Locally Advanced Or Metastatic Breast Cancer Research Articles

Abstract GS01-10: HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer

Abstract Background Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor approved in combination with trastuzumab and capecitabine for previously treated HER2+ locally advanced or metastatic breast cancer (LA/MBC). Trastuzumab emtansine (T-DM1) is a HER2-directed antibody-drug conjugate approved to treat HER2+ LA/MBC previously treated with trastuzumab and a taxane. This is the first report of HER2CLIMB-02 (NCT03975647), a randomized, double-blind, placebo-controlled phase 3 study assessing the efficacy and safety of tucatinib combined with T-DM1 in patients with previously treated HER2+ LA/MBC. Methods Eligible patients had HER2+ LA/MBC previously treated with trastuzumab and a taxane in any setting with ECOG performance status ≤1 and adequate hepatic, renal, hematologic, and cardiac function. Patients with previously treated stable, progressing, or untreated brain metastases (BMs) not requiring immediate local therapy were also eligible. Patients were randomly assigned 1:1 to receive 21-day cycles of either tucatinib (300 mg orally twice a day [PO BID]) or placebo (PO BID), combined with T-DM1 (3.6 mg/kg intravenously every 3 weeks). The primary endpoint was progression-free survival (PFS) by investigator assessment per RECIST v1.1. Alpha-controlled secondary endpoints included overall survival (OS) and objective response rate (ORR) per RECIST v1.1 for the overall population, and PFS and OS for the subset of patients with BMs at baseline. Safety was analyzed as a secondary endpoint. Results From October 8, 2019, to June 16, 2022, 463 patients were randomly assigned, comprising 228 to the tucatinib arm (tucatinib + T-DM1) and 235 to the control arm (placebo + T-DM1). The median duration of follow-up (OS) was 24.4 months for the overall population. Patient demographics and baseline characteristics were balanced between the 2 arms. Almost half (44.1%) of the overall population had either active or stable BMs at baseline. As of the data cutoff (June 29, 2023), the study met its primary endpoint with a statistically significant improvement in PFS in the tucatinib arm vs control arm. The risk of progression or death decreased by 24.1% in the tucatinib arm (hazard ratio [HR]=0.759 [95% CI, 0.607-0.950]; P=0.0163). Median PFS was 9.5 months (95% CI, 7.4-10.9) vs 7.4 months (95% CI, 5.6-8.1) for the tucatinib and control arms, respectively. HRs for PFS across all prespecified subgroups were consistent with the HR of the overall population, including patients with BMs at baseline (HR=0.639 [95% CI, 0.459-0.891]). The interim OS results were immature with 134 of 253 total required events (53%) and did not meet the prespecified crossing boundary. The confirmed ORR was numerically higher in the tucatinib arm (42.0%) vs the control arm (36.1%). The most common treatment-emergent adverse events (TEAEs) included nausea (65.4% vs 49.4% for tucatinib and control arms, respectively), diarrhea (56.7% vs 26.6%), and fatigue (48.9% vs 37.3%). The most common grade ≥3 TEAEs in the tucatinib arm were alanine and aspartate aminotransferase elevations, each reported in 38 patients (16.5%) in the tucatinib arm and 6 patients (2.6%) in the control arm. TEAEs associated with any treatment discontinuation occurred in 51 patients (22.1%) in the tucatinib arm and 27 (11.6%) in the control arm. TEAEs leading to deaths occurred in 3 patients (1.3%) in the tucatinib arm and 2 patients (0.9%) in the control arm. Conclusion HER2CLIMB-02 demonstrated that the addition of tucatinib to T-DM1 significantly improved median PFS in patients with previously treated HER2+ LA/MBC, including those with BMs. Although discontinuations due to TEAEs were more common in the tucatinib arm, no new safety signals emerged for the combination therapy. Citation Format: Sara Hurvitz, Sherene Loi, Joyce O'Shaughnessy, Alicia Okines, Sara Tolaney, Joo Hyuk Sohn, Cristina Saura, Xiaofu Zhu, David Cameron, Thomas Bachelot, Erika Hamilton, Giuseppe Curigliano, Antonio Wolff, Nadia Harbeck, Norikazu Masuda, Linda Vahdat, Khalil Zaman, Frances Valdes-Albini, Margaret Block, Timothy Pluard, Tira Tan, Chelsea Gawryletz, Arlene Chan, Philippe Bedard, Rinat Yerushalmi, Binghe Xu, Konstantinos Tryfonidis, Michael Schmitt, Joan Xie, Virginia Borges. HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-10.

Characteristics, Treatment, and Outcomes of Real-World Talazoparib-Treated Patients With Germline BRCA-Mutated Advanced HER2-Negative Breast Cancer.

Talazoparib is a poly (adenosine diphosphate-ribose) polymerase inhibitor approved for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative, locally advanced or metastatic breast cancer (LA/mBC), with approval based on the EMBRACA trial. To date, there are no published data on talazoparib use in the real-world United States (USA) setting. Characteristics, treatment patterns, and clinical outcomes of real-world US patients with gBRCAm HER2-negative LA/mBC treated with talazoparib monotherapy were collected via retrospective chart review and summarized using descriptive statistics. Among 84 eligible patients, 35.7% had hormone receptor-positive tumors and 64.3% had triple-negative LA/mBC (TNBC). At talazoparib initiation, 29.8% had ECOG PS of ≥2 and 19.0% had brain metastasis. Mutations in gBRCA1 or 2 were detected among 64.3% and 35.7% of patients, respectively. Talazoparib was given as 1st-line therapy in 14.3% of patients, 2nd-line in 40.5%, and 3rd- or 4th-line in 45.2%. Median time to talazoparib treatment failure was 8.5 months (95% CI, 8.0-9.7), median progression-free survival was 8.7 months (95% CI, 8.0-9.9), the median time from initiation to chemotherapy was 12.2 months (95% CI, 10.5-20.1), and the overall response rate was 63.1%. No differences in clinical outcomes were observed between patients with HR-positive/HER2-negative LA/mBC and patients with TNBC by using unadjusted statistical comparisons. Brain metastasis and ECOG PS ≥2 at talazoparib initiation were associated with treatment failure and progression or mortality. Overall, talazoparib clinical outcomes in this real-world population are consistent with findings from EMBRACA.

P66-3 Safety and efficacy of eribulin in patients with locally advanced or metastatic breast cancer: A phase IV study in India

Eribulin mesylate, a synthetic analogue of halichondrin B, exhibits anti-tumor effects through a unique cytotoxic and non-cyctotoxic actions. In landmark phase-3 EMBRACE trial, eribulin showed promising beneficial outcomes in the treatment of locally advanced or metastatic breast cancer (LA/MBC). A limited number of Asian subset of the population were involved in the previous trials. Here, we report the safety and efficacy of eribulin in Indian patients with LA/MBC from a post marketing phase IV study.

Results from VERONICA: A randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC).

1004 Background: For patients (pts) with ER-positive, HER2-negative MBC, CDK4/6 inhibitors + endocrine therapy (ET) is standard first-line treatment, with single-agent ET considered for second-line. Nevertheless, most pts progress. A novel therapeutic target is the antiapoptotic protein BCL2, which is overexpressed in ̃85% of primary ER-positive breast cancers. VEN is a potent, selective BCL2 inhibitor that has shown promising clinical activity in pts with ER-positive and BCL2-positive MBC who have received prior ET. We report the prespecified primary and updated (for overall survival [OS]) analysis of VERONICA (NCT03584009), a phase II study of VEN + F vs F in ER-positive, HER2-negative LA/MBC. Methods: Pts were ≥18-year-old women with ER-positive, HER2-negative LA/MBC, who received ≤2 prior lines of ET and no prior chemotherapy in the LA/MBC setting and experienced disease recurrence/progression during/after CDK4/6 inhibitor therapy (received ≥8 weeks prior). Pts were randomized 1:1 to VEN (oral; 800 mg daily) + F (intramuscular; 500 mg day 1 and 15 of cycle 1; day 1 of subsequent 28-day cycles) or F, and were treated until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. Pts were stratified by prior lines of therapy in the LA/MBC setting (1 vs 2) and BCL2 status (high vs low). Primary endpoint was clinical benefit rate (CBR; complete response, partial response, and stable disease ≥24 weeks). Secondary endpoints included progression-free survival (PFS) and OS; safety and exploratory subgroup analyses were also conducted. Results: At primary analysis (cutoff: Aug 5, 2020), 103 pts had been randomized (intention-to-treat [ITT] population). Median age was 58.0 and 59.5 years in the VEN + F and F arms, respectively. CBR was similar between arms (VEN + F: 11.8% [n = 6/51; 95% confidence interval (CI) 4.44–23.87]; F: 13.7% [7/51; 5.70–26.26]; risk difference: -1.96% [95% CI -16.86–12.94]). Median PFS was 2.69 months (95% CI 1.94–3.71) in the VEN + F vs 1.94 months (1.84–3.55) in the F arm (stratified hazard ratio: 0.94 [95% CI 0.61–1.45]). Results for CBR and PFS were similar in the BCL2-high and -low subgroups vs the ITT population. More grade 3–4 adverse events (AEs) were observed in the VEN + F vs F arm (n = 13/50 [26%] vs 6/51 [11.8%]). AEs observed with VEN + F were consistent with their individual safety profiles. At updated analysis (cutoff: Oct 22, 2020), OS data were not mature (35.0% event/pt ratio); median OS was 16.99 months in the VEN + F vs not reached in the F arm (stratified hazard ratio: 2.06 [1.04–4.09]). Conclusions: From the primary analysis, VERONICA did not show an improved CBR or PFS with VEN + F, vs F alone, in pts with endocrine- and CDK4/6 inhibitor-refractory LA/MBC. Biomarker analysis is ongoing. Clinical trial information: NCT03584009 .

AcelERA Breast Cancer (BC): Phase II study evaluating efficacy and safety of giredestrant (GDC-9545) versus physician’s choice of endocrine monotherapy in patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2-) locally advanced or metastatic breast cancer (LA/mBC).

TPS1100 Background: The standard-of-care therapy for ER+ BC typically involves modulation of estrogen synthesis and/or ER activity. Despite disease progression with standard treatments, growth and survival of the majority of tumors are thought to remain dependent on ER signaling; therefore, pts with ER+ BC can still respond to second- or third-line endocrine treatment (ET) after progression on prior therapy (Di Leo 2010; Baselga 2012). ESR1 mutations may drive estrogen-independent transcription and proliferation leading to resistance. The highly potent, nonsteroidal oral selective ER degrader, giredestrant, achieves robust ER occupancy and is active regardless of ESR1 mutation status. Phase I data have shown that giredestrant is well tolerated and active both as a single agent and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), palbociclib (Lim 2020). Single-agent giredestrant has also shown encouraging antitumor activity in pts previously treated with fulvestrant and/or a CDK4/6i. Methods: acelERA BC (NCT04576455) is a randomized, open-label, multicenter phase II study evaluating the efficacy and safety of giredestrant vs. physician’s choice of ET (fulvestrant or aromatase inhibitor) in males, or postmenopausal or pre/perimenopausal females with ER+/HER2– LA/mBC who have received 1–2 prior lines of systemic therapy in the LA or mBC settings, at least one of which must be ET. Randomization: 1:1 to receive giredestrant (30 mg PO QD on Days 1–28 of each 28-day cycle) or physician’s choice of ET per local guidelines. Men and pre-/perimenopausal women will receive a luteinizing hormone-releasing hormone agonist. Eligibility: ≥18 years, ECOG PS 0–1, histologically or cytologically confirmed diagnosis of LA (recurrent or progressed) or metastatic adenocarcinoma of the breast, measurable disease (per modified RECIST v1.1) or evaluable bone lesions, and ER+/HER2– tumors (locally assessed). Primary endpoint: progression-free survival (PFS; investigator-assessed per RECIST v1.1). Secondary endpoints: overall survival, objective response rate, duration of response, clinical benefit rate, PFS in pts with baseline ESR1 mutations, and quality of life. Safety, pharmacokinetics, biomarkers, and health status utility will also be assessed. Stratification: site of disease (visceral vs. nonvisceral), prior treatment with CDK4/6i (yes vs. no), and prior treatment with fulvestrant (yes vs. no). PFS will be compared using a stratified log-rank test; median PFS, using Kaplan–Meier analyses. Recruitment for the global enrollment phase is ongoing, the first patient was enrolled November 27, 2020. Clinical trial information: NCT04576455 .

CONTESSA: A multinational, multicenter, randomized, phase III registration study of tesetaxel plus a reduced dose of capecitabine in patients (pts) with HER2-, hormone receptor + (HR+) locally advanced or metastatic breast cancer (LA/MBC) who have previously received a taxane.

TPS1107 Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and Q3W dosing regimen; no observed hypersensitivity reactions; preclinical evidence of CNS penetration; and improved activity against chemotherapy-resistant tumors. Over 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a Phase 2 study in 38 pts with HER2-, HR+ MBC who received T Q3W, with a confirmed ORR per RECIST 1.1 of 45% and median PFS of 5.4 mo. The confirmed ORR in taxane-pretreated pts was 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine (C) in combination with a taxane may result in reduced toxicity without reduction in efficacy. Preclinical data also suggest that T may penetrate the brain at clinically relevant concentrations. CONTESSA investigates T plus a reduced dose of C as an all-oral regimen in HER2-, HR+ LA/MBC, with revised eligibility criteria to allow inclusion of pts with CNS metastases. Methods: CONTESSA is a 600-pt, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing T (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of C alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in pts with HER2-, HR+ LA/MBC previously treated with a taxane in the (neo)adjuvant setting. The protocol was newly amended to allow pts with known CNS metastases. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are OS, ORR, and disease control rate. Enrollment began in Dec 2017. Following review in Jan 2019, the Independent Data Monitoring Committee recommended that the Study continue as planned. Clinical trial information: NCT03326674.

Health-related quality of life from the FALCON phase III randomised trial of fulvestrant 500 mg versus anastrozole for hormone receptor-positive advanced breast cancer

BackgroundThe phase III randomised FALCON trial (NCT01602380) demonstrated improved progression-free survival with fulvestrant 500 mg versus anastrozole 1 mg in endocrine therapy-naïve postmenopausal women with hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC). Furthermore, overall health-related quality of life (HRQoL) was maintained and comparable for fulvestrant and anastrozole. Here, we present additional analyses of patient-reported HRQoL outcomes from FALCON. MethodsWomen with endocrine therapy-naïve HR+ LA/MBC were randomised 1:1 to fulvestrant (days 0, 14, 28, then every 28 d) or anastrozole (daily) until disease progression or discontinuation. HRQoL was assessed by FACT-B questionnaire (TOI and FACT-B total score) at randomisation and every 12 weeks during treatment. HRQoL data post-treatment (with or without progression) were also collected. ResultsIn total, 462 patients were randomised (fulvestrant, n = 230; anastrozole, n = 232). Compliance to FACT-B overall ranged from 60.0 to 97.4%. Mean change from baseline in TOI and FACT-B total score remained broadly stable (approximately ± 3 points to week 132) and was similar between arms during treatment. HRQoL was also maintained in FACT-B subscales. Approximately one-third of patients had improved TOI (≥+6 points) and FACT-B (≥+8 points) total scores from baseline up to week 120 and 132, respectively, of treatment with fulvestrant (ranges 26.4–45.0% and 22.4–35.8%, respectively) and anastrozole (ranges 18.6–32.9%, and 22.7–37.9%, respectively). ConclusionsMean change from baseline in TOI and FACT-B total score was maintained for fulvestrant and anastrozole; similar proportions of patients in both arms had improved TOI and FACT-B total scores. ClinicalTrials.gov identifierNCT01602380.

Abstract PD5-09: Fulvestrant for hormone receptor-positive advanced breast cancer in patients with visceral vs non-visceral metastases: Findings from FALCON, FIRST, and CONFIRM

Abstract BACKGROUND Patients with hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC) and non-visceral metastases (non-VM) generally have a better prognosis than patients with visceral metastases (VM). However, in the absence of visceral crisis, endocrine therapy (ET) remains an effective treatment option in both patient groups. This descriptive analysis examined the treatment effect of fulvestrant 500 mg vs comparators in postmenopausal patients with HR+ LA/MBC, with or without VM. METHODS Three randomized studies of fulvestrant 500 mg for postmenopausal HR+ LA/MBC were included. The Phase 3 FALCON study (NCT01602380) compared fulvestrant 500 mg with anastrozole in patients without any prior ET (n=462; fulvestrant 500 mg: 58.7% with VM; anastrozole: 51.3% with VM). The Phase 2 FIRST study (NCT00274469) compared fulvestrant 500 mg with anastrozole in patients who had not received ET for advanced disease (n=205; fulvestrant 500 mg: 47.1% with VM; anastrozole: 56.3% with VM). The Phase 3 CONFIRM study (NCT00099437) compared fulvestrant 500 mg with fulvestrant 250 mg (n=736; fulvestrant 500 mg: 56.6% with VM; fulvestrant 250 mg: 52.9% with VM); patients had received prior ET for adjuvant/advanced disease. The treatment effect of fulvestrant 500 mg vs comparator ET was determined using log-rank tests. RESULTS In FALCON, there was a greater treatment effect with fulvestrant 500 mg vs anastrozole for progression-free survival (PFS) in the non-VM group (hazard ratio [HR] 0.59) vs the VM group (HR 0.99). A consistent treatment effect was observed for fulvestrant 500 mg vs comparator for PFS in FIRST (non-VM HR 0.58; VM HR 0.82) and CONFIRM (non-VM HR 0.72; VM HR 0.86). Median PFS of fulvestrant 500 mg vs comparator in non-VM and VM subgroups was: 22.3 months (m) vs 13.8 m and 13.8 m vs 15.9 m, respectively, in FALCON; 34.0 m vs 21.3 m and 9.8 m vs 9.9 m in FIRST; and 10.4 m vs 5.9 m and 4.7 m vs 4.0 m in CONFIRM. Clinical benefit rate with fulvestrant 500 mg vs anastrozole in FALCON was 87.4% vs 75.2% in the non-VM group, and 71.9% vs 73.1% in the VM group. Overall survival (OS) in FALCON (31% maturity) showed a greater treatment effect with fulvestrant 500 mg vs anastrozole in the non-VM group vs the VM group (HR 0.60 vs 1.09). In terms of OS, in FIRST there was a greater treatment effect with fulvestrant 500 mg vs anastrozole in the non-VM group compared with the VM group (HR 0.68 vs 0.86). In CONFIRM, improved OS was observed with fulvestrant 500 mg vs fulvestrant 250 mg; this treatment effect was consistent in non-VM (HR 0.78) and VM subgroups (HR 0.83). CONCLUSIONS In three studies, an improved treatment effect of fulvestrant 500 mg vs comparator ET for HR+ LA/MBC was observed in patients with non-VM. The treatment effect of fulvestrant 500 mg vs comparator for PFS across all three studies appeared consistent. A reduced treatment effect of fulvestrant 500 mg vs comparator was generally seen in patients with VM, although fulvestrant 500 mg was still as effective as, or slightly more effective than, the comparator. These data suggest that patients without VM may benefit more from fulvestrant 500 mg than patients with VM. Citation Format: Roberston JFR, Di Leo A, Fazal M, Lichfield J, Ellis MJ. Fulvestrant for hormone receptor-positive advanced breast cancer in patients with visceral vs non-visceral metastases: Findings from FALCON, FIRST, and CONFIRM [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 PD5-09.

Abstract PD3-14: Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer

Abstract Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which disrupts microtubulin and induces apoptosis. Methods This ongoing, phase 1 study evaluates safety, tolerability, pharmacokinetics, and antitumor activity of SGN-LIV1A (q3wks IV) in women with LIV-1-positive, unresectable, locally advanced or metastatic breast cancer (LA/MBC) (NCT01969643). Patients (pts) with measurable disease and ≥2 prior cytotoxic regimens for LA/MBC are eligible. Pts with ≥ Grade 2 neuropathy are excluded. Response is assessed per RECIST v1.1; pts with stable disease (SD) or better can continue treatment until disease progression or intolerable toxicity. At completion of dose escalation in hormone receptor-positive/HER2-negative (HR+/HER2–) and triple-negative (TN) pts, expansion cohorts were opened to further evaluate safety and antitumor activity of monotherapy in TN pts. Tumor biopsies are evaluated for LIV-1 expression. Results To date, 69 pts (18 HR+/HER2–, 51 TN) have received a median of 3 cycles (range, 1–12) of SGN-LIV1A at doses of 0.5–2.8 mg/kg. Median age was 56 yrs. Pts had a median of 3 prior cytotoxic regimens for LA/MBC; 58 had visceral disease and 37 had bone metastases. No dose-limiting toxicities (DLTs) occurred in 19 DLT-evaluable pts; maximum tolerated dose was not exceeded at 2.8 mg/kg. Expansion cohorts of TN pts were opened at 2.0 and 2.5 mg/kg. Treatment-emergent adverse events (AEs) reported in ≥25% of pts were fatigue (59%), nausea (51%), peripheral neuropathy (44%), alopecia (36%), decreased appetite (33%), constipation (30%), abdominal pain, diarrhea, and neutropenia (25% each). Most AEs were Grade 1/2; AEs ≥ Grade 3 included neutropenia (25%) and anemia (15%). Febrile neutropenia occurred in 2 pts whose total dose exceeded 200 mg per cycle, including 1 treatment-related death due to sepsis. No other treatment-related deaths occurred on-study. Seven pts discontinued treatment due to AEs. In dose escalation, activity was observed in 17 efficacy evaluable (EE) HR+/HER2- pts, with a disease control rate (DCR= CR+PR+SD) of 59% (10 SD), including 1 pt with SD ≥24 wks. Among the 44 EE TN pts (dose escalation plus expansion cohorts), the objective response rate (ORR) was 32% (14 PR) with a confirmed PR rate of 21%, DCR was 64% (14 PR, 14 SD), and clinical benefit rate (CBR=CR+PR+SD ≥24 wks) was 36% (16 pts). For TN pts, median PFS was 11.3 wks (95% CI: 6.1, 17.1); 10 pts remain on treatment. Of 631 MBC tumor samples of all clinical subtypes evaluated for LIV-1, 91% were positive; 75% had moderate-to-high expression (H-score ≥100). Conclusions LIV-1 is expressed in almost all MBC tumors. SGN-LIV1A monotherapy was generally well tolerated and showed encouraging antitumor activity in heavily pretreated TN MBC, with a PR rate of 32%, confirmed PR rate of 21%, and CBR (≥24 wks) of 36%. Response duration data continue to evolve. Enrollment continues in the TN monotherapy expansion cohort. Citation Format: Modi S, Pusztai L, Forero A, Mita M, Miller KD, Weise A, Krop I, Burris III H, Kalinsky K, Tsai M, Liu MC, Hurvitz SA, Wilks S, Ademuyiwa F, Diab S, Han HS, Kato G, Nanda R, O'Shaughnessy J, Kostic A, Li M, Specht J. Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer [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 PD3-14.

A European, Observational Study of Endocrine Therapy Administration in Patients With an Initial Diagnosis of Hormone Receptor-Positive Advanced Breast Cancer

BackgroundDespite guideline recommendations, reports suggest that a proportion of patients with hormone receptor (HR)-positive locally advanced or metastatic breast cancer (LA/MBC) might not receive endocrine therapy. The aims of this study were to estimate the proportion of postmenopausal patients with an initial (primary) diagnosis of HR-positive LA/MBC in Europe, and to assess the administration of endocrine treatment in these patients. Materials and MethodsFourteen national and regional cancer registries across Europe were invited to participate in this observational study. Six registries each provided anonymized clinical information on > 5000 postmenopausal women with breast cancer diagnosed between January 2000 and December 2014, including age at diagnosis, estrogen and/or progesterone receptor status, disease stage, and receipt of endocrine therapy. The proportion of patients with an initial diagnosis of HR-positive LA/MBC and, of these, the proportion who received endocrine therapy, was calculated. ResultsRegistries from Belgium, England, Ireland, Norway, The Netherlands, and Munich, Germany provided data. In total, 316,680 postmenopausal women were diagnosed with breast cancer, including 244,268 with known HR status and disease stage. Of these patients, 19,002 (7.8%) had a primary diagnosis of HR-positive LA/MBC. This proportion ranged from 5.4% (N = 4484) in England to 12.7% (N = 4085) in Germany. Most of these patients (n = 14,157; 74.5%) received endocrine treatment, ranging from 55.5% (n = 445) in Norway to 88.1% (n = 443) in Belgium. ConclusionThese results indicate that a sizeable proportion of postmenopausal patients in Europe received a primary diagnosis of HR-positive LA/MBC, and that almost three-quarters received subsequent endocrine therapy as per guideline recommendations.

A network meta-analysis of fulvestrant vs alternative first-line endocrine therapies for endocrine therapy-naive postmenopausal hormone receptor-positive advanced or metastatic breast cancer.

e12545 Background: Fulvestrant (F) is a selective estrogen degrader for hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC). This network meta-analysis examined the efficacy of F (500 mg) vs alternative endocrine therapies (ETs) for first-line treatment of ET-naïve HR+ LA/MBC. Methods: Randomized controlled trials of first-line F, tamoxifen (Tam), anastrozole (A), exemestane (E), letrozole (L), and toremifene (T) for women (≥18 years) with HR+ LA/MBC and no prior ET were identified in a systematic review of MEDLINE, EMBASE, and Cochrane databases from inception to October 2016. Conference proceedings of the American Society of Clinical Oncology, European Society of Medical Oncology, and San Antonio Breast Cancer Symposium from 2013-2016 were hand searched. Trials of targeted combination therapies were excluded. Studies were checked for heterogeneity. A standard fixed-effect Bayesian network meta-analysis was conducted based on hazard ratios (HRs) and assuming proportional hazards for progression-free and overall survival (PFS/OS). Results: Seven eligible studies (1 Phase [Ph] 2, 5 Ph 3, 1 Ph 2/3) were identified. All had PFS data; five had OS data. Two trials compared F vs A; PFS data were available for both trials; sufficiently mature OS data for F were available from Ph 2 only. The proportional hazards assumption was met for PFS only.F had significantly improved PFS vs Tam (HR 0.57, 95% credibility interval [Crl] 0.44-0.73), A (HR 0.75, 95% Crl 0.62-0.91), E (HR 0.65, 95% Crl 0.47-0.91), and T (HR 0.53, 95% Crl 0.37-0.78). Numerically improved PFS was observed for F vs L (HR 0.81, 95% Crl 0.59-1.11). F had significantly improved OS vs Tam (HR 0.63, 95% Crl 0.40-0.98), A (HR 0.63, 95% Crl 0.42-0.94), and E (HR 0.56, 95% Crl 0.33-0.95). OS was numerically improved with F vs L (HR 0.66, 95% Crl 0.41-1.04). Conclusions: This analysis suggests improved PFS and OS for fulvestrant vs tamoxifen, anastrozole, exemestane, and letrozole, and PFS for fulvestrant vs toremifene. Further analysis should be conducted, using non-proportional hazard methods and more mature OS data, to confirm the OS results.

Abstract P5-08-20: A real-world evidence study to define the prevalence of endocrine therapy-naïve hormone receptor-positive locally advanced or metastatic breast cancer in the US

Abstract BACKGROUND The recently completed FALCON trial (NCT01602380) compared the efficacy of the selective estrogen receptor degrader (SERD) fulvestrant 500 mg with anastrozole in postmenopausal women with hormone receptor (HR)-positive locally advanced or metastatic breast cancer (LA/MBC) who had received no prior endocrine therapy (ET). To better understand the size of the US population to which the results of the FALCON trial are applicable, this study estimated the proportion of postmenopausal patients with HR-positive, human epidermal growth factor receptor (HER)2-negative LA/MBC who had received no prior ET, using data from a US medical record database. METHODS This observational study retrospectively analyzed data from the Optum Electronic Health Record Database, obtained from provider groups across the US. Women over 40 years of age with breast cancer diagnoses (January 2008–March 2015) were included, provided they had at least 12 months of recorded medical history prior to index, and at least one recorded physician office visit in that time. Incident (newly diagnosed) and prevalent (previous diagnosis of early or advanced breast cancer) cases were identified. Free-text clinical notes were reviewed using natural language processing to identify a target patient population of postmenopausal women with HR-positive, HER2-negative LA/MBC who had received no prior ET (similar to the FALCON entry criteria); additionally, diagnostic codes or treatment history were also used to identify HR status in the absence of confirmation from the free-text notes. The results of this analysis were extrapolated to estimate the size of the target population at a national level, using statistics from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. Results are presented descriptively. RESULTS Overall, 63,962 women with breast cancer were identified, of whom 11,831 had discernible information on menopausal status, HER2 status, HR status, and disease stage. Of these, 1,923 patients were identified with postmenopausal, HR-positive, HER2-negative (or unknown) LA/MBC. Within this population of patients, 70.7% (1,360/1,923) had not previously received ET (88.5% [920/1,040] incident cases; 49.8% [440/883] prevalent cases), representing 11.5% (1,360/11,831) of the total breast cancer population with known menopausal status, HER2 status, HR status, and cancer disease stage information. The proportion of patients with postmenopausal, HR-positive, HER2-negative LA/MBC who had received no prior ET in this sample was extrapolated using US national estimates of the size of the postmenopausal, HR-positive, HER2-negative LA/MBC population taken from SEER. This approach suggests a 5-year limited-duration prevalence of postmenopausal patients with HR-positive, HER2-negative LA/MBC who have received no prior ET of approximately 50,000 cases and an annual incidence of about 15,000 patients. CONCLUSIONS These real-world data provide an estimate of the number of postmenopausal patients with HR-positive, HER2-negative, LA/MBC in the US who have not previously received ET. This population corresponds to the recently completed Phase 3 FALCON trial of fulvestrant compared with anastrozole. Citation Format: Nunes AP, Green E, Dalvi T, Lewis J, Jones N, Seeger JD. A real-world evidence study to define the prevalence of endocrine therapy-naïve hormone receptor-positive locally advanced or metastatic breast cancer in the US [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-20.

Abstract P6-07-21: High reduction of circulating tumour cells in HER2-negative locally advanced or metastatic breast cancer (LAMBC) patients treated with eribulin as third line chemotherapy (ONSITE study)

Abstract Background Circulating tumour cells (CTC) may be a good biomarker to guide the management of patients with LAMBC (Cristofanilli, NEJM 2004). Detection of CTCs in peripheral blood is a simple procedure. Eribulin monotherapy has shown improved survival in patients with LAMBC that has progressed after 2 or 3 chemotherapy regimens (EMBRACE study). The aims of this study were to evaluate the kinetics of CTCs before and after eribulin treatment, and its correlation with clinical outcomes. Methods Patients received eribulin (1.23 mg/m2 on days 1 and 8 of every 21-day cycle) as third-line therapy until progression, unacceptable toxicity or withdrawal. CTCs were measured in 7.5ml of blood at baseline and after the second cycle of treatment. Cell counting was performed using the CellSearch System, Veridex. Cox proportional hazards regression modeling was used to identify independent prognostic factors for survival endpoints. Results Out of 59 eligible women (mean age 57.7 years), 58 (98.3%) had received previous taxanes and/or anthracyclines. Nearly all (98.3%) had HER2-negative tumors, 72% were positive for estrogens, 21% were triple-negative; 64.4% had liver metastasis and 57.6% bone metastasis. The mean number of administered cycles was 6.9 ± 5.4. Follow-up was performed in 54 patients, with 18.5% (n=10) partial response, 42.6% (n=23) stable disease, and 38.9% (n=21) progressive disease. Clinical benefit was achieved in 33 patients (61.1%). Median progression-free survival (PFS) was 5.13 months (95% CI 3.23, 8.90) and median overall survival (OS) was 13.6 months (95% CI 11.8, not reached). CTC levels were measured in 50 patients. The mean number of CTCs at baseline was 16.8 (IQR 0-21) and on cycle 2, 5.4 (IQR 0-8.5), p<0.001. In patients with CTC ≥ 5 at baseline, 52.4% reduced their levels to CTC < 5 on cycle 2 (p=0.043). No significant differences (p=0.066) were found in PFS when baseline CTC levels were < 5 or ≥ 5 cells/ml. Statistical differences were, however, found in OS (p= 0.0083). On cycle 2, significant differences were observed for both PFS (p=0.045) and OS (p=0.0129) with CTC levels <5 or ≥ 5 cells/ml. No correlation could be found between CTC levels and the objective response at baseline or on cycle 2. Conclusions Our study suggests there is a significant correlation between levels of CTCs and disease prognosis. Eribulin monotherapy was related to a significant reduction in CTCs. (EudraCT number 2013-001416-30). Keywords eribulin, metastatic, breast cancer, circulating tumour cells. Citation Format: Manso Sánchez L, Moreno Antón F, Izarzugaza Perón Y, Delgado Mingorance I, Borrega García P, Echarri González MJ, Martínez Jáñez N, López González A, Olier Garate C, Ballesteros García A, Chacón López-Muñiz I, Ciruelos Gil EM, García Sáenz JA, Paz-Ares Rodríguez L. High reduction of circulating tumour cells in HER2-negative locally advanced or metastatic breast cancer (LAMBC) patients treated with eribulin as third line chemotherapy (ONSITE 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 P6-07-21.

Abstract P2-08-09: Progression-free survival results in postmenopausal Asian women: Subgroup analysis from a phase 3 randomized trial of fulvestrant 500 mg vs anastrozole for hormone receptor-positive advanced breast cancer (FALCON)

Abstract BACKGROUND Fulvestrant is a selective estrogen receptor degrader (SERD) with no known agonist effects. In the open-label Phase 2 FIRST study, fulvestrant 500 mg suggested improved efficacy as first-line treatment vs anastrozole in patients with hormone receptor-positive locally advanced or metastatic breast cancer (LA/MBC). The Phase 3, randomized, double-blind, multicenter FALCON trial (NCT01602380) compared fulvestrant 500 mg with anastrozole 1 mg in patients with hormone receptor-positive LA/MBC who had not received prior hormonal therapy. The primary endpoint of the study, progression-free survival (PFS) assessed via RECIST 1.1, surgery/radiotherapy for disease worsening, or death (any cause), was met, as shown by a statistically significant improvement in PFS for fulvestrant 500 mg vs anastrozole. This analysis evaluated PFS in the Asian patient subgroup, which included all randomized patients from centers in China, Japan, and Taiwan. METHODS Eligible patients had ER and/or progesterone receptor-positive breast cancer, WHO performance status 0–2, and ≥1 measurable/non-measurable lesion(s). Patients were randomized (1:1) to receive fulvestrant 500 mg (IM on Days 0, 14, 28, and each 28 days thereafter) or anastrozole 1 mg daily, and were stratified according to LA or MBC; prior or no prior treatment with chemotherapy for LA/MBC; and measurable or non-measurable disease. The consistency of effect across patient subgroups was assessed via hazard ratios and 95% confidence intervals using a log-rank test. RESULTS In total, 462 patients were randomized (n=230 fulvestrant 500 mg; n=232 anastrozole). The Asian subgroup comprised 67 patients (n=34 fulvestrant 500 mg; n=33 anastrozole). PFS outcomes for the Asian and non-Asian subgroups are presented (Table). The most commonly reported adverse event (AE) was arthralgia (18.2% vs 12.1% of patients with fulvestrant 500 mg and anastrozole, respectively). The rate of AEs leading to discontinuation of treatment was 3.0% and 3.0%, respectively. CONCLUSIONS Based on a preliminary assessment of 67 patients, the treatment effect in the Asian patient subgroup from the FALCON trial appears to be broadly consistent with the non-Asian population. PFS in Asian and non-Asian patient subgroupsGeographic regionNumber of patients (%) with event Hazard ratio (95% CI) Fulvestrant 500 mg n=230Anastrozole n=232 Asia19/34 (55.9%)22/33 (66.7%)0.81 (0.44, 1.50)Non-Asia124/196 (63.3%)144/199 (72.4%)0.79 (0.62, 1.01) Citation Format: Shao Z, Ellis MJ, Robertson JFR, Grinsted LM, Fazal M, Noguchi S. Progression-free survival results in postmenopausal Asian women: Subgroup analysis from a phase 3 randomized trial of fulvestrant 500 mg vs anastrozole for hormone receptor-positive advanced breast cancer (FALCON) [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 P2-08-09.

Abstract P6-12-04: Phase 1 study of the antibody-drug conjugate (ADC) SGN-LIV1A in patients with heavily pretreated metastatic breast cancer

Abstract Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which binds to tubulin and induces G2/M arrest and apoptosis. Methods This is an ongoing, phase 1 dose-escalation study evaluating safety, tolerability, pharmacokinetics, and antitumor activity of SGN-LIV1A (q3 wks IV) in women with LIV-1-positive, unresectable, locally advanced or metastatic breast cancer (LA/MBC) (NCT01969643). Patients (pts) with measurable disease and ≥2 prior cytotoxic regimens for LA/MBC were eligible. Pts with ≥Grade 2 neuropathy were excluded. Response was assessed per RECIST v1.1; pts with stable disease (SD) or better could continue treatment until disease progression or intolerable toxicity. At completion of dose escalation in hormone receptor-positive/HER2-negative (HR+/HER2–) and triple-negative (TN) pts, expansion cohorts were opened to further evaluate safety and antitumor activity of monotherapy in TN pts and combination therapy with trastuzumab (Tz) in HER2-positive (HER2+) pts. Pre- and post-treatment tumor biopsies were done to evaluate LIV-1 expression and other correlative endpoints. Results To date, 39 pts (18 HR+/HER2–, 21 TN) have received a median of 3 cycles (range, 1–10) of SGN-LIV1A monotherapy at doses of 0.5–2.8 mg/kg. Median age was 57 yrs (range, 33–79). At baseline, pts had a median of 4 prior cytotoxic regimens for LA/MBC (range, 2–8); 36 had visceral disease and 25 had bone involvement. No dose-limiting toxicities (DLT) occurred in 19 DLT-evaluable pts; maximum tolerated dose was not exceeded at 2.8 mg/kg. Treatment-emergent adverse events (AEs) reported in ≥30% of pts were: fatigue (64%), nausea (54%), alopecia (46%), decreased appetite (41%), constipation (39%), neutropenia (33%), and vomiting (31%). Peripheral neuropathy was reported in 9 pts (23%). Most AEs were Grade 1/2, except neutropenia (all ≥Grade 3). Four pts discontinued treatment due to AEs (acute respiratory distress syndrome, nausea, pneumonia, tachycardia). In dose escalation, modest activity was observed in 17 efficacy evaluable (EE) HR+/HER2- pts, with a disease control rate (DCR) of 59% (10 SD), including 1 pt with SD≥24 wks. Among the 17 EE TN pts (dose escalation plus cohort expansion), the overall response rate (ORR) was 41% (7 PR), DCR was 82% (7 PR, 7 SD) and clinical benefit rate (CBR=OR+SD≥24 wks) was 53% (9 pts). For TN pts, median PFS was 17.1 wks (95% CI: 6.0, 18.4); 6 pts remain on treatment. Of 281 MBC tumor samples evaluated for LIV-1, 93% were positive; 81% had moderate-to-high expression (H-score ≥100). Conclusions LIV-1 is expressed in almost all MBC tumors. SGN-LIV1A monotherapy has been generally well tolerated and shown encouraging antitumor activity in heavily pretreated TN MBC, with a PR rate of 41% and a CBR at ≥24 wks of 53%. Response duration data continue to evolve. Enrollment continues in the TN monotherapy expansion cohort and the HER2+ combination cohort with Tz. Citation Format: Forero-Torres A, Modi S, Specht J, Miller K, Weise A, Burris III H, Liu M, Krop I, Pusztai L, Kostic A, Li M, Mita M. Phase 1 study of the antibody-drug conjugate (ADC) SGN-LIV1A in patients with heavily pretreated metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-04.

Abstract P2-08-02: Progression-free survival results in patient subgroups from a Phase 3 randomized trial of fulvestrant 500 mg vs anastrozole for hormone receptor-positive advanced breast cancer (FALCON)

Abstract BACKGROUND Improved efficacy was suggested for fulvestrant 500 mg, a selective estrogen receptor degrader (SERD), vs anastrozole as first-line treatment for hormone receptor-positive locally advanced or metastatic breast cancer (LA/MBC) in the open-label Phase 2 FIRST trial. The Phase 3, randomized, double-blind, multicenter FALCON trial (NCT01602380) compared fulvestrant 500 mg with anastrozole 1 mg in patients with hormone receptor-positive LA/MBC who had not received prior hormonal therapy. The primary endpoint of the study was met, such that there was a statistically significant improvement in progression-free survival (PFS) for fulvestrant 500 mg vs anastrozole. We present an analysis of PFS for pre-specified patient subgroups in the FALCON trial. METHODS Eligible patients had ER and/or progesterone receptor (PgR)-positive breast cancer, WHO performance status 0–2 and ≥1 measurable/non-measurable lesion(s). Patients were randomized (1:1) to receive fulvestrant 500 mg (IM on Days 0, 14, 28, and each 28 days thereafter) or anastrozole 1 mg daily. The primary endpoint was PFS, assessed via RECIST 1.1, surgery/radiotherapy for disease worsening, or death (any cause). PFS was evaluated in patient subgroups defined by pre-specified baseline covariates. The consistency of effect across patient subgroups was assessed via hazard ratios and 95% confidence intervals using a log-rank test. RESULTS Overall, 462 patients were randomized to treatment: 230 received fulvestrant 500 mg and 232 received anastrozole. PFS outcomes in each patient subgroup are presented in the Table. CONCLUSIONS This analysis of patient subgroups from the FALCON trial suggests that treatment effects were largely consistent across the subgroups analyzed with some possible exceptions (e.g. patients with visceral vs non-visceral disease). Further work is ongoing to understand the possible treatment effect in these subgroups. PFS in pre-specified patient subgroupsSubgroup Number of patients (%) with event Hazard ratio (95% CI) Fulvestrant 500 mg n=230 Anastrozole n=232 Breast cancer type Locally advanced11/28 (39.3%)14/32 (43.8%)0.79 (0.36, 1.73)Metastatic132/202 (65.3%)152/200 (76.0%)0.78 (0.62, 0.99)Prior chemotherapy for LA/MBC Yes31/36 (86.1%)33/43 (76.7%)1.08 (0.66, 1.77)No112/194 (57.7%)133/189 (70.4%)0.75 (0.59, 0.97)Geographic regiona US/Canada16/25 (64.0%)19/24 (79.2%)0.66 (0.34, 1.30)Non-US/Canada127/205 (62.0%)147/208 (70.7%)0.81 (0.64, 1.03)Measurable disease Yes124/193 (64.2%)143/196 (73.0%)0.76 (0.60, 0.97)No19/37 (51.4%)23/36 (63.9%)0.99 (0.53, 1.82)ER-positive and PgR-positive Yes103/175 (58.9%)127/179 (70.9%)0.73 (0.56, 0.94)No40/55 (72.7%)39/53 (73.6%)1.04 (0.67, 1.62)Bisphosphonate use at baseline Yes44/61 (72.1%)53/62 (85.5%)0.69 (0.46, 1.03)No99/169 (58.6%)113/170 (66.5%)0.82 (0.63, 1.07)Visceral disease Yes92/135 (68.1%)87/119 (73.1%)0.99 (0.74, 1.33)No51/95 (53.7%)79/113 (69.9%)0.59 (0.42, 0.84)ªData for Asia/non-Asia subgroups are presented in a separate abstract Citation Format: Robertson JFR, Noguchi S, Shao Z, Grinsted LM, Fazal M, Ellis MJ. Progression-free survival results in patient subgroups from a Phase 3 randomized trial of fulvestrant 500 mg vs anastrozole for hormone receptor-positive advanced breast cancer (FALCON) [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 P2-08-02.

Phase I dose escalation study of oral lapatinib in combination with docetaxel in patients with HER2-positive locally advanced or metastatic breast cancer (LAMBC): Initial safety and tolerability results.

e11529 Background: Previous studies evidenced that the combination docetaxel (D) (75 mg/m²) + lapatinib (L) (1,250 mg/d) is well tolerated in heavily pretreated HER2-positive metastatic breast cancer patients (pts) in association with systematic G-CSF. This phase I study was conducted to assess safety, optimal tolerated regimen (OTR) and clinical activity of D + L in naïve treatment pts with HER-2 positive LAMBC without primary use of growth factor. Methods: Women with HER2+ LAMBC, naïve of treatment for advanced or metastatic disease, ECOG PS 0-2, were eligible for this study. Pts received once daily oral dosing of L with intravenous D on day 1 of every 3 week cycle. Initial dose was D (75 mg/m²) + L (1,250 mg/d) escalating up to D 100 mg/m² and L 1,500 mg/d until the Maximal Tolerated Dose (MTD) was reached. An expansion cohort of 6 pts was treated at the OTR level. Primary use of G-CSF was not permitted. Results: From Aug 2008 to Nov 2011, 17 pts were enrolled: median age 54.4 years [34.6-77], 59% were PS 0. All patients have metastatic disease with lung (29,4%), bone (41,2%), liver (76.5%) and lymph nodes (35.3%) metastasis. 7 pts received previously chemotherapy in adjuvant setting, 5 pts hormonotherapy and 7 pts radiotherapy. All but two pts were evaluable for dose limiting toxicities (DLT). 1 DLT/6 pts (FN) was observed at dose level (DL) 1 (D 75 mg/m² + L 1,250 mg/d) and 2 DLT/3 pts (gr 3 diarrhoea; gr4 neutropenia >7 d) at DL2 (D 75 mg/m² + L 1,500 mg/d). Only one DLT (FN) was observed in expansion cohort at OTR (D 75 mg/m² + L 1,250 mg/d; 6 pts). Over all C1, other significant toxicities (% pts) included gr4 neutropenia 53%, gr3 transaminase increase 6%, gr2 skin rash 36%, gr2 nausea/vomiting 18%, gr2 diarrhoea 12%, gr2 stomatitis 12%, gr2 hand-foot syndrome 6%; no decrease of cardiac function occurred. Conclusions: OTR for D and L was 75 mg/m² once every 3 weeks and 1,250 mg once daily respectively. This study demonstrates that this combination could be administered without systematic use of G-CSF in non pretreated pts with LAMBC. Additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation. Clinical trial information: NCT01044485.

Pharmacokinetic (PK) Interactions between Lapatinib (L) and Vinorelbine (VNR) in a Phase I Study in Locally Advanced or Metastatic Breast Cancer (LAMBC) Patients(Pts) Overexpressing HER2. GEP-01 – A Study of the FNCLCC-Group of Early Phase Trials.

Abstract Background: Lapatinib is effective in overexpressing HER2 LAMBC pts. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Both drugs use the same main metabolic pathway: Cytochrome P450 3A4. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies, and looking for the PK interactions between the 2 drugs.Methods: Women with HER2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7 day (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w iv regimen. L was given po continuously. G-CSF as primary prophylaxis of febrile neutropenia (FN) was not permitted. Dose levels (DL) (L mg/VNR mg/m²) ranged from 750/20 to 1250/30 with 3 patients per DL. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. PK time points analysis was performed on plasma for L and whole blood for VNR. For both drugs the analytical method was Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry (MS-MS) as detection. VNR PK parameters were estimated by nonlinear mixed effect modeling (NONMEM) and L PK parameters were estimated by non compartmental software (MicroPharm).Results: Seventeen pts and 68 PK time points were available for VNR analysis. VNR was ascribed to a tri-compartment model. When considering all VNR data together, VNR clearance (CL) was 37.8±16.7 L/h, while it showed a gradual decrease according to specific dose of L: 47.5±20.4 L/h for L 750 mg (3 patients) vs 35.6±4.3 L/h for pooled data for L 1000 and 1250 (14 patients). This trend was not significant likely due to low number of patients treated at lower dose of L, while no significant difference was observed between L 1000 and L 1250. The mean elimination half life time (t1/2) of VNR was 0.12 h. Six patients and 42 PK time points were analyzed for L. L CL were respectively 83.8 ± 41.3 and 57.1 ± 5.5 L/h for patients who received 750 mg (3 patients) and 1000 mg (3 patients) of L with 20 mg of VNR. The mean elimination half life time (t1/2) of L was 2.89 h.Conclusions: A potential PK interference occurred between VNR and L. When the dose of L increased, both VNR and L CL decreased, likely due to CYP450-3A4 interactions. This trend should be confirmed by the PK analysis of L and VNR in more patients, including an intermediate DL (1250/22.5) still ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5091.

GEP01: A phase I study of lapatinib (L) and vinorelbine (VNR) in HER2 overexpressing (HER2+) locally advanced or metastatic breast cancer (LAMBC) patients (pts): A FNCLCC Group of early phase trials study

1051 Background: Lapatinib is an effective anti-HER-2 therapy in LAMBC pts, currently investigated in the adjuvant setting. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Its main toxicity consists of neutropenia and may challenge the standard weekly, day D1 and D8 regimen. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies and the potential pharmacokinetic (PK) interactions. Methods: Women with a HER-2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7D (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w IV regimen. L was given orally continuously. Primary prophylaxis of febrile neutropenia (FN) with G-CSF was not permitted. Dose levels (DL, L [mg]/VNR [mg/m2]) ranged from 750/20 to 1250/30 with 3 pts/DL (6 in case of dose-limiting toxicity [DLT]). DLT was defined on tolerance at cycle 1 and included grade (gr) 4 neutropenia (PN) ≥ 7D, FN, thrombocytopenia (gr4 or symptomatic gr3), omission of D8 for haematological toxicity, and any drug-related gr3–4 non-haematological toxicity. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. Results: From August 2007 to December 2008, 15 evaluable pts were enrolled (median age 58 [46–75], 43% PS 0, 8 pts previously exposed to only 1 line of trastuzumab) and 65 cycles were administered. Toxicity is available for 13 pts. Of 3 pts treated at DL4 (1000/25), 2 developed a DLT: 1 FN and 1 gr4 PN > 7D. Other significant toxicities (% pts) included gr2 anaemia 8%, gr4 PN 46%, gr1 diarrhoea 62%, gr2 nausea/vomiting 8%, gr1 skin rash 23%, gr2 transaminases 23%; no decrease of cardiac function occurred. From DL1 to DL3 (750/20, 1000/22.5), total body clearance of VNR decreased by 50% (32 ± 19 L/h vs 17 ± 7 L/h). Conclusions: Maximal tolerated dose has been reached at 1000/22.5 for the combination of L with VNR given on a D1 and D8 q3w schedule. Given a potential PK interference which would yield to higher exposure to VNR, an intermediate DL is going to be explored (1250/22.5) to allow an accurate definition of the recommanded dose of the combination for future phase II comparison studies. [Table: see text]

Results of a phase II study of liposomal doxorubicin (Myocet ®) in combination with weekly paclitaxel and trastuzumab (Herceptin ®) In patients with HER2-positive locally advanced or metastatic breast cancer (LA/MBC)

Results of a phase II study of liposomal doxorubicin (Myocet ®) in combination with weekly paclitaxel and trastuzumab (Herceptin ®) In patients with HER2-positive locally advanced or metastatic breast cancer (LA/MBC)