Prior Trastuzumab Research Articles

Efficacy and Safety of Gemcitabine With Trastuzumab and Pertuzumab After Prior Pertuzumab-Based Therapy Among Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Taxanes with trastuzumab and pertuzumab for initial treatment of human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-positive metastatic breast cancer is associated with improved progression-free survival (PFS) and overall survival. While continued use of trastuzumab in therapeutic combinations after disease progression is standard, the efficacy of continuing pertuzumab is unknown. To evaluate the efficacy and safety of pertuzumab in combination with gemcitabine and trastuzumab after prior treatment with pertuzumab for ERBB2-positive metastatic breast cancer. This is a phase 2 single-arm clinical trial of dual anti-ERBB2 therapy after prior treatment with pertuzumab. The study took place at a single academic center from March 2015 to April 2017 among women with ERBB2-positive metastatic breast cancer, prior pertuzumab-based treatment, and 3 or fewer prior chemotherapy regimens. Data were analyzed between January 2019 and March 2019. Treatment consisted of gemcitabine, 1200 mg/m2 (later amended to 1000 mg/m2) on days 1 and 8 every 3 weeks, plus trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks. The primary end point was 3-month PFS. Based on prior trials, a target rate of 70% or higher was selected as the promising progression-free rate at 3 months. Secondary outcomes included safety, tolerability, and overall survival. A total of 45 patients (median [range] age, 57.1 [31.7-77.2] years) were enrolled; 22 (49%) were treated in the second-line setting, and 23 (51%) were treated in the third-line setting or beyond. Of these, 22 (49%) received prior trastuzumab emtansine (T-DM1). At a median (range) follow-up of 27.6 (8.3-36.0) months, 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months). Treatment was well tolerated, with no occurrences of febrile neutropenia or symptomatic left ventricular systolic dysfunction. In this phase 2 trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month PFS rate of 73.3% and was well tolerated. Continuation of pertuzumab beyond progression was associated with apparent clinical benefit. ClinicalTrials.gov identifier: NCT02252887.

T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study

BackgroundT-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer progressing on prior trastuzumab plus a taxane. A paucity of data is available on T-DM1 efficacy after dual anti-HER2 blockade with pertuzumab and trastuzumab plus a taxane, which represents the current first-line standard of care. The present study is a retrospective/prospective evaluation of the efficacy and activity of second-line T-DM1 after front-line pertuzumab-based therapy. Patients and MethodsEligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer (ClinicalTrials.gov Identifier: NCT02284581). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS. ResultsOf 445 patients with HER2+ metastatic breast cancer, 77 were eligible for the analysis. At a median follow-up of 7 months, median PFS was 6.3 months (95% confidence intervals [CI], 4.8-7.7 months), and median TTF was 6.2 months (95% CI, 4-8.6 months). More than one-third of patients (37.6%; n = 29) experienced PDT with an ORR of 27.1%. At data cutoff, the median OS was not reached, and the 1-year OS was 82%. ConclusionsOur results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane, with about 27% of patients having an objective response and 40% of patients achieving durable disease control.

355P - Safety and efficacy of T-DM1 in 128 patients with advanced HER2+ breast cancer: The Royal Marsden experience

BackgroundAdo-trastuzumab emtansine (T-DM1) is standard of care for patients with advanced HER2+ breast cancer who relapse within 6 months of adjuvant trastuzumab or progress on anti-HER2 therapy. Hepatotoxicity on T-DM1 requires careful monitoring especially on long-term treatment. We evaluated its safety and efficacy in our real-world population, with particular attention to liver toxicity. MethodsWe identified patients on T-DM1 from 01/01/2014 to 12/03/2018 from our electronic records. Patients’ and tumour characteristics were recorded, along with safety and efficacy outcomes. Chi-squared/Fishers exact test and Kaplan-Meier statistical methods were utilised. Results128 patients treated with T-DM1 were included in the analysis with a median age of 55 years (26-85). 115 (89.8%) had ECOG PS 0-1 and 95 (74.2%) were postmenopausal. 27 (21.1%) had de novo metastatic, 74 (57.8%) ER-positive disease. Metastatic spread involved bones in 82 patients (64.1%), liver in 71 (55.5%), lung in 62 (48.4%), nodes in 78 (60.9%), chest wall in 26 (20.3%) and central nervous system in 49 (38.3%). All patients had received prior trastuzumab and 39 (30.5%) pertuzumab. Neutropenia occurred in 29 patients (22.7% - G3-4 in 1 [3.5%]), anemia in 51 (39.2% - G3-4 in 8 [15.7%] and thrombocytopenia in 56 (43.8% - G3-4 in 6 [12.8%]). 88 patients (68.8%) had deranged liver function (G3-4 in 25 [28.4%]), 5 (3.9%) spider naevi and 12 (9.4%) bleeding. 7 patients (5.5%) experienced diarrhoea, 33 (25.8%) nausea, 82 (64.1%) fatigue, 10 (7.8%) skin rash. Cardiotoxicity occurred in 5 patients (3.9%), lung toxicity in 1 (0.8%). 46 (35.9%) required dose reductions, mostly due to neuropathy (30.4%), fatigue (23.9%), thrombocytopenia (17.4%), liver toxicity (17.4%). T-DM1 was stopped due to toxicity in 14 patients (12.6%). Responses were seen in 77 patients (64.1%). Median PFS was 7 months (95% CI 5-8) and OS 15 months (95% CI 12-17). No significant differences were seen based on prior pertuzumab use. ConclusionsThe safety of T-DM1 in this population is overall similar to those reported in literature, although we observed slightly higher rates of thrombocytopenia and deranged liver function. Responses were higher but more short-lived. Legal entity responsible for the studyThe Royal Marsden NHS Foundation Trust. FundingHas not received any funding. DisclosureN.M.L. Battisti: Travel / Accommodation / Expenses: Genomic Health; Speaker Bureau / Expert testimony: Pfizer. A. Ring: Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: Lilly. All other authors have declared no conflicts of interest.

Ramucirumab and Paclitaxel in Patients with Gastric Cancer and Prior Trastuzumab: Subgroup Analysis from RAINBOW Study

Aim: This subgroup analysis of the RAINBOW study evaluated the efficacy and safety of ramucirumab in patients with gastric cancer/gastroesophageal junction adenocarcinoma who received prior trastuzumab therapy. Patients & methods: Of adult patients enrolled in the RAINBOW study, 39 had received prior trastuzumab therapy. Of these, 20 patients were treated with ramucirumab plus paclitaxel and 19 patients with placebo plus paclitaxel within the RAINBOW trial. Results: Overall survival was longer with ramucirumab plus paclitaxel (11.4 months; 95% CI: 7.0-17.9) versus placebo plus paclitaxel (7.0 months; 95% CI: 3.4-14.6), hazard ratio: 0.68 (0.33-1.41); p=0.30. Longer progression-free survival, higher objective response were observed in ramucirumab combination group. Conclusion: Ramucirumab plus paclitaxel demonstrated efficacy benefits with manageable safety profile in a subgroup of patients pretreated with trastuzumab. Clinical trial registration number: NCT01170663.

Ado-trastuzumab emtansine in patients with HER2 amplified salivary gland cancers (SGCs): Results from a phase II basket trial.

6001 Background: SGCs are rare tumors with no approved therapy for metastatic disease. HER2 amplification occurs in 8% among all SGC histologies, and 25-33% of the aggressive salivary duct carcinoma (SDC) histologic subtype. We hypothesized that ado-trastuzumab emtansine, a HER2 targeted antibody drug conjugate, may be clinically active in these patients. Methods: A cohort of patients with HER2 amplified SGCs were enrolled into a multi-histology basket trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) by RECIST v1.1 or PERCIST. A Simon two-stage optimal design was applied with type I error rate under 2.7%, power of 89%, H0 10%, H1 40%; H0 will be rejected if 6 or more responses are observed in 24 patients. Other endpoints include duration of response (DOR), progression-free survival (PFS), and toxicity. HER2 amplification was identified by next generation sequencing (NGS), and tumors were subsequently tested by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Fluorescence lifetime imaging microscopy - Förster resonance energy transfer (FLIM-FRET) assessed the propensity for HER2-HER3 heterodimerization, which leads to receptor internalization. Results: 10 patients with HER2 amplified SGCs were treated. The median age was 65 (range 36-90 years), 90% were male. The median lines of prior systemic therapy was 2 (range 0-3). ORR was 90% (9/10, 95% CI 56-100%) including 5 complete responses after prior trastuzumab, pertuzumab and anti-androgen therapy. After a median follow up period of 12 months (range 4-20 months), median DOR (range 2-19+) and median PFS (95% CI 4–22+ months) were not reached. Toxicities included grade 1 or 2 infusion reaction, thrombocytopenia and transaminitis; there were no treatment related deaths. HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with HER2/CEP17≥2 by FISH (8/8 tested) or IHC3+ (10/10 tested). FLIM-FRET tested positive in 3/3. Conclusions: Ado-trastuzumab emtansine is highly efficacious in patients with HER2 amplified SGCs as identified by NGS. This study has met its primary endpoint, and cohort expansion is warranted to confirm these results. Clinical trial information: NCT02675829.

Phase II trial of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab in patients with HER2-positive metastatic breast cancer.

e12508 Background: Metronomic chemotherapy is an emerging paradigm of cancer therapy in which low doses of chemotherapy are delivered at frequent intervals. Activity in patients with metastatic breast cancer (MBC) has been demonstrated in several phase II clinical trials. Methods: We proposed a regimen with metronomic chemotherapy and dual HER2 inhibition in HER2 positive patients with MBC. We hypothesized that this regimen will be highly active in MBC and have a favorable toxicity profile. Patients were treated on a 21-day cycle with capecitabine 1500mg PO daily, cyclophosphamide 50mg daily, lapatinib 1000mg PO daily and trastuzumab 6mg/kg IV once per 21-day cycle. This regimen was continued until disease progression or unacceptable toxicity. Primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety and tolerability of this regimen. Eligibility criteria were patients 18 years of age and older who had histologically confirmed HER2-positive metastatic breast cancer with prior trastuzumab use in the adjuvant or metastatic setting with no more than two prior regimens for MBC. Results: Ten patients were accrued from Jan 2014-Oct 2016. Median age was 52 (range 38 - 79) years. Median number of chemotherapy regimens for metastatic disease was 0.5 (range 0-2). Median PFS was 13.7 (95% CI: 2.6, 16.6) months. Median OS was 29.6 (95% CI: 11.8, 60.5+) months. ORR was 30%, and CBR was 70%. Grade 3 or 4 toxicities were identified in 6 patients. The most common toxicities of any grade were fatigue (100%), diarrhea (80%), anemia, neutropenia, ALT increase, nausea and hand-foot syndrome 50% each. One patient achieved CR for over 3 years and continues on treatment at time of this report. 8 patients progressed and 1 patient withdrew from study without response evaluation. The trial was closed due to lack of accrual. Conclusions: The proposed regimen of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab appears to be active in patients with HER2 positive MBC but with significant toxicity. Clinical trial information: NCT01873833.

Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

BackgroundData on immune checkpoint inhibitor efficacy in patients with human epidermal growth factor receptor 2-positive (HER2+) advanced gastric/gastroesophageal junction (G/GEJ) cancer are lacking. Because HER2 status was not captured in the ATTRACTION-2 trial, we used patients with prior trastuzumab use (Tmab+) as surrogate for HER2 expression status to evaluate the efficacy and safety of nivolumab as third- or later-line therapy in these patients.MethodsIn ATTRACTION-2, a randomized, double-blind, placebo-controlled, phase 3 multicenter trial, patients were randomized (2:1) to receive nivolumab (3 mg/kg) or placebo every 2 weeks until disease progression or toxicity requiring study discontinuation. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were assessed.ResultsOf 493 enrolled patients, 81 (nivolumab, n = 59; placebo, n = 22) were Tmab+ and 412 (nivolumab, n = 271; placebo, n = 141) were Tmab−. In both groups, patients receiving nivolumab showed a longer median OS vs placebo (Tmab+, 8.3 [95% confidence interval, 5.3–12.9] vs 3.1 [1.9–5.3] months, hazard ratio, 0.38 [0.22–0.66]; P = 0.0006; Tmab−, 4.8 [4.1–6.0] vs 4.2 [3.6–4.9] months, 0.71 [0.57–0.88]; P = 0.0022). PFS was longer in both groups receiving nivolumab vs placebo (Tmab+, 1.6 [1.5–4.0] vs 1.5 [1.3–2.9] months, 0.49 [0.29–0.85]; P = 0.0111; Tmab−, 1.6 [1.5–2.4] vs 1.5 [1.5–1.5] months, 0.64 [0.51–0.80]; P = 0.0001).ConclusionsNivolumab was efficacious and safe as third- or later-line therapy regardless of prior trastuzumab use in patients with advanced G/GEJ cancer.

Lapatinib activity in metastatic human epidermal growth factor receptor 2-positive breast cancers that received prior therapy with trastuzumab, pertuzumab, and/or ado-trastuzumab emtansine (T-DM1).

Lapatinib (L) is approved in combination with capecitabine or letrozole for patients with trastuzumab-resistant HER2-positive metastatic breast cancer (MBC). However, there is no efficacy data of L in patients who received prior pertuzumab (P) and ado-trastuzumab emtansine (T-DM1), now included as standard first- and second-line therapies, respectively. The goal of this study was to assess the efficacy of L in a contemporary patient population that received prior P and/or T-DM1. We identified patients with HER2-positive MBC who received L (n = 520) between 2003 and 2017at MD Anderson Cancer Center and selected a target cohort who received L after prior P or T-DM1 (n = 43) with the remaining included in the comparison cohort (n = 477). We evaluated outcome measures including clinical benefit rate (CBR), best tumor response (BTR), duration on L, and time to progression (TTP). Survival analyses used Kaplan-Meier statistics. CBR was 28% (95% CI 10-32) for the target cohort and 40% (95% CI 36-45) for the comparison cohort. The median duration on L was 5 months (95% CI 3.0-9.0) in the target cohort and 6.7 months (5.9-8.0) in the comparison cohort. In both cohorts, the median time to progression (TTP) and overall survival (OS) were longer in patients with de novo metastatic disease compared to patients with disease recurrence. L-based therapy is an active therapeutic option and remains a viable option for HER2 + MBC after prior trastuzumab, P and/or T-DM1.

Abstract P6-17-19: What to do with trastuzumab therapy after achieving radiological complete remission (rCR) in HER2+ metastatic breast cancer (MBC)?

Abstract Intro MBC is generally considered incurable, but patients with HER2+ disease treated with trastuzumab do relatively well and some have an exceptional durable response and survive over 10 years. We analyzed the clinical-pathological characteristics associated with long-term survival in patients with HER2+ MBC treated with trastuzumab. In addition, we studied the effect of stopping trastuzumab in case of rCR. Methods We included all patients with HER2+ MBC treated with first- or second-line trastuzumab-based palliative therapy between January 2000 and December 2014 in 8 Dutch hospitals (Netherlands Cancer Institute, Erasmus Medical Center, Albert Schweitzer Hospital, Reinier de Graaf Hospital, Amphia Hospital, St. Antonius Hospital, Ikazia Hospital, Haga Hospital). Patients were identified through the Netherlands Cancer Registry and linkage with the institutes' tumor registries. Data was collected from medical records using case record forms. Primary endpoint was overall survival (OS), defined as first-date of MBC until death due to any cause. Kaplan-Meier survival estimates were calculated and multivariable Cox-regression models used to identify prognostic factors for improved survival. Time to progression (TTP) after achieving rCR for patients who continued and stopped trastuzumab and breast cancer specific survival were secondary outcomes. Results We included 744 patients (median age 53, range 24-87). Median follow-up (FU) was 109 months (range 0-178). Clinical factors associated with improved survival in multivariable analyses were single-organ metastases, ER-positivity, no skin or liver metastases, no prior trastuzumab, local therapy of metastatic disease and achievement of rCR. In line with our first single center analyses1, achievement of rCR was the strongest predictor of improved survival (multivariable HR 0.30, 95%CI 0.20-0.46). RCR was observed in 71 patients (10%), of whom 60 had been treated with trastuzumab and chemotherapy, 9 with trastuzumab and hormonal therapy, and 2 with hormonal therapy. In patients with rCR the estimated 10-year OS was 53% versus 7% in patients who did not achieve rCR (p<0.001). Thirty patients stopped trastuzumab after achieving rCR. Median time between onset of rCR and last gift of trastuzumab in these patients was 6 months (0-132). Twenty-one patients (70%) remain in complete remission after a median FU of 75 months (range 54-90) since onset of rCR. Nine patients experienced disease progression after a median time of 14 months (range 9-62) since last gift of trastuzumab. Of these, 8 patients died due to MBC and one again achieved an ongoing rCR. Out of 39 patients who continued trastuzumab after achieving rCR, 12 are in ongoing remission after a median FU of 71 months (range 51-91). In this group median TTP was 14 months (range 5-23). Conclusion Achieving rCR is strongly associated with long-term survival in patients with HER2+ MBC. Seventy percent of patients who stopped trastuzumab after achieving rCR remained in remission, suggesting this can be an attractive approach in selected patients. External validation of these findings is required, however, as well as additional analyses to characterize the patients -and their tumors- who achieved rCR. 1 Steenbruggen, CancerRes 2017 Citation Format: Steenbruggen TG, Bouwer NI, Smorenburg CH, Rier HN, Jager A, Beelen KJ, ten Tije AJ, de Jong PC, Drooger JC, Holterhues C, Horlings HM, Sanders J, Levin M-D, Sonke GS. What to do with trastuzumab therapy after achieving radiological complete remission (rCR) in HER2+ metastatic breast cancer (MBC)? [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 P6-17-19.

Abstract P6-17-28: Outcomes of real-world use of eribulin plus trastuzumab for HER2-positive metastatic breast cancer

Abstract Background Eribulin mesylate is approved for the treatment of metastatic breast cancer (mBC) after two prior chemotherapy regimens including an anthracycline or a taxane in either the metastatic or adjuvant setting. Eribulin in combination with trastuzumab (E+T) has demonstrated tolerability and anti-tumor activity in phase I and II trials but is not FDA-approved for the treatment of HER2-positive mBC. Case series and retrospective research have noted the use of E+T in clinical practice. We sought to describe patient characteristics and long-term outcomes of treatment with E+T for HER2-positive mBC patients treated outside of clinical trials in the US. Methods US-based community oncologists from an open network of over 7,000 oncologists, hematologists, and urologists were invited to participate in identifying HER2-positive mBC patients treated with E+T between 01/01/11 and 12/31/13 outside of clinical trials. Data were collected from 03/18/2016 until 09/01/2016. Providers completed an electronic case report form (CRF) by abstracting data on disease characteristics, treatment patterns, disease response (per provider assessment), adverse events (Aes), and date of death. Duration of treatment and overall survival (OS) were calculated from the initiation of the E+T regimen. The target sample size was 60 patients and patients were selected according to resource available for chart data abstraction. Results Twenty-three providers submitted CRFs for 62 total patients. After data collection, 59 of 62 submitted records were validated for analysis. At mBC diagnosis, 69.4% of patients were ER/PR negative and 42.4% of patient had de novo stage IV disease. At initiation of E+T, the median age was 57 years and 81.4% were ECOG-OS 0/1. Mean length of follow-up from the initiation of any therapy was 33.6 months. Twenty-two (37.3%) patients initiated E+T as their first- or second-line of treatment; those remaining were in third-line or greater. At initiation of E+T, 72.8% of patients had prior treatment with trastuzumab in combination with chemotherapy, 25.4% had prior trastuzumab in combination with pertuzumab and chemotherapy, and 16.9% had received TDM-1. Mean duration of E+T treatment was 5.2 months (SD=2.4). A response (complete [CR] or partial [PR]) was recorded by the providers for 64.4% of patients (not independently verified). The most common Aes reported were fatigue (67.8%), weakness (50.8%), decreased appetite (28.8%), decreased hemoglobin (27.1%), peripheral neuropathy (25.4%), and neutropenia (18.6%). At the end of the study period, 34 patients (57.6%) were deceased; the median OS from the initiation of E+T was 23.9 months (95% CI: 17.8-30.4). Conclusions In a small cohort of patients treated with E+T in the community setting, the observed response rate of 64.4% (CR+PR) was comparable to that of a prior phase II trial of E+T which reported an ORR with first-line E+T of 71.2% overall, 77.4% among T-naïve and 61.9% in T-pretreated patients. Further research is warranted to examine the tolerability and efficacy of E+T for metastatic HER2-positive breast cancer patients in different treatment settings. Citation Format: Mougalian SS, Copher R, McAllister L, Radtchenko J, Wang EC, Broscious M, Yu H-T, Kish J. Outcomes of real-world use of eribulin plus trastuzumab for HER2-positive metastatic breast cancer [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 P6-17-28.

Abstract P3-10-19: Significance of baseline neutrophil-to-lymphocyte ratio for progression-free survival of patients with HER2-positive locally advanced and metastatic breast cancer treated with trastuzumab emtansine

Abstract Purpose The prognosis of human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancers (MBCs) has dramatically improved due to the introduction of trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1). The efficacy of T-DM1 is prolonged for some patients; however, the predictive factors remain unknown. There is a report that T-DM1 induced antitumor immunity in patients treated with neoadjuvant therapy, with tumor infiltrating lymphocytes (TILs) increasing after the administration of T-DM1. Based on these observations, the benefits of T-DM1 for prognosis may be mediated by an immune reaction against breast cancers, at least in part. As an indicator of cancer immunity, in addition to TILs, the neutrophil-to-lymphocyte ratio (NLR) has been established in early breast cancers. In the present study, we investigated the usefulness of the NLR for treatment efficacy of T-DM1 in HER2-positive MBCs. Methods Fifty-three advanced or metastatic breast cancers treated with T-DM1 were retrospectively recruited from three institutes. The NLR in the peripheral blood was measured at baseline (just before the start of T-DM1) and after one cycle (just before the start of cycle 2). The cutoff value of the NLR was set at 2.56 (median value) and progression-free survival (PFS) and overall survival (OS) according to NLR levels were evaluated. Results The PFS of patients with NLR-low at baseline (NLR<2.56; n=26; median, not reached) was significantly better than that of patients with NLR-high (NLR≥2.56; n=27; median, 4.13 months; hazard ratio [HR], 0.226; 95% confidence interval [CI], 0.112-0.493; p=0.0001). There was a significant association between improved OS and a low NLR (HR, 0.384; 95% CI, 0.170-0.910; p=0.0296). In the subgroup analysis, patients with NLR-low consistently had improved PFS compared to those with NLR-high irrespective of the number of prior chemotherapy regimens, prior trastuzumab use, visceral metastasis, estrogen receptor status, and HER2 immunohistochemical staining score. According to univariable analysis of each clinical and biological factor for PFS, the NLR-low group was solely and significantly associated with favorable PFS compared with the NLR-high group (HR, 0.226; 95% CI, 0.112-0.493; p=0.0001). The NLR at baseline was significantly decreased (p=0.0010) and lymphocyte count was significantly increased after one cycle treatment (p=0.0005). Interestingly, the PFS of patients whose NLR was high at baseline but changed to low after one cycle (n=12; median PFS, 6.47 months) was better than that of patients with a consistently high NLR (n=14; median PFS, 3.27 months). Conclusion and Discussion A low baseline NLR was found to be significantly associated with improved PFS for patients treated with T-DM1. Interestingly, lymphocyte count was significantly increased in patients in the NLR-low group but not in the NLR-high group after one cycle treatment. Although detailed mechanisms remain unknown, the treatment efficacy of T-DM1 may be partly mediated by immunoreaction on the basis of present data. A low baseline NLR appears to be beneficial for treatment with T-DM1 in HER2-positive breast cancers. Citation Format: Imamura M, Morimoto T, Egawa C, Miyagawa Y, Miyoshi Y. Significance of baseline neutrophil-to-lymphocyte ratio for progression-free survival of patients with HER2-positive locally advanced and metastatic breast cancer treated with trastuzumab emtansine [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 P3-10-19.

Abstract P2-13-01: Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early-stage breast cancer: Subgroup analyses from the phase III ExteNET trial

Abstract Background: The international, randomized, placebo-controlled phase III ExteNET trial showed that 1 year (yr) of neratinib 240 mg/day after trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) in 2840 patients with early-stage HER2+ breast cancer at 2 yr (hazard ratio 0.67; 95% CI 0.50–0.91; p=0.009) [Chan 2016] and 5 yr (hazard ratio 0.73; 95% CI 0.57-0.92; p=0.008) [Martin 2017]. A prespecified subgroup analysis by hormone receptor (HR) status suggested enhanced efficacy with neratinib in patients with HR+ (2-yr hazard ratio 0.51; 95% CI 0.33–0.77) vs. HR– tumors (2-yr hazard ratio 0.93; 95% CI 0.60–1.43). The efficacy of neratinib was also greater in patients who initiated treatment within 1 yr of prior trastuzumab compared with those who started neratinib later. The European Medicines Agency's Committee for Medicinal Products for Human Use recently recommended neratinib for use in patients with HR+ tumors who initiate treatment within 1 yr of completing trastuzumab-based adjuvant therapy. Subgroup analyses from ExteNET examining iDFS benefits in this patient population are presented here. Methods: Patients with early-stage HER2+ breast cancer who completed trastuzumab-based (neo)adjuvant therapy were assigned to oral neratinib 240 mg/day or placebo for 1 yr. Randomization was stratified by HR status (determined locally before trial entry), nodal status, and trastuzumab regimen. Endocrine therapy was allowed in patients with HR+ disease. The primary endpoint, iDFS, was tested by 2-sided log-rank test and hazard ratios (95% CI) were estimated using Cox proportional hazards models. Kaplan-Meier methods were used to estimate iDFS rates. Secondary endpoints were DFS-DCIS, time to distant recurrence, distant DFS, and CNS recurrences. The primary analysis was conducted at 2 yr, and a sensitivity analysis conducted at 5 yr. Clinicaltrials.gov:NCT00878709. Results: Of the 2840 patients (neratinib, n=1420; placebo, n=1420), 1631 (57%) had HR+ disease (neratinib, n=816; placebo, n=815). Most (93%) HR+ patients were receiving endocrine therapy at baseline. 1334 of 1631 (82%) patients with HR+ tumors were randomized to start neratinib within 1 yr of last trastuzumab dose (neratinib, n=670; placebo, n=664). iDFS benefits from neratinib in this population are shown in the table. Secondary endpoints were also improved with neratinib vs. placebo in this population. Safety data in this subset will be presented at the meeting. Table. iDFS in patients with an interval between last trastuzumab dose and randomization of ≤1 yr HR+ population (N=1334)ITT population (N=2297) Hazard ratiob Hazard ratiob Δ, %a(95% CI)P-valueΔ, %a(95% CI)P-value2-yr analysisc+4.50.490.002+2.90.630.006 (0.30–0.78) (0.45–0.88) 5-yr analysisd+5.10.580.002+3.20.700.006 (0.41–0.82) (0.54–0.90) aDifference in iDFS rates between neratinib vs. placebo; bNeratinib vs. placebo; cData cut-off: July 2014; dData cut-off: March 2017 Conclusions: Neratinib may have enhanced and sustained efficacy in patients with HR+ disease who initiate treatment within 1 yr of trastuzumab-based adjuvant therapy. Citation Format: Gnant M, Martin M, Holmes F-A, Jackisch C, Chia SK, Iwata H, Moy B, Martinez N, Mansi J, Morales S, Ruiz-Borrego M, von Minckwitz G, Buyse M, Delaloge S, Bhandari M, Murias Rosales A, Galeano T, Fujita T, Luczak A, Barrios CH, Saura C, Rugo HS, Chien J, Johnston SR, Spencer M, Xu F, Barnett B, Chan A, Ejlertsen B. Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early-stage breast cancer: Subgroup analyses from the phase III ExteNET trial [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 P2-13-01.

Significance of baseline neutrophil-to-lymphocyte ratio for progression-free survival of patients with HER2-positive breast cancer treated with trastuzumab emtansine

The efficacy of trastuzumab emtansine (T-DM1) is prolonged for some patients; however, the predictive factors remain unknown. We focused on a peripheral blood biomarker, the neutrophil-to-lymphocyte ratio (NLR), regarding T-DM1 treatment efficacy. Fifty-three advanced or metastatic breast cancers treated with T-DM1 were retrospectively recruited from three institutes. The NLR in the peripheral blood was measured at baseline and after one cycle. The cutoff value of the NLR was set at median value 2.56. The progression-free survival (PFS) of patients with NLR-low at baseline (n = 26; median, not reached) was significantly better than that of patients with NLR-high (n = 27; median, 4.13 months; hazard ratio [HR], 0.226; 95% confidence interval [CI], 0.112–0.493; p = 0.0001). Longer overall survival was significantly associated with a low NLR (HR, 0.384; 95% CI, 0.170–0.910; p = 0.0296). In the subgroup analysis, patients with NLR-low consistently had longer PFS compared to those with NLR-high irrespective of the number of prior chemotherapy regimens, prior trastuzumab, visceral metastasis, estrogen receptor status, and human epidermal growth factor receptor 2 (HER2) score. Although detailed mechanisms remain unknown, treatment efficacy of T-DM1 may be partly mediated by activation of the immune system. Low baseline NLR appears to be beneficial for treatment with T-DM1 in HER2-positive breast cancers.

ASCO 2018: highlights in HER2-positive metastatic breast cancer.

SummaryAt the 2018 ASCO Annual Meeting, data from several interesting studies in HER2-positive metastatic breast cancer were presented. While not immediately practice changing, these trials indicate the future directions of drug development in this field. Early phase studies with novel antibody-drug conjugates (ADCs) such as trastuzumab-deruxtecan and trastuzumab-duocarmazine suggest relevant clinical activity of these drugs in pretreated patients; in addition, these ADCs may offer activity in low HER2-expressing tumours as well. ZW25, a bispecific HER2-directed antibody targeting the extracellular domains 2 and 4, showed excellent tolerability and considerable single-agent activity. A combination of T‑DM1 with the tyrosine-kinase inhibitor neratinib yielded high response rates, while a study of trastuzumab plus durvalumab reported disappointing results. Although formally negative, overall survival data from the PHEREXA trial suggest clinical activity of dual HER2-inhibition with trastuzumab and pertuzumab in patients with prior trastuzumab treatment for advanced disease. A combined analysis of two tucatinib studies showed that systemic therapy is active when continued in case of isolated central nervous system progression and stable extracranial disease after local therapy of brain metastases; finally, a small prospective observation in asymptomatic patients with reduced left ventricular ejection fraction suggests that anti-HER2 treatment may be reasonably safe in this population.

NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DM1) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC).

1027Background: T-DM1 is an antibody-drug conjugate composed of trastuzumab and the maytansinoid antimicrotubule, DM1. T-DM1 was granted FDA approval in 2nd-line MBC after prior trastuzumab (T) and...

Abstract PD3-08: A randomized phase II trial of pyrotinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines and/or trastuzumab

Abstract Background:Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI) with activity against epidermal growth factor receptor (EGFR) / HER1, HER2, and HER4. Lapatinib in combination with capecitabine is one of the standards of care for patients with HER2-positive metastatic breast cancer (MBC) who have received prior taxanes, anthracyclines and/or trastuzumab. Methods: We conducted an open label, multicenter, randomized phase II trial to comparatively evaluate efficacy and safety of pyrotinib + capecitabine (PC) or lapatinib + capecitabine (LC) in women with HER2-positive MBC. Key eligibility criteria included prior treatment with taxanes, anthracyclines and/or trastuzumab, ≤2 prior chemotherapies for metastatic disease, no CNS metastases, and no prior treatment with HER2 targeted TKI. Eligible patients were randomized 1:1 to PC Arm (P 400 mg QD D1–21 + C 1000 mg/m2BID D1–14, 21-D cycle) or LC Arm (L 1250 mg QD D1–21 + C 1000 mg/m2BID D1–14, 21-D cycle). The primary endpoint was objective response rate (ORR) as assessed by investigator, and secondary endpoints included progression-free survival (PFS), time to progression (TTP), duration of response (DoR), overall survival (OS), and safety. Results: Between May 2015 and Mar 2016, 128 patients (65 in PC arm and 63 in LC arm) were enrolled in this study. Median age was 48 years (range 25-70), ECOG performance status was 0 (53.9%) or 1 (46.1%), 62.5% had hormone receptor-positive disease, 76.6% had visceral disease and 53.9% had received prior trastuzumab in (neo)adjuvant and/or mestastatic setting. Baseline characteristics were well balanced in two arms. Median follow-up time was 15.0 months. ORR was 78.5% in PC arm and 57.1% in LC arm (p=0.01), Median PFS was 18.1 months in PC arm and 7.0 months in LC arm (hazard ratio 0.363; 95% CI 0.228, 0.579; p<0.0001), PFS benefit in PC arm compared to LC arm was observed irrespective of prior trastuzumab or not. Treatment related Grade 3-4 toxicities occurred in >2% patients in PC arm vs LC arm included hand-foot syndrome (21.5% vs 19.0%), diarrhea (13.8% vs 4.8%), decreased neutrophil (7.7% vs 1.6%), decreased WBC (6.2% vs 1.6%), vomiting (4.6% vs 0%), increased AST (3.1% vs 1.6%), decreased hemoglobin (3.1% vs 1.6%), increased total bilirubin (0% vs 4.8%) and increased conjugated bilirubin (0% vs 3.2%). Conclusions: In women with HER2-positive MBC previously treated with taxanes, anthracyclines and/or trastuzumab, pyrotinib + capecitabine yield statistically significant better PFS and ORR than lapatinib + capecitabine in this randomized phase II trial. Phase III study is ongoing to validate this finding. Citation Format: Xu B, Ma F, Ouyang Q, Li W, Jiang Z, Tong Z, Liu Y, Li H, Yu S, Feng J, Wang S, Hu X, Zhu X, Zou J. A randomized phase II trial of pyrotinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines and/or trastuzumab [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-08.

Abstract P5-20-03: Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcome in 2863 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program

Abstract Background: The management of HER2+ BC has changed dramatically with the introduction and widespread use of HER2-targeted therapies, especially in the adjuvant setting. However, there is relatively limited real-world information on the impact of adjuvant Trastuzumab (aT) on patterns of recurrence and outcome of HER2+ MBC. Methods: In 2014, the 18 French Cancer Centers launched the Epidemiological Strategy and Medical Economics (ESME) program to provide real-world data on MBC patients (pts). All pts who started a 1st-line treatment for MBC between 01-Jan-2008 and 31-Dec-2014 were included. We examined clinical characteristics and outcomes (overall survival [OS] and time to next treatment [TNT]) in patients with HER2+ MBC pretreated with trastuzumab in the adjuvant setting (aT) compared with trastuzumab-naïve patients (nT) and patients with de novo HER2+ MBC (dn). Multivariate analyses adjusted for baseline demographic, prognostic factors and year of diagnosis (prior or after 2005, when aT was approved and widely administered in France for early HER2+ breast cancer). Results: Among the 15170 pts of the ESME database, 2863 (19%) were HER2+: 1093 pts (38%) had de novo and 1765 pts (62%) recurrent MBC; 63% were Hormone Receptor (HR) +; 54%, 25% and 21% had respectively 1, 2, or > 2 metastatic sites (68% visceral and 12% brain). Median time to 1st metastasis was 43.4 months (m) (95% CI: 24.6-84.4): 54 m in HR+ and 30 m in HR-. Among pts with recurrent MBC, 55% (995) had received aT. As 1st-line therapy for MBC, 90 % of pts received HER2-targeted agents (73% T-based). With a median follow-up of 46 m, median OS is 45 m (95% CI: 42.5-48). OS is significantly higher in de novo compared to recurrent MBC: 54 m (95% CI: 50.2-60.4) vs. 38.4 m (95% CI: 36.7-41.9), (p < 0.0001). Among pts with recurrent cancers, median OS is inferior in pts who had received aT, as compared to those who had not: 33.4 m (95% CI: 29.6-36.7) vs. 49.5 m (95% CI: 44.3-56.8), (p < 0.0001). Statistically significant differences persist after adjustment for age at MBC, disease-free interval, metastatic sites and RH status in the multivariate model (HR=1.45, 95% CI: 1.26-1.67) but not after adjustment for year of diagnosis (prior or after 2005) (HR=0.90, 95% CI: 0.70-1.15). Conclusions: These large-scale real-world data in patients with HER2+ MBC provide evidence that the survival outcome remain similar in patients with failure of adjuvant trastuzumab compared with trastuzumab-naïve patients after adjustment for year of diagnosis. De novo HER2+ MBC pts have the best outcomes. Data on clinical characteristics of metastasis and time to next treatment for the three subgroups will be presented at the meeting. Citation Format: Saghatchian M, Carton M, Piot I, Pérol D, Pistilli B, Brain E, Ghouadni A, Ricci F, Vanlemmens L, Loeb A, Levy C, Goncalves A, Dalenc F, Lefeuvre-Plesse C, Campone M, Jaffre A, Gourgou S, Cailliot C, Robain M, Dieras V. Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcome in 2863 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-03.

Abstract P1-13-03: Effects of neratinib after trastuzumab-based adjuvant therapy in hormone receptor-positive HER2+ early-stage breast cancer: Exploratory analyses from the phase III ExteNET trial

Abstract Background: The international, randomized, placebo-controlled phase III ExteNET trial showed that a 1-year course of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in patients with early-stage HER2+ breast cancer (BC) (hazard ratio 0.67; 95% CI 0.50–0.91; p=0.009) [Chan et al. Lancet Oncol 2016]. The significant iDFS benefit with neratinib was maintained after a median 5 years' follow-up (hazard ratio 0.73; 95% CI 0.57-0.92; p=0.008) [Martin et al. ESMO 2017]. At both time-points, marked benefit with neratinib was evident in patients with hormone receptor (HR)+ tumors, whereas in patients with HR– disease, initial improvements with neratinib diminished after completing treatment. We report exploratory analyses from the ExteNET trial done to better characterize the effects of neratinib in the HR+ subgroup. Methods: Patients with early-stage HER2+ BC were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year after standard primary therapy and trastuzumab-based adjuvant therapy. Randomization was stratified by HR status (locally assessed), nodal status, and trastuzumab regimen. Adjuvant endocrine therapy was recommended for patients with HR+ disease. Data concerning disease recurrences were collected prospectively during year 1-2 post-randomization, and from medical records during year 3–5 post-randomization. Primary endpoint: iDFS. Secondary endpoints: DFS including ductal carcinoma in situ (DFS-DCIS); time to distant recurrence (TTDR); distant DFS (DDFS); cumulative incidence of central nervous system (CNS) recurrences; overall survival (OS). Hazard ratios (95% CI) were estimated using Cox proportional-hazards models. Data cut-off: March 2017. Clinicaltrials.gov: NCT00878709. Results: 2840 patients were randomized (neratinib, n=1420; placebo, n=1420); 1631 (57%) patients had HR+ tumors (neratinib, n=816; placebo, n=815). 93% and 94% of HR+ patients in the neratinib and placebo groups, respectively, were receiving adjuvant endocrine therapy at baseline. Efficacy outcomes in the HR+ cohort after a median follow-up of 5.2 years are shown in the table. In subgroup analyses of the HR+ cohort, hazard ratios for iDFS were 0.49 in centrally confirmed HER2+ patients (n=951), and 0.58 in patients who had completed prior trastuzumab ≤12 months before randomization (n=1334). CNS recurrence and OS data are not yet mature. Updated 2-year analysis5-year analysis Hazard ratiobP-value Hazard ratiobP-value Δ, %a(95% CI)(2 sided)Δ, %a(95% CI)(2 sided)iDFS4.10.49 (0.31–0.75)0.0014.40.60 (0.43–0.83)0.002DFS-DCIS4.80.45 (0.29–0.69)<0.0015.10.57 (0.42–0.79)<0.001DDFS3.10.52 (0.32–0.84)0.0084.00.60 (0.42–0.85)0.004TTDR2.90.52 (0.31–0.85)0.013.80.61 (0.42–0.86)0.006a. Difference in event rates between neratinib vs placebo; b. Neratinib vs placebo Conclusions: Neratinib was associated with an absolute iDFS benefit of 4.4% in patients with HR+/HER2+ BC after 5 years' follow-up. HR/HER2 receptor cross-talk may underpin the notable effect of neratinib in patients with HR+ tumors when given in combination with endocrine therapy. Citation Format: Chia SKL, Martin M, Iwata H, Moy B, Lalani AS, Holmes FA, Mansi J, von Minckwitz G, Buyse M, Delaloge S, Ejlertsen B, Yao B, Murias Rosales A, Hellerstedt B, Cold S, Inoue K, Shen Z-Z, Galeano T, Barrios CH, Chan A. Effects of neratinib after trastuzumab-based adjuvant therapy in hormone receptor-positive HER2+ early-stage breast cancer: Exploratory analyses from the phase III ExteNET trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-03.

Abstract P5-21-26: T-DM1 activity in metastatic HER2-positive breast cancer patients who have received prior trastuzumab and pertuzumab: NSABP B-005

Abstract Background : The pivotal phase III EMILIA trial reported a progression free survival (PFS) rate of 9.6 months and an objective response rate of 43% with T-DM1 in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. However, there is very limited data on the efficacy of T-DM1 in patients who have received prior pertuzumab either neoadjuvantly or as first line therapy in the metastatic setting. The primary goal of this study was to assess the clinical efficacy (tumor response rates and median duration on therapy) of T-DM1 in patients previously treated with pertuzumab and trastuzumab. Methods: After IRB approval, a cancer data registry and electronic pharmacy database were utilized to identify breast cancer patients receiving treatment with T-DM1 at Cleveland Clinic and University of Pittsburgh. Patients that received trastuzumab and pertuzumab, in either the neoadjuvant or metastatic setting, with baseline and follow up imaging available for review were identified. Patient charts were reviewed to collect accurate information about the treatment sequencing and outcomes. RECIST version 1.1 was utilized for tumor assessment and patients with measurable disease and non measurable disease were included in the study. Results: We identified a total of 23 patients with a median age of 55 years that met the inclusion criteria. 69% percent of patients received T-DM1 as first line or second line therapy and 31% received it as third line or later. All patients had at least 1 measurable lesion. Best overall response showed rates of complete response, partial response and stable disease of 17%, 26% and 22% respectively. 35% patients progressed on first assessment after start of treatment. The median duration on therapy was 5.3 months (range 3 weeks to 33 months) with 43% of patients receiving T-DM1 for greater than 6 months. Conclusion: Our results were comparable to those reported by EMILIA trial. T-DM1 has reasonable clinical efficacy in patients who have received prior treatment with pertuzumab and trastuzumab with an overall response rate of 43% and median duration on therapy of 5.3 months. Citation Format: Tiwari SR, Sussman T, Kota K, Moore HC, Montero AJ, Budd GT, Puhalha S, Abraham J. T-DM1 activity in metastatic HER2-positive breast cancer patients who have received prior trastuzumab and pertuzumab: NSABP B-005 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-26.

Lapatinib.

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases plays an important role in the biology of many cancers. In breast and gastrointestinal cancer, and at lower rates also in additional tumor types, HER2 and its homo- or heterodimerization with HER1 or HER3 are essential for cancer cell growth and survival. Breast cancer patients overexpressing HER2 have a more aggressive course of their disease. The poor prognosis associated with HER2 overexpression can be substantially improved by adding HER2-targeted therapy to standard of care using the monoclonal antibody trastuzumab. Lapatinib, an oral dual tyrosine kinase inhibitor, blocks HER1 and HER2 tyrosine kinase activity by binding to the ATP-binding site of the receptor's intracellular domain, resulting in inhibition of tumor cell growth. Lapatinib is generally well tolerated with diarrhea being the most common adverse effect. However, although being mainly of mild to moderate severity, interruption or discontinuation of treatment has been reported in a substantial proportion of patients in clinical trials. In 2007, lapatinib has been approved in combination with capecitabine in patients with advanced HER2-positive breast cancer upon progressive disease following standard therapy with anthracyclines, taxanes, and trastuzumab. In 2013, the approval was extended to a chemotherapy-free combination with trastuzumab for patients with metastatic HER2-positive, hormone receptor-negative breast cancer progressing on prior trastuzumab and chemotherapy. Since 2010, lapatinib is approved in combination with letrozole in the treatment of postmenopausal women with advanced HER2- and hormone receptor-positive breast cancer. In contrast, in first-line cytotoxic-based therapy of both early and advanced HER2-positive breast cancer, data from clinical trials did not provide evidence of additional benefit of lapatinib compared to trastuzumab. Moreover, over the past few years, novel HER2-targeted drugs, either alone or as a combined anti-HER2 approach, have been extensively evaluated, demonstrating a more favorable outcome. Also, neither in first- nor second-line treatment of advanced gastric cancer, lapatinib has been proven to be superior compared to trastuzumab as hitherto standard of care HER2 blockade. Therefore, lapatinib has become somewhat less important in patients with HER2-positive breast cancer during the past 10years since its first introduction. Nevertheless, consideration of treatment with lapatinib appears to be reasonable in selected patients not only in the approved applications but also beyond, and further indications such as HER2-positive refractory metastatic colorectal cancer may arise in future. Also, lapatinib may have distinct advantages over antibodies in targeting truncated HER2 and crossing the blood-brain barrier. Finally, the favorable cardiac toxicity profile of lapatinib makes it an attractive alternative to trastuzumab-based regimens in patients at risk for cardiac events.