadjuvant for 1st-line therapy for MBC. A retrospective analysis of T-DM1 after T-P found a much lower tumor response rate (17%) than T-DM1 after T and taxane, as reported in EMILIA (43%). In NSABP FB-8, combining T, N, and paclitaxel achieved responses after T-DM1 progression, raising the possibility that N could reverse resistance to T-DM1. Methods: Eligible pts had prior T-P as neoadjuvant therapy for 1st-line metastatic treatment for HER2+ measurable disease, ECOG PS <2, adequate hematologic, renal, and liver function. Treatment consisted of T-DM1 at 3.6 mg/kg iv q 3 wk and N at escalating doses of 120, 160, 200, and 240 mg/d continuously, using 3+3 design. Each cycle was 21 d. Clinical endpoints include determination of safety and efficacy. Primary diarrhea prophylaxis with intensive loperamide was required. To compare steady-state blood levels of N across dose levels samples were drawn at the start of cycle 2. Results: The RP2D is still undergoing evaluation. 17 T-P resistant pts were enrolled. Treatment-related grade 3 toxicities included diarrhea (2 pts), thrombocytopenia (3 pts), hypertension (2 pts), ALT elevation (1 pt), nausea (1 pt), and neutropenia (1 pt). Of 14 pts who were evaluable after 2 cycles of therapy, 3 had CRs and 6 had PRs (ORR 64%). Dose (mg/day)No. of objective responses (CR/PR)/No. of evaluable (CR/PR/SD/PD)Duration of objective response (weeks)DLTs1205/5 (CR 2, PR 3)66+,51,26,15,91 (nausea and dehydration)1602/4 (CR 1, PR 1, PD 2)39+,6No2001/3 (PR 1, SD 1, PD 1)21No2401/2 (PR 1, SD 1)152 (diarrhea, nausea, vomiting) Conclusions: T-DM1 plus N was well tolerated at doses of 120, 160, and 200 mg/d. Anti-tumor activity did not appear to be dose-dependent. 5 evaluable pts treated at lowest dose of N (120 mg/d) responded. A randomized phase II study comparing N at 120 mg/d and 200 mg/d with T-DM1 is planned to better define efficacy and tolerance. Support: Puma Biotechnology Citation Format: Jame Abraham, Shannon L. Puhalla, Wiliam M. Sikov, Alberto J. Montero, Jan H. Beumer, Marc E. Buyse, Laura M. Adamson, Ashok Srinivasan, Katherine L. Pogue-Geile, Samuel A. Jacobs. NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT013. doi:10.1158/1538-7445.AM2017-CT013

Duration of second-line T-DM1 therapy: Is it associated with duration of first-line anti-Her2 therapy in metastatic HER2 + breast cancer?

e12512 Background: Tumors with HER2 overexpression usually respond to HER2-targeted therapies. Since the CLEOPATRA and EMILIA trials, a taxane plus trastuzumab and pertuzumab (TTP) are the first-line standard for the management of HER2 + metastatic breast cancer (MBC) and trastuzumab emtansine (TDM-1) is the second-line standard. Intrinsic subtypes existing within HER2+ tumors may impact the degree of a patient’s response to anti HER2 therapy; however HER2 subtyping for predicting response is still experimental and not in routine clinical use. In this retrospective population-based study, we aimed to assess whether duration of treatment (DOT) of second-line TDM1 is associated with the DOT of first-line TTP, and might serve as a hint for a HER2 subtype. Methods: Clalit Health Services (CHS) manages health care of 52% of the Israeli population. We identified 113 HER2+ CHS MBC patients, treated with TTP as first-line treatment that initiated TDM1 as second-line, until Dec. 31, 2016. Patient's (pts) demography, HER2 and HR status were recorded. A Cox proportional hazard model, stratified by HR status, adjusted for age and prior adjuvant trastuzumab, was used to explore the association between second-line and first-line DOT in HR positive and negative pts. Results: Pts baseline characteristics and DOT in first- and second-line treatment are presented in the table. A statistically significant association between DOT of both treatment lines was found in HR positive pts with a trend also in HR negative pts. Conclusions: The observed association between first- and second-line DOT, unrelated to hormonal status, may result from a primary characteristic of the intrinsic tumor subtype, that impacts acquired resistance. Longer observations in larger patient cohorts are required to confirm this observation. [Table: see text]

A phase Ib, first-in-human, dose escalation and expansion study of XMT-1522, a novel antibody-drug conjugate (ADC) directed against HER2, in patients with advanced breast cancer and other advanced tumors expressing HER2.

TPS2606 Background: XMT-1522 is an ADC consisting of a novel human IgG1 anti-HER2 monoclonal antibody conjugated to an auristatin-based cytotoxic payload (AF-HPA). An average of 12 AF-HPA molecules is conjugated to each antibody via a biodegradable polymer. In pre-clinical xenograft experiments XMT-1522 achieved complete, durable tumor regressions in models of HER2-positive and HER2 1+/2+ breast cancer, HER2 2+/3+ NSCLC, and HER2-positive and HER2 1+ gastric cancer. Methods: This study (NCT02952729) is comprised of two parts: a dose escalation segment (DES) and an expansion segment (EXP). The primary objectives of the DES are determination of the maximum tolerated dose and recommended Phase 2 dose (RP2D) and assessment of safety and tolerability. The DES will enroll patients with advanced or metastatic breast cancer who have progressed following standard therapies and have HER2 protein at least 1+ by IHC. XMT-1522 will be administered intravenously every 3 weeks. DES uses a 3+3 design. Post-dose assessments include LVEF measurement at the end of cycles 1, 3, then every 3 cycles, ophthalmologic exams at the end of cycles 1, 2, then every 2 cycles, and re-staging CT scans every 2 cycles. Pharmacokinetics of antibody, AF-HPA payload and an AF-HPA metabolite will be measured. Two patients have completed dose level 1 without DLT. The EXP segment will open at the RP2D and will further assess safety and tolerability of XMT-1522 and assess efficacy in selected patient populations. EXP will enroll 4 cohorts (N = 20 each). Cohort 1: HER2 1+/2+ advanced breast cancer with 2-3 prior chemotherapy regimens Cohort 2: HER2-positive advanced breast cancer with prior pertuzumab and ado-trastuzumab emtansine (T-DM1) Cohort 3: HER2-positive advanced gastric cancer with prior trastuzumab Cohort 4: HER2 2+/3+ NSCLC with at least 1 prior platinum regimen The protocol requires archival tumor tissue for central confirmation of HER2 status, alternative HER2 measurements, and targeted gene expression and sequencing studies. Tumor biopsies will be requested at the time of progression from patients who responded to XMT-1522. Clinical trial information: NCT02952729.

Abstract P4-21-30: Long-term survival in HER2-positive metastatic breast cancer: The first blow is half the battle

Abstract Introduction: Metastatic breast cancer (MBC) is considered an incurable disease. However, long-term survival is increasingly observed in HER2-positive disease since the introduction of trastuzumab. We explored factors associated with long-term survival in a retrospective series at our Institute. Methods: All patients with histologically proven HER2-positive (3+ score by IHC or HER2 amplification) MBC treated starting first-line trastuzumab-based palliative therapy between January 2003 to January 2013 were included. Patients were identified from the Institute's tumor registry and data were collected from patient records. The primary endpoint was overall survival. Kaplan-Meier survival estimates were calculated and multivariable survival analyses were performed to identify independent prognostic factors. Radiologic complete response (CR) was a secondary endpoint. Results: We identified 113 patients with a median age at diagnosis of MBC of 52 years (range 27-82). Median follow-up for MBC was 39 months (range 2-148 months). Thirty-eight percent presented with synchronous metastases; 62% had recurrent disease of whom 42% had received prior trastuzumab as part of (neo-)adjuvant treatment. First-line palliative treatment consisted of trastuzumab plus vinorelbine (56%), a taxane (28%), capecitabine (10%), other chemotherapy (3%), or endocrine therapy (2%), and resulted in a CR in 27 patients (24%). In addition, one patient achieved CR to third-line therapy. Most patients with CR had received trastuzumab with a taxane (57%) followed by vinorelbine (32%). Fourteen out of 28 patients with CR are still alive without evidence of disease at a median follow-up of 91 months (range 23-148 months), of whom 8 still receive trastuzumab. Fourteen patients had disease relapse (8 on maintenance trastuzumab, 6 after discontinuation). Overall, 35 patients (31%) survived more than 5 years. Factors associated with long-term survival in univariable analyses were oligo-metastatic disease (1-3 distant metastases), synchronous metastases, no skin or brain metastases, no prior (neo-)adjuvant trastuzumab, first-line palliative treatment with trastuzumab and taxanes, and achieving a radiologic CR on treatment (see table 1). Achieving CR and the absence of skin metastases remained significant factors in multivariable analyses. Conclusion: Thirty-one percent of patients with metastatic HER2-positive MBC survive over 5 years. Long-term response is particularly seen in patients who achieve a complete radiologic response on first-line treatment. This finding supports a strategy to administer the most effective agents as first line treatment, as is often but not always applied in clinical practice. Table 1. Prognostic factors associated with overall survival Univariable Multivariable HR95% CIpHR95% CIpSynchronous metastases No- - Yes0.44(0.27-0.70)<0.0010.80(0.46-1.40)0.43Oligo-metastatic disease No- - Yes0.37(0.22-0.62)<0.010.66(0.36-1.17)0.14Skin metastases No- - Yes5.40(2.91-10.01)<0.014.10(2.08-8.14)<0.01Brain metastases No- - Yes2.25(1.03-4.93)0.041.46(0.55-3.98)0.45(Neo-)adjuvant trastuzumab No- - Yes1.87(1.16-2.99)0.011.66(0.93-2.96)0.09Trastuzumab + taxane No- - Yes0.54(0.32-0.89)0.020.69(0.40-1.20)0.19Complete radiologic response No- - Yes0.13(0.06-0.29)<0.010.22(0.09-0.53)0.001 Citation Format: Steenbruggen TG, van Ramshorst MS, Stouthard JML, Rodenhuis S, Linn SC, Sonke GS, Smorenburg CH. Long-term survival in HER2-positive metastatic breast cancer: The first blow is half the battle [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 P4-21-30.

Abstract P4-22-13: Everolimus plus trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: Overall survival results from BOLERO-1

Abstract Background Everolimus (EVE), an mTOR inhibitor has shown activity in HER2+ advanced breast cancer (ABC) in both preclinical and clinical studies. In the pivotal BOLERO-1 trial (NCT00876395), the progression-free survival (PFS) was not significantly different between the EVE + trastuzumab (TRAS) + paclitaxel (PAC) combination and placebo (PBO) + TRAS + PAC in the full HER2+ population (EVE, 15.0 mo vs PBO, 14.5 mo; HR=0.89; 95% CI: 0.73-1.08; p=0.1166). Although not reaching protocol defined level for statistical significance, the hormone receptor negative (HR-) subpopulation appeared to benefit from EVE, with a 7.2 mo PFS benefit vs PBO arm (EVE, 20.3 mo vs PBO, 13.1 mo; HR=0.66; 95% CI: 0.48-0.91; p=0.0049). The final exploratory overall survival (OS) analysis from the study is presented here. Methods In this phase 3 randomized trial, 719 women with HER2+ ABC without prior TRAS or chemotherapy in the metastatic setting were randomized 2:1 to receive either EVE (10 mg/d) or placebo (PBO) and weekly PAC+TRAS, stratified by visceral metastasis (lung, liver, peritoneal or pleural: yes vs no) and prior adjuvant or neo-adjuvant treatment with TRAS (yes vs no). As the primary objectives (PFS on full population and on HR- subpopulation) of BOLERO-1 were not met, the key secondary endpoint of OS was not formally statistically tested. However, given the results of PFS, in particular in the HR- subpopulation, a change to the OS analysis plan was made by introducing one final exploratory OS analysis at the time of study termination. Results At data cutoff (Dec 31, 2015), the median duration of exposure was 40.8 weeks (range: 0.6-320.4) in the EVE arm and 48.1 weeks (range: 1.1-308.0) in the PBO arm. After a median follow-up of 60.3 mo, 350 deaths were recorded in the full population, 238 (49.6%) in the EVE arm and 112 (46.9%) pts in the PBO arm. In the full population, the median OS was comparable in the EVE vs PBO arms (48.6 mo vs 50.0 mo respectively; HR = 1.13; 95% CI: 0.90-1.42). In the HR- subpopulation, 138 deaths were recorded; 88 (42.3%) pts in the EVE arm and 50 (48.5%) pts in the PBO arm. In the HR- subpopulation, the median OS in the EVE arm was longer compared to PBO arm (57.0 mo vs 41.6 mo respectively; HR = 0.83; 95% CI: 0.59-1.18). Stomatitis, diarrhea, alopecia, cough, rash, pyrexia, neutropenia, and fatigue were the most frequent adverse events (AEs) reported in EVE arm (≥35%). AEs leading to dose interruption and/or change were reported in 441 (93.4%) pts in EVE arm and 165 (69.3%) pts in the PBO arm respectively. Overall, AEs leading to treatment discontinuation were reported in 262 (55.5%) pts in EVE arm and 98 (41.2%) pts in PBO arm. Serious AEs were reported in 171 (36.2%) pts in the EVE arm and 40 (16.8%) pts in the PBO arm respectively. On treatment AE related deaths were reported for 3.6% pts in the EVE arm and 0% pts in the PBO arm. Conclusions The median OS was similar in the EVE vs PBO arms for overall population. However, a prolongation of 15.4 mo in median OS of HR- subpopulation was observed in the EVE arm vs PBO arm in this exploratory analysis. Pts in the EVE arm had a manageable safety, consistent with the safety profile of EVE and no new safety signals were identified. Citation Format: Yardley D, Hurvitz S, Jiang Z-f, Toi M, Burris H, Buyse M, Slamon D, Makhson A, Elsaid A, Lerzo G, Hellerstedt B, Nuzzo F, Sohn J, Manzyuk L, Cabaribere D, Lincy J, Weimann A, Noel-Baron F, Pacaud L, Andre F. Everolimus plus trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: Overall survival results from BOLERO-1 [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 P4-22-13.

Abstract S1-08: Prognostic associations of tumor-infiltrating lymphocytes (TIL) in metastatic HER2-positive breast cancer (BC) treated with trastuzumab and pertuzumab: A secondary analysis of the CLEOPATRA study

Abstract Background The presence of stromal TILs (sTILs) is associated with a better prognosis with anti-HER2 therapy in primary HER2-positive BC. The prognostic value of TILs in the advanced setting with pertuzumab-based therapy is unknown. Methods The CLEOPATRA trial randomly assigned 808 patients with metastatic HER2-positive BC to receive pertuzumab or placebo in combination with trastuzumab and docetaxel. We evaluated %TILs using our previously described method. For concordance evaluation, 40 slides from metastatic samples were independently analysed by two pathologists. TILs were examined for associations with clinicopathological factors, progression-free survival (PFS), overall survival (OS), and treatment interactions using Cox regression models fitting sTILs as a continuous variable (per 10%) adjusting for treatment arm, age, estrogen receptor (ER) status, PIK3CA genotype, and visceral vs. non-visceral disease at screening. Results Tumour samples from 678 (84%) participants were available. 519 (76.5%) were archival and 155 (22.9%) were obtained fresh, ≤45 days prior to study treatment start. Median follow-up for OS was 50 months, with 519 PFS events and 358 deaths. 54% of patients were treatment naïve i.e. had not received prior chemotherapy nor trastuzumab. The median sTIL level was 10% (1-95%). sTIL evaluation was highly concordant between pathologists (R=0.93). Fresh vs. archival samples had significantly lower sTILs (10% vs 15%, p=0.0004). sTIL levels significantly differed by ethnicity (15% Asians, 10% white, 5% African-Americans, p=0.0007), but not age (p=0.26). Higher sTILs were observed in ER-negative vs. ER-positive tumors (15% vs 10%, p<0.001). In the whole cohort for PFS, higher sTIL levels trended towards a better outcome independent of treatment (adjusted HR:0.95, 95%CI:0.90-1.00, p=0.06). For OS, the prognostic effect of sTILs reached statistical significance, with each 10% increase in sTILs associated with an 11% reduction in the risk of death (adjusted HR:0.89, 95%CI:0.83-0.96, p=0.001). The prognostic effect was observed independent of treatment arm, ER status, PIK3CA genotype, prior treatment or presence of visceral disease at screening, and in both fresh and archival tissue samples. There was no significant interaction (int) between pertuzumab and sTILs for PFS (Pint=0.4) nor OS (Pint=0.6). There were no significant interactions between pertuzumab and sTILs for OS in subgroups of PIK3CA mutated (Pint=0.2) or PIK3CA WT (Pin=0.2), nor treatment naive (Pint=0.3) vs prior treatment (Pint=0.5). The 5-year estimates of OS according to median ≤10% vs >10% sTILs in the placebo arm were 26% (95%CI:19-37) vs. 39% (95%CI:32-48), while in the pertuzumab arm 42% (95%CI:33-53) vs. 56% (95%CI:47-66) respectively. Conclusion In advanced HER2-positive disease, sTILs are still evident, though at lower levels, but are nevertheless significantly associated with prognosis, with effects stronger for OS than PFS. This suggests that the influence of anti-tumour immunity persists in the advanced first line setting and that enhancement by immunotherapeutic approaches could potentially further improve survival. Citation Format: Luen S, Salgado R, Stephen F, Peter S, Jennifer E-W, Emma C, Astrid K, Sandra SM, Jose B, Stefan M, Sherene L. Prognostic associations of tumor-infiltrating lymphocytes (TIL) in metastatic HER2-positive breast cancer (BC) treated with trastuzumab and pertuzumab: A secondary analysis of the CLEOPATRA study [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 S1-08.

Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: results from a Phase II, single-arm, multicenter study.

Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for the treatment of patients with metastatic breast cancer who previously received ≥2 chemotherapy regimens in the metastatic setting. Primary data from a Phase II trial for the first-line combination of eribulin plus trastuzumab in human epidermal growth factor receptor 2 positive patients showed a 71% objective response rate and tolerability consistent with the known profile of these agents. Here, we present prespecified analyses of efficacy of this combination based on prior trastuzumab use. Patients received eribulin mesylate 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) intravenously on days 1 and 8 plus trastuzumab (8 mg/kg intravenously/cycle 1, then 6 mg/kg) on day 1 of each 21-day cycle. Objective response rates, progression-free survival, and tolerability were assessed in patients who had and had not received prior adjuvant or neoadjuvant (neo/adjuvant) trastuzumab treatment. Fifty-two patients (median age: 59.5 years) received eribulin/trastuzumab for a median treatment duration of ~31 weeks; 40.4% (n=21) had been previously treated with neo/adjuvant trastuzumab prior to treatment with eribulin plus trastuzumab for metastatic disease (median time between neo/adjuvant and study treatment: 23 months). In trastuzumab-naïve patients (n=31) compared with those who had received prior trastuzumab, objective response rate was 77.4% versus 61.9%, respectively; duration of response was 11.8 versus 9.5 months, respectively; clinical benefit rate was 87.1% versus 81.0%, respectively; and median progression-free survival was 12.2 versus 11.5 months, respectively. The most common grade 3/4 treatment-emergent adverse events (occuring in ≥5% of patients) in patients who received prior trastuzumab versus trastuzumab naïve patients, respectively, were neutropenia (47.6% vs 32.3%), peripheral neuropathy (14.3% vs 25.8%), febrile neutropenia (14.3% vs 3.2%), fatigue (9.5% vs 6.5%), nausea (9.5% vs 0%), vomiting (9.5% vs 3.2%), and leukopenia (9.5% vs 3.2%). In patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, first-line eribulin/trastuzumab treatment demonstrated substantial antitumor activity and was well tolerated, regardless of prior neo/adjuvant trastuzumab treatment.

T-DM1 Activity in Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancers That Received Prior Therapy With Trastuzumab and Pertuzumab.

Purpose Ado-trastuzumab emtansine (T-DM1) is currently approved for treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (MBC) who previously received trastuzumab and a taxane. However, there are no data on the activity of T-DM1 in patients who received prior pertuzumab, which is now included as standard first-line therapy. The goal of this study was to assess the efficacy of T-DM1 in routine clinical practice in a contemporary patient population that received both prior trastuzumab and pertuzumab. Patients and Methods We identified all patients with HER2-positive MBC who received T-DM1 after trastuzumab and pertuzumab between March 1, 2013, and July 15, 2015, via electronic pharmacy records and departmental databases at three institutions: MD Anderson Cancer Center, Smilow Cancer Hospital at Yale, and The James Cancer Hospital at the Ohio State University. We reviewed medical records of each case to confirm treatment sequencing and outcome. Results Of patients, 82 were identified and 78 were available for outcome analysis; 32% received T-DM1 as first- and second-line line therapy, and 48% received it as fourth-line treatment or later. Rate of prolonged duration on therapy, defined as duration on therapy ≥ 6 months, was 30.8% (95% CI, 20.6% to 41.1%), and tumor response rate was 17.9% (95% CI, 9.4% to 26.4%). Median duration on therapy was 4.0 months (95% CI, 2.7 to 5.1; range, 0 to 22.5 months). T-DM1 was discontinued for disease progression in 84% of patients and for toxicity in 10%. Conclusion Tumor response rates were lower than in prior reports of trastuzumab-resistant, HER2-positive MBC, but one third of patients received therapy with T-DM1 for ≥ 6 months, which suggests a clinically relevant benefit in patients who received prior pertuzumab.

315TiP - 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 T-DM1

Although HER2-targeted therapies such as pertuzumab and ado-trastuzumab emtansine (T-DM1) have improved patient outcomes, treatment resistance typically occurs. MM-302 is a HER2-targeted antibody-liposomal doxorubicin conjugate 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 is a randomized Phase 2, two-arm, open-label trial in patients with anthracycline naïve, 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 physician's choice (vinorelbine, capecitabine, or gemcitabine) plus trastuzumab (6mg/kg, Q3W). Eligibility criteria: Centrally confirmed HER2-positive LABC/MBC, no prior anthracycline exposure, prior trastuzumab, prior T-DM1 in the LABC/MBC setting, prior pertuzumab in LABC/MBC setting or disease recurrence within 12 months of neoadjuvant/adjuvant treatment, unlimited prior lines, 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 progression free survival (PFS) assessed by an independent blinded review. 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 HR 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. Status: First patient treated was in December 2014 and enrollment is expected to be complete in 2017. Sites are open in the US, Canada and Western Europe. Clinical trial identification: NCT02213744 Legal entity responsible for the study: Merrimack Pharmaceuticals

Abstract 1207: Preclinical development of 2nd generation HER2-directed antibody-drug conjugates

Abstract The HER2 receptor tyrosine kinase is amplified in approximately 20% of human breast cancer and is associated with poor clinical outcome. The humanized antibodies trastuzumab and pertuzumab are approved for use in both early and metastatic HER2-positive breast cancer, and are most often given with chemotherapy. Antibody-drug conjugates (ADCs) are anti-tumor agents designed to deliver potent cytotoxic drugs selectively to target-expressing tumor cells. Trastuzumab emtansine is a HER2-directed ADC comprised of trastuzumab covalently linked to the microtubule inhibitor DM1, through the stable MCC linker. Trastuzumab emtansine is approved for use in HER2-positive metastatic breast cancer as a single agent in patients who have received prior trastuzumab and a taxane. We are now exploring new HER2-directed ADCs (‘2nd generation ADCs’) with different mechanisms of action (MOA) than trastuzumab emtansine by investigating ADCs utilizing DNA-damaging agents, such as pyrrolobenzodiazepine (PBD) dimers and cyclopropylbenzindole (CBI) dimers, as the cytotoxic drug components. These agents have been conjugated to either trastuzumab or the humanized anti-HER2 antibody 7C2 (hu7C2) using both uncleavable and cleavable linkers. As free drugs and ADCs, the PBDs and CBIs show similar or greater potency in cell proliferation assays in vitro compared to DM1 and trastuzumab emtansine. However, unlike DM1, these agents are not strong substrates of Pgp/MDR1. Moreover, the PBDs and CBIs are active on non-dividing cells, whereas microtubule inhibitors such as DM1 do not affect non-dividing cells. Robust anti-tumor activity was observed in vivo in the fo5 HER2 transgenic tumor transplant model with the 2nd generation ADCs. Efficacious doses resulting in tumor stasis or regression ranged from 0.25-3 mg/kg administered as a single injection. In contrast, doses of trastuzumab emtansine required for stasis/regression in this model are 10 and 15 mg/kg, respectively. Efficacious doses were well-tolerated in the mouse xenograft models. Further tolerability studies of the 2nd generation ADCs were performed in rats. As rats are a non-binding species for trastuzumab and hu7C2, these studies assessed antigen-independent toxicities. Maximum tolerated doses for the different ADCs ranged from 2.5-15 mg/kg administered as a single injection, compared to 46 mg/kg for trastuzumab emtansine (Poon et al., 2013), likely reflecting both the different MOA and greater potency of the cytotoxic agents utilized in the 2nd generation HER2-directed ADCs. Overall, our findings demonstrate robust in vitro and in vivo activity of HER2 ADCs comprised of DNA-active agents, allowing for further development of a HER2-directed ADC distinct from trastuzumab emtansine. Citation Format: Gail D. Lewis Phillips, Guangmin Li, Jun Guo, Jeffrey Lau, Shang-Fan Yu, Thomas Pillow, Byoung-Chul Lee, Jack Sadowsky, Melissa Schutten, Carter Fields, Mark X. Sliwkowski. Preclinical development of 2nd generation HER2-directed antibody-drug conjugates. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1207.

Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin.

LBA503 Background: Trastuzumab has revolutionized treatment of HER2+ breast cancer. Globally accessible alternatives are a critical need. We evaluated Myl-1401O, a proposed trastuzumab biosimilar, as treatment for HER2+ metastatic breast cancer (MBC), based on physicochemical analyses, nonclinical, pharmacokinetic and pharmacodynamic studies*. Methods: Heritage is a double-blind, randomized clinical trial designed to evaluate comparative efficacy and safety of Myl-1401O vs Herceptin. Eligible patients (pts) had centrally confirmed, measurable HER2+ MBC without prior chemotherapy or trastuzumab for metastatic disease. Pts were randomized to receive either Myl-1401O or Herceptin with docetaxel or paclitaxel for a minimum of 8 cycles. Trastuzumab was continued until progression. The primary endpoint was overall response (ORR) at Week 24 by blinded central evaluation using RECIST 1.1. Secondary endpoints include progression free survival (PFS), overall survival, and safety. A sample size of 456 pts was calculated to demonstrate equivalence in ORR at Week 24 for MYL-1401O vs Herceptin, defined as a 90% confidence interval (CI) for the ratio of best ORR within the equivalence margin (0.81, 1.24). Results: 500 pts were randomized, 458 were evaluable for efficacy. 44% had hormone receptor positive MBC, 84% received docetaxel. Week 24 ORR was 69.6% for Myl-14010 compared to 64% for Herceptin. The ratio of ORR was 1.09; both 90% CI (0.974-1.211) and 95% CI (0.954-1.237) were within the pre-defined equivalence margin. Median PFS is not yet reached (41 events for MYL-1401O vs 48 events for Herceptin). Safety was comparable; serious adverse events (primarily neutropenia related) occurred in 38% (MYL-1401O) vs 36% (Herceptin), with 4 fatal events in each arm. There was no significant change in cardiac function from baseline to Week 24 in either arm. Conclusions: MYL-1401O was equivalent to Herceptin, given in combination with a taxane as first-line therapy for MBC, as measured by 24 week ORR. Safety was comparable. The proposed trastuzumab biosimilar MYL-1401O could be a new treatment option for HER2+ MBC. * Presented at: British Pharmacological Society, Pharmacology Meeting; 2015 Dec 15-17; London, UK. Clinical trial information: 2011-001965-42.

Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer

ImportanceEfficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed.ObjectiveTo determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer.Design, Setting, and ParticipantsIn the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region.InterventionsWomen received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory.Main Outcome and MeasuresThe primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety.ResultsThe intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower (relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004). Common grade 3 to 4 adverse events were diarrhea (73 of 240 patients [30.4%] with neratinib-paclitaxel and 9 of 234 patients [3.8%] with trastuzumab-paclitaxel), neutropenia (31 patients [12.9%] vs 34 patients [14.5%]) and leukopenia (19 patients [7.9%] vs 25 patients [10.7%]); no grade 4 diarrhea was observed.Conclusions and RelevanceIn first-line ERBB2-positive metastatic breast cancer, neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of progression-free survival. In spite of similar overall efficacy, neratinib-paclitaxel may delay the onset and reduce the frequency of central nervous system progression, a finding that requires a larger study to confirm.Trial Registrationclinicaltrials.gov Identifier: NCT00915018

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 naïve, 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 physician's 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 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]. 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 S5-02: Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET)

Abstract Background: Neratinib (Puma Biotechnology Inc), an irreversible pan-HER tyrosine kinase inhibitor, was evaluated in a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET) to assess for improved invasive DFS (iDFS) in women with early-stage HER2+ breast cancer (BC) after trastuzumab-based therapy (clinicaltrials.gov NCT00878709). Primary efficacy analysis at 2-yrs demonstrated iDFS of 93.9% and 91.6% neratinib and placebo, respectively (HR 0.67, 95% CI 0.50–0.91; P=0.009). Greater benefit was observed in hormone-receptor (HR)-positive and centrally- confirmed HER2 subsets – HR 0.51, p=0.001 and HR 0.51 p=0.002, respectively [Chan et al. ASCO 2015]. We report an exploratory analysis of efficacy after 3-yrs of follow-up. Methods: Women with HER2+ BC were randomly assigned to oral neratinib 240 mg/day or matching placebo for 1 year, stratified by nodal status, HR-status and prior trastuzumab regimen. The study was initiated in April 2009 with recruitment ceased in October 2011, limiting follow-up to 2 years. In January 2014, follow-up was restored to 5 years. During year 1, physical examinations were performed at 3-monthly intervals, at 4-monthly intervals in year 2 and then 6-monthly to 5-years; with mammography performed annually. Patients were asked to re-consent following ethics approval of the January 2014 protocol amendment. During years 3 to 5, disease-free survival (DFS) and survival events were identified from medical records. A descriptive analysis of iDFS, to investigate the durability of neratinib effect was performed after 3-yrs of follow-up. Data for overall survival remains blinded until 248 events have occurred. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using stratified Cox proportional-hazards models. Results: The intention-to-treat population included 2840 patients (neratinib, N 1420; placebo, P=1420). Central HER2 testing has now been performed in 2041 pts (72%) - HER2-positive 1709 (84%) and HER2-negative 332 (16%). Pts were randomized within 12-months of completion of prior adjuvant trastuzumab in 2297 (81%) pts. Three-yr iDFS for ITT population demonstrated HR 0.74, [95% CI 0.56-0.96]. In the ITT pts who were randomized within 1-yr of trastuzumab completion, iDFS HR 0.72 [0.54-0.95]. For pts who had centrally-confirmed (cc) HER2-positive disease , iDFS HR 0.70 [0.50-0.98]. Pts with HR-positive disease had 3-yr iDFS HR 0.57 [0.39-0.82] and HR-negative pts HR 0.96 [0.67-1.45]. Overall survival data are not yet mature. Conclusions: Exploratory analysis at 3-years supports the significant benefit seen in the primary analysis of 12-months of neratinib following adjuvant trastuzumab-based therapy. Patients who consistently derived the greatest benefit were 1) patients who received neratinib within 12 months of completing adjuvant trastuzumab; 2) centrally confirmed HER2 positive patients and 3) HR positive patients. Citation Format: Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harker G, Masuda N, Neskovic Konstantinovic ZB, Petrakova K, Guerrero Zotano AL, Iannotti N, Rodriguez GI, Tassone P, von Minckwitz G, Ejlertsen B, Chia SKL, Mansi J, Barrios CH, Buyse M, Wong A, Bryce R, Ye Y, Martin M. Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET). [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 S5-02.

A phase II trial of trastuzumab combined with irinotecan in patients with advanced HER2-positive chemo-refractory gastric cancer: OGSG1203 (HERBIS-5).

128 Background: Irinotecan is a key drug in second- or further-line chemotherapy for patients with advanced gastric cancer. Continuous administration of trastuzumab beyond first progression is expected to contribute to the benefit of chemotherapy for HER2-positive gastric cancer. We assessed the efficacy and safety of combination chemotherapy with trastuzumab and irinotecan in Japanese patients with advanced HER2-positive chemo-refractory gastric cancer. Methods: Intravenous infusion of irinotecan every 2 weeks at a dose of 150 mg/m2; intravenous infusion of trastuzumab at a dose of 8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks. Administration of irinotecan and trastuzumab were repeated in independent schedules. The primary endpoint was disease control rate. The secondary endpoints were adverse events, response rate, time-to-treatment failure, progression-free survival, overall survival, and response rate stratified by prior trastuzumab use. This study was conducted by the Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG). Results: From October 2012 to Augst 2014, 30 patients were enrolled and one patient withdrew before study treatment. Accordingly, 29 patients were assessable for efficacy and safety. The disease control rate was 65.5% [95% C.I. 45.7 - 82.1%], and the response rate was 20.7% [95% C.I. 8.0 - 39.7%]. The median progression free survival and the median overall survival were 3.7 and 7.5 months, respectively. The major grade 3/4 toxic effects were neutropenia (24%); anemia (24%); leucopenia (21%); anorexia (11%); fatigue (14%); hypoalbuminemia (24%); and hypokalemia (14%). One death (NOS) was considered to be related to the study. Conclusions: The results of combination Trastuzumab with irinotecan showed feasible and promising efficacy against advanced HER2-positive chemo-refractory gastric cancer. These findings indicated that trastuzumab continuation use might be beneficial. Clinical trial information: 000008626.

203P A phase II trial of trastuzumab combined with irinotecan in patients with advanced HER2-positive chemo-refractory gastric cancer: Osaka Gastrointestinal Cancer Chemotherapy Study Group OGSG1203 (HERBIS-5)

Irinotecan is a key drug in second- or further-line chemotherapy for patients with advanced gastric cancer. Continuous administration of trastuzumab beyond first progression is expected to contribute to the benefit of chemotherapy for human epidermal growth factor receptor 2-positive gastric cancer. The aim of this trial is to evaluate the efficacy and safety of combination chemotherapy with trastuzumab and irinotecan in Japanese patients with advanced human epidermal growth factor receptor 2-positive chemo-refractory gastric cancer. The primary endpoint is the disease control rate. The secondary endpoints are adverse events, overall response rate, time to treatment failure, progression-free survival, overall survival and response rate stratified by prior trastuzumab use. A total of 30 patients will be enrolled in this Osaka Gastrointestinal Cancer Chemotherapy Study Group trial.

Invasive disease-free survival benefit following neratinib as extended adjuvant therapy in centrally-confirmed HER2+ early-stage breast cancer: The ExteNET phase III randomized placebo-controlled trial.

117 Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor with clinical efficacy in trastuzumab pre-treated HER2-positive (HER2+) metastatic breast cancer (BC). ExteNET is an ongoing multicenter randomized placebo-controlled phase III trial evaluating the efficacy and safety of a 1-year course of neratinib in patients with early-stage HER2+ BC after trastuzumab-based adjuvant therapy (clinicaltrials.gov: NCT00878709). Methods: Women with locally-confirmed early-stage HER2+ BC were randomly assigned to oral neratinib 240mg/day or matching placebo for 1 year. Archived diagnostic tumor samples were submitted for HER2 gene amplification testing at a central laboratory. Primary endpoint: invasive disease-free survival (iDFS). Secondary endpoints: DFS including ductal carcinoma in situ (DFS+DCIS); distant disease-free survival (DDFS); time to distant recurrence (TDR). Stratified Cox proportional-hazards models were used to estimate hazard ratios (HR) for the ITT and amended ITT (aITT) populations; unstratified models were used for the centrally confirmed HER2 population. Treatment groups were compared using 2-sided log-rank tests. Results: The ITT population included 2840 patients (neratinib, N=1420; placebo, N=1420). The higher-risk aITT population (i.e. node-positive disease and randomized ≤1 year of completing prior trastuzumab) included 1873 patients (neratinib, N=938; placebo, N=935). Of the tumor samples analyzed, 1463 (86%) were centrally confirmed (neratinib, N=741; placebo, N=722). Conclusions: Neratinib significantly improves iDFS in trastuzumab-treated early-stage HER2+ BC patients. An enhanced treatment effect is observed with neratinib in women with centrally confirmed HER2+ tumors. Clinical trial information: NCT00878709. [Table: see text]

Final overall survival analysis of a phase II trial evaluating vinorelbine and lapatinib in women with ErbB2 overexpressing metastatic breast cancer

Lapatinib plus capecitabine (lap+cap) is approved as treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), who have progressed on prior trastuzumab in the metastatic setting.We previously reported progression-free survival (PFS), overall survival (OS) and safety results from this open-label, multicentre, phase II study (VITAL; NCT01013740) conducted in women with HER2 positive MBC, to evaluate the efficacy and safety of lap plus vinorelbine (lap+vin), an important chemotherapy option for MBC, compared with lap+cap. In total, 112 patients were randomised 2:1 to treatment with lap+vin (N = 75) or lap+cap (N = 37). Results showed that the median PFS (primary endpoint) and OS (secondary endpoint) post-randomisation were comparable between treatment arms, with no new safety signals detected.Here, we assessed the final OS in this study at 40 months post-randomisation. At the time of final analyses, 24 (32%) patients were ongoing in the lap+vin arm, compared with 14 (38%) patients in the lap+cap arm (92% in both arms had discontinued treatment). Median OS in the lap+vin arm was 23.3 months (95% confidence intervals [CI]: 18.5, 31.1), compared with 20.3 months (95% CI: 16.4, 31.8) in the lap+cap arm. The median follow-up in the lap+vin arm was 18.86 months (95% CI: 10.68, 26.02), compared with 19.38 (95% CI: 25.56) months in the lap+cap arm. Similar rates of death (56–57%) were observed in both arms.The final OS was consistent with the previously reported data and suggest that lap+vin offers an effective treatment option for women with HER2-positive MBC.

1863 First line trastuzumab- or lapatinib-based therapy in her2-positive metastatic breast cancer patients after prior (neo)adjuvant trastuzumab

1863 First line trastuzumab- or lapatinib-based therapy in her2-positive metastatic breast cancer patients after prior (neo)adjuvant trastuzumab