PURPOSEDr Reddy's Laboratories Trastuzumab (DRL_TZ) is a biosimilar to Herceptin under development. The present study was conducted to evaluate efficacy, safety, pharmacokinetics (PKs), and immunogenicity of DRL_TZ in comparison with the reference medicinal product (RMP) along with concomitant weekly paclitaxel in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC).METHODSThis was a randomized, double-blind study in female patients with HER2-positive MBC, randomly assigned in a 1:1 ratio to receive either DRL_TZ or the RMP, that is, an innovator product sourced from the European region, along with additional chemotherapy, as first-line treatment for up to 24 weeks. The primary end point was the best overall response rate (ORR) as per RECIST 1.1 criteria. Progression-free survival rate at 6 months (PFS6), safety, immunogenicity, and PK parameters were assessed as secondary end points.RESULTSA total of 164 patients were randomly assigned to receive either DRL_TZ or the RMP. Best ORR in the per-protocol population was comparable, 91.9% (93.3% CI, 83.2 to 96.3) versus 82.1% (93.3% CI, 72.0 to 89.1) in DRL_TZ and RMP arms, respectively; the difference between the arms was 9.8% with a 93.3% CI of –1.3 to 20.8. The PFS6 rate, safety, PK profile, and antidrug antibody incidence were comparable. An additional 44 patients were recruited in the postrandomization phase, in an open-label manner, and started on DRL_TZ to generate more data on efficacy, safety, and immunogenicity. The additional data with DRL_TZ, when pooled, were similar to the RMP data.CONCLUSIONDRL_TZ was found to have similar efficacy and comparable safety, PK, and immunogenicity profiles as the RMP.

587 Background: Ligand-driven ErbB3 signaling has been implicated as a mechanism of resistance to conventional therapies across multiple malignancies, including endocrine resistant metastatic breast cancer (mBC). Here we present results of a trial evaluating MM-121 (M) or placebo (P) in combination with exemestane in postmenopausal women with ER/PR+ HER2-negative mBC. Methods: This study enrolled women with locally advanced or mBC who had failed adjuvant therapy or progressed in the metastatic setting. The primary endpoint was progression free survival (PFS) and the study was powered to detect a HR of < 0.5. Secondary and exploratory analyses included overall survival (OS), safety, and analyses of a pre-specified set of mechanistically-linked biomarkers ((BM), heregulin, betacellulin, EGFR, ErbB2, and ErbB3) in archived tissues. Results: 115 randomized and treated patients (56 (M), 59 (P)) were included in safety and efficacy analyses. Baseline demographics and disease characteristics were balanced. At the time of the analysis, 92 (80%) patients (78.6% (M), 81.4% (P)) had discontinued treatment, mainly due to progressive disease (66.1% (M), 76.3% (P)). PFS was analyzed after 84 events (38 (M), 46 (P)). The median PFS was 15.9 weeks (M) vs. 10.7 weeks (P), with a stratified hazard ratio (HR) of 0.772 (95% CI [0.496- 1.201]), p=0.249). OS data were immature at the time of the primary analysis (29 events: 11 (M), 18 (P)), with a stratified HR of 0.436 (95% CI [0.197 – 0.966]). In patients positive for two of the pre-specified BMs (31%: 17 of the 55 patients with BM data), the HR for PFS was 0.32 (95% CI [0.10-1.00]). Common adverse events (AEs, >20%) of any grade and causality (M vs. P), were diarrhea (50% vs. 23.7%), nausea (28.6% vs. 23.7%), fatigue (23.2 % vs. 23.7%), and arthralgia (17.9% vs. 20.3%). Conclusions: The addition of MM-121 to exemestane did not significantly prolong PFS in the unselected population, although the HR appears to favor the MM-121 arm. The biomarker findings were consistent with preclinical hypotheses, as well as an independently conducted Phase 2 study in platinum resistant ovarian cancer. Clinical trial information: NCT01151046.

PURPOSE:Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer. PATIENTS AND METHODS:In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) -negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m(2) plus ramucirumab 10 mg/kg or docetaxel 75 mg/m(2) plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS. RESULTS:Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio [HR], 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis. CONCLUSION:Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.

629 Background: CT-P6(C) is an anti-HER2 MoAb, a biosimilar to trastuzumab (T). This trial is a global phase III study to compare C with T, both in combination with paclitaxel (P) as first-line treatment in women with HER2+ MBC. Methods: 475 patients with centrally confirmed HER2+ MBC were randomized to receive either C+P (n=244) or T+P (n=231). Patients had to have a baseline LVEF ≥50% and no history of serious cardiac disease. Study medication was as follows: C or T 8 mg/kg i.v. (day 1), followed by 3-weekly C or T 6 mg/kg. P (175 mg/m23-weekly) was co-administered. The primary endpoint was overall response rate (ORR) as determined by independent review. Pooled analysis with data from phase I/IIb (NCT01084863) and III studies (NCT01084876) was predefined and endorsed by the EMA. Patient safety was monitored throughout the study by an independent data monitoring committee. Treatment was continued until disease progression, death or patient’s withdrawal. Results: In the pooled ITT population, ORR was 57% for C+P and 62% for T+P (difference: 5%; 95% CI: -0.14, 0.04) during the first 8 cycles of treatment. The limits of the 95% CIs for the difference in the proportions of responders were contained within the pre-defined range [-0.15, 0.15] required for equivalence. Median time to progression and median time to response were 11.07 vs. 12.52 months (P =0.10), and 1.38 vs. 1.38 months (P =0.37) for C+P and T+P, respectively. Frequency of treatment-related AEs is shown in the Table. Conclusions: Equivalence of C and T was observed for ORR in patients with HER2+ MBC in combination with P as first-line therapy. Secondary efficacy endpoints also supported the comparability between C and T. C was well tolerated with a safety profile comparable to that of T. Clinical trial information: NCT01084876. [Table: see text]