Fulvestrant AD, LD and HD had similar efficacy and tolerability profiles in postmenopausal Japanese women with ER-positive advanced breast cancer.

No abstract

Introduction: A previous large-scale phase III study demonstrated that, compared with docetaxel (T) alone, capecitabine (X) and T in combination (XT) offered significantly superior progression free survival (PFS) and overall survival (OS) in metastatic breast cancer (MBC). However, XT increased Grade 3/4 adverse events (AEs) which led to more frequent dose reductions than with T alone. Optimal dose of XT in Japanese was examined in a phase Ib study. Based on the background, we conducted a phase III randomized study in Japanese HER2 negative MBC patients pre-treated with anthracycline to compare efficacy and safety of XT therapy and T therapy. Methods: Eligible pts were HER2-negative MBC pts with anthracycline-pretreatment, a measurable tumor, and ECOG performance status of 0 or 1. Pts were randomly assigned to the XT group or the T→X group. The XT group received concurrent therapy of X (1650 mg/m2/day from day 1 to 14) and T (60 mg/m2) in 3-week cycle. The T→X group received sequential therapy of T (70 mg/m2) in 3-week cycle followed at disease progression by X (2500 mg/m2/day from day 1 to 14 followed by 1-week rest). Primary endpoint was PFS. Secondary endpoints were OS, overall response rate (ORR), time to treatment failure (TTF), safety, and quality of life. The XT group and the T phase of the T→X group (T group) were compared in our evaluation. Results: Of 163 pts enrolled, 156 were eligible. Baseline characteristics of all pts in each group were well balanced. The median delivered dose was 79.0% and 95.1% of the planned dose respectively for X and T in the XT group, and it was 97.2% in the T group. Median PFS in the XT group was 10.5 months compared to 9.8 months in the T group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40–0.97). The ORR was 70% and 61%; the median TTF was 9.6 months and 7.0 months in the XT group and the T group, respectively. Median OS has not been reached yet. Subgroup analysis showed PFS was longer in pts with liver metastasis (HR, 0.39; 95% CI, 0.19–0.84) and in pts with lung metastasis (HR, 0.43; 95% CI, 0.21–0.90) in the XT group. Incidence of treatment related AEs (TR-AEs) ≥Grade 3 was 74.4% (61 pts) in the XT group and 76.3% (61 pts) in the T group. Frequently reported TR-AEs ≥Grade 3 were; decrease in neutrophil count (XT, 57.3%; T, 60.0%), neutropenia (XT, 8.5%; T, 12.5%) and febrile neutropenia (XT, 6.1%; T, 10.0%). TR-AE ≥Grade 3 in the XT group with incidence at least 5% higher than the T group was hand-foot syndrome (XT, 7.3%; T, 0%). On the other hand, TR-AEs ≥Grade 3 in the T group with incidence at least 5% higher than the XT group were fatigue (XT, 2.4%; T, 8.8%) and peripheral edema (XT, 1.2%; T, 6.3%). Conclusion: The concurrent therapy of XT demonstrated significant improvement of PFS compared with T alone. Superior efficacy of XT therapy was reported as same as the previously reported study on XT versus T although the dose was lower in our study. Considering the efficacy and tolerability, we consider concurrent Japanease dose XT therapy is a preferable treatment for MBC pts with liver or lung metastasis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-01.

Background: Current breast cancer knowledge is based largely on studies conducted in western populations. Their findings may not be generalizable to Asian women because of ethnic, genetic and lifestyle differences. Neratinib (N) is an irreversible tyrosine kinase inhibitor of HER1, 2 and 4. The international, randomized, placebo (P)-controlled phase III ExteNET trial showed that 1 year (yr) of N after trastuzumab (T)-based adjuvant therapy significantly improved 2-yr invasive disease-free survival (iDFS) in patients (pts) with early-stage HER2+ breast cancer (HR 0.67; 95% CI 0.50–0.91; p=0.009) [Chan et al. Lancet Oncol 2016]. The significant iDFS benefit with N was shown to be durable after 5 yrs' follow-up (HR 0.73; 95% CI 0.57-0.92; p=0.008) [Martin et al. ESMO 2017]. We report efficacy and safety findings from pts enrolled from Asian centers (China, Hong Kong, Japan, Korea, Malaysia, Singapore, and Taiwan) on the ExteNET trial to better characterize the effects of N in Asian women. Methods: Pts with early-stage HER2+ breast cancer were randomly assigned to oral N 240 mg/day or P for 1 yr after standard primary therapy and T-based adjuvant therapy. Antidiarrheal prophylaxis was not required by protocol. Data concerning disease recurrences were collected prospectively during yr 1-2 post-randomization, and from medical records during yr 3–5 post-randomization. Primary endpoint: iDFS. HR (95% CI) estimated using Cox proportional-hazards models stratified by nodal status, hormone-receptor status and prior T regimen. Data cut-off: 2-yr analysis, July 2014; 5-yr analysis, March 2017. Clinicaltrials.gov:NCT00878709. Results: Of 2840 randomized pts (N, n=1420; P, n=1420), 341 (12%) were enrolled from Asian centers (N, n=165; P, n=176). Baseline characteristics: median age 53 yr; hormone receptor-positive 48%. Median treatment duration was similar in both groups (N, 351 days; P, 352 days). iDFS events in Asian vs ITT populations are shown in the Table.  Primary 2-yr analysisa5-yr analysis NPNPAsian population, n165176165176iDFS events, n10151222HR (95% CI)b0.71 (0.31-1.57)0.54 (0.26-1.08)P-value (2-sided)0.4040.085ITT population, n1420142014201420iDFS events, n67106116163HR (95% CI)b0.66 (0.49-0.90)0.73 (0.57-0.92)P-value (2-sided)0.0080.008a. Primary study endpoint; b. Neratinib vs placebo The incidence of grade 3/4 diarrhea with N was slightly higher in Asian pts (46.1% vs ITT, 39.8%). All other grade 3/4 adverse events with N were rare among Asian pts (elevated ALT, mucosal inflammation, 2 pts each; other events, 1 pt each). Compliance with N in Asian pts was also improved (71% vs ITT, 61%). Conclusions: In Asian pts enrolled into ExteNET, compliance with N was better and the magnitude of N effect was similar or greater that that observed in the ITT population. Although N-related grade 3/4 diarrhea was more common in Asian pts than in the ITT population, all other grade 3/4 events were rare. Despite small pt numbers, our analyses suggest that the findings from ExteNET are applicable to Asian pts, and support the conclusion that N reduces disease recurrences in Asian pts with early-stage HER2+ breast cancer after T-based adjuvant therapy. Citation Format: Iwata H, Masuda N, Kim S-B, Inoue K, Rai Y, Fujita T, Shen Z-Z, Chiu JW, Ohtani S, Takahashi M, Yamamoto N, Miyaki T, Sun Q, Yen-Shen L, Xu B, Yap YS, Bustam AZ, Lee JR, Zhang B, Bryce R, Chan A. Neratinib in the extended adjuvant treatment of patients from Asia with early-stage HER2+ breast cancer after trastuzumab-based therapy: 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 P1-13-11.

Background: Trastuzumab emtansine (T-DM1) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate in development for the treatment of HER2-positive recurrent, locally advanced or metastatic breast cancer (MBC). T-DM1 comprises trastuzumab, DM1—a microtubule inhibitory cytotoxic agent derived from maytansine—and the stable linker ([N-maleimidomethyl] cyclohexane-1-carboxylate) that conjugates DM1 and trastuzumab. A phase 1 study in Japanese patients determined a maximum tolerated dose for T-DM1 of 3.6 mg/kg every 3 weeks (q3w), which was identical to that reported in Western populations (TDM3569g). Single-agent T-DM1 has demonstrated robust clinical efficacy in Western phase 2 and phase 3 clinical studies (TDM4258g, TDM4374g and EMILIA). Since the efficacy of T-DM1 in Japanese patients has not previously been investigated, this study examined the efficacy and safety of T-DM1 in Japanese patients with pretreated HER2-positive MBC. Methods: JO22997 is a phase 2, multicenter, single arm clinical study assessing the efficacy and safety of single-agent T-DM1 given at 3.6 mg/kg q3w to patients with HER2-positive MBC. Key eligibility criteria were prior treatment with trastuzumab and at least 1 chemotherapy, ECOG performance status (PS) of ≤2, and adequate organ function. Patients were required to have target lesions according to the guidelines of the Response Evaluation Criteria In Solid Tumors, v1.1. The primary objective of the study was to assess the objective response rate (ORR) by independent review committee (IRC); secondary objectives were progression-free survival (PFS), safety, and to obtain pharmacokinetic data in Japanese patients. Results: 73 patients received T-DM1. Median age was 58 years (range, 36–82 years); 61 (83.6%), 10 (13.7%), and 2 (2.7%) patients had ECOG PS of 0, 1, and 2, respectively; 39 (53.4%) patients had tumors that were estrogen receptor– and/or progesterone receptor–positive. The median number of prior chemotherapy regimens for MBC was 3 (range, 1–8) including lapatinib in 43 (58.9%) patients. Median duration of treatment with T-DM1 was 23.1 weeks (range, 0.1–63.3 weeks). The ORR by IRC was 38.4% (90% confidence interval [CI], 28.8%–48.6%; partial response only), and clinical benefit rate (partial response + stable disease ≥24 weeks) was 45.2% (95% CI, 33.5%–57.3%). Median PFS by IRC was 5.6 months (95% CI, 4.6–8.2 months). The most frequently observed grade ≥3 adverse events were thrombocytopenia (21.9%), increased aspartate aminotransferase (13.7%), increased alanine aminotransferase (8.2%) and vomiting (5.5%). One patient (1.4%) discontinued treatment due to thrombocytopenia. No patient received platelet transfusion. Grade 3/4 hemorrhage was observed in one patient (1.4%). PK parameters for T-DM1 and its metabolites were consistent with previous phase I results. Conclusion: Single-agent T-DM1 has promising activity in Japanese patients with previously treated HER2-positive MBC and was well tolerated. Although the incidence of grade 3/4 thrombocytopenia tends to be higher than in Western studies, this was not associated with clinically important manifestations. (JapicCTI-101277) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-16.