Date: 2016-05-17
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer, in Miami , Florida
Company: Merrimack Pharmaceuticals (USA - MA)
Product: MM-121
Action
mechanism: monoclonal antibody. MM-121 is a fully human monoclonal antibody that targets ErbB3, a cell surface receptor implicated in tumor growth and survival. By inhibiting ErbB3 signaling, MM-121 is designed to restore sensitivity, delay resistance and enhance the anti-tumor effect of a combination therapy partner. Sanofi and Merrimack entered into an exclusive, global license and collaboration agreement for MM-121 in 2009. Merrimack Pharmaceuticals reached an agreement with Sanofi to regain worldwide rights to MM-121 in June 2014.
Disease: ER/PR+, HER2 negative breast cancer
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The Phase 2 Study of MM-121 in Combination with Exemestane in Metastatic ER/PR+, HER2 Negative Breast Cancer is a randomized, double-blinded, placebo-controlled study evaluated whether the combination of MM-121 and exemestane.The Phase 2 Study of MM-121 in Combination with Paclitaxel in Neoadjuvant ER/PR+, HER2 Negative Breast Cancer is a randomized, open-label Phase 2 study. The trial was designed to compare the pathologic complete response (pCR) rate in ER/PR+ breast cancer patients (n=99) treated in the neoadjuvant setting with MM-121 in combination with paclitaxel followed by doxorubicin and cyclophosphamide, with the pCR rate in patients receiving paclitaxel alone followed by doxorubicin and cyclophosphamide. pCR measures the absence of invasive cancer in breast and lymph node tissue following neoadjuvant therapy and is widely viewed as a strong indicator for prolonged disease-free survival.
Latest
news: * On May 17, 2016, Merrimack Pharmaceuticals presented an expanded analysis of its Phase 2 study of seribantumab (MM-121) in combination with exemestane in HER2-negative, hormone receptor positive metastatic breast cancer. Top line results from this study were announced in 2014. The final analysis, as well as a poster on Merrimack's investigational companion diagnostic for seribantumab, were presented at the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer, in Miami , Florida. * On September 30, 2014, Merrimack Pharmaceuticals announced additional clinical and biomarker data from a Phase 2 study in ER/PR-positive, HER2-negative metastatic breast cancer showing that patients with high heregulin mRNA levels achieved a statistically significant benefit from combining the novel agent MM-121 with exemestane. Updated data from this biomarker subgroup, representing 45% of patients with metastatic breast cancer, showed a hazard ratio of 0.26 with a p-value of 0.003. The data were presented at the European Society of Medical Oncology (ESMO) 2014 Congress as part of a meta-analysis of the biomarker data from three Phase 2 studies of MM-121 in combination with standard-of-care agents across breast, lung and ovarian cancers. Previous results from the MM-121 Phase 2 program presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting identified high heregulin mRNA as prognostic of poor response to standard-of-care therapy across multiple cancers. These results also showed that patients with heregulin-high tumors experienced a reduction in their risk of progression when they received a combination of MM-121 with their standard-of-care therapy as compared to patients who received the standard therapy alone. The previous analysis included 55 patients with breast cancer, 17 of whom were biomarker positive. The poster presented at ESMO 2014 provides biomarker data on 76 ER/PR positive, HER2-negative patients with metastatic breast cancer, 34 of whom were biomarker positive (heregulin-high). The poster also provides the first cross-indication analysis of biomarker data from platinum-resistant ovarian cancer, ER/PR+ HER2- breast cancer and EGFR wild-type non-small cell lung cancer. Biomarker data across the three studies are as follows: Heregulin is a potential biomarker for insensitivity to standard-of-care therapy and a predictor of clinical benefit in late-stage ovarian, lung, and breast cancers. An additional 17 biomarker positive patients with metastatic breast cancer were included in this study analysis. Patients in this population with high heregulin levels have a greater risk of disease progression on standard-of-care therapy compared than those who have low heregulin levels. With the addition of MM-121 to standard-of-care therapy, however, patients with high heregulin levels have a significantly reduced risk of progression (PFS HR 0.26, 95% CI [0.11-0.63]). There was a consistent but modest and tolerable increase in adverse events when MM-121 was combined with the three different standard-of-care regimens. * On November 26, 2013, Merrimack Pharmaceuticals has announced the results of two Phase 2 studies evaluating MM-121 in the treatment of women with ER/PR+, HER2 negative breast cancer. One study was conducted in metastatic breast cancer (mBC) in combination with exemestane. The second was conducted in the neoadjuvant setting in combination with paclitaxel followed by doxorubicin and cyclophosphamide.
The study was randomized, double-blinded and placebo-controlled to evaluate whether the combination of seribantumab and exemestane was more effective in prolonging progression free survival (PFS) than exemestane in ER/PR+ metastatic breast cancer (n=118) who had previously failed anti-estrogen therapy. Of the patients with tissue available for heregulin testing, 45% (n=34/76) were heregulin-positive. Patients in the heregulin-positive group who received seribantumab had a 74% decrease in risk of progression, (HR 0.26; 95% CI [0.11 — 0.63], p=0.003) compared with patients who did not receive seribantumab. The study did not meet its primary endpoint of PFS though the overall study population trended in favor of the MM-121 arm (HR 0.772; 95% CI [0.496 — 1.201]). Notably, across all treated patients, overall survival data trended in favor of the seribantumab arm with a 59% decrease in risk of death (HR 0.436; 95% CI [0.197 — 0.966]) versus patients on the standard-of-care arm. .
Identification of heregulin expression as a driver of a difficult-to-treat cancer phenotype and development of a prospective companion diagnostic for the heregulin-ErbB3 targeting drug seribantumab.
A poster highlighting the potential importance of a diagnostic in treating heregulin-positive patients across three different solid tumors (breast, lung and ovarian cancers) was also presented. In three Phase 2 studies, Merrimack's novel heregulin assay was able to identify patients with heregulin-positive tumors where the addition of seribantumab to standard-of-care therapies may provide benefit. Heregulin was detected at significant levels across multiple solid tumor types, with a prevalence of between 30-60% of patients, potentially defining a critical patient phenotype that has a high-unmet need. Tumor biopsies were measured by RNA-ISH. A fully validated RNA-ISH assay is currently being used to identify heregulin-positive patients in a Phase 2 randomized trial of seribantumab in patients with NSCLC. Merrimack recently announced a strategic partnership with Leica Biosystems to develop Merrimack's novel heregulin assay for seribantumab into a kit for commercial use. Study Biomarker Positive* No. of Patients Hazard Ratio Prevalence P-Value Breast 34 0.26 (95% CI [0.11-0.63]) 45% 0.003 Ovarian 57 0.37 (95% CI [0.18-0.76]) 38% 0.007 Lung 37 0.35 (95% CI [0.16-0.76]) 54% 0.008 Results from the Phase 2 Study of MM-121 in Combination with Exemestane in Metastatic ER/PR+, HER2 Negative Breast Cancer: This randomized, double-blinded, placebo-controlled study evaluated whether the combination of MM-121 and exemestane was more effective in prolonging progression free survival (PFS) than exemestane in ER/PR+ mBC patients (n=118) who have previously failed anti-estrogen therapy.The estimated hazard ratio (HR) for PFS in the overall study population trended in favor of the MM-121 arm (HR 0.75; 95% CI [0.48 — 1.15]), although the primary endpoint of the study (HR < 0.5) was not met. Overall survival data also trended in favor of the MM-121 arm (HR 0.41; 95% CI [0.19 — 0.90]), but is at this point immature (~25% of patients).Analysis of a pre-specified set of biomarkers mechanistically linked to ErbB3 signaling revealed a subpopulation of patients (31% of the 55 biomarker-evaluable patients) in which the observed HR for PFS was 0.32 (95% CI [0.10-1.0]). The HR for PFS in the biomarker negative population was 0.89 [95% CI 0.44-1.79]. The undisclosed biomarkers identified in this study matched the two biomarkers previously reported for a study combining MM-121 with paclitaxel in women with platinum resistant ovarian cancer.Overall, similar frequencies were reported for adverse events of any grade between the treatment and control arms, with no unexpected toxicities experienced and no increase in serious adverse events (Grade 3 or worse events 25.0% on treatment arm vs. 25.4% on control arm). Increased frequencies for individual adverse events of all grades on the treatment arm were reported for diarrhea (50.0% vs. 23.7%), mucosal inflammation, (16.1% vs. 3.4%) and decreased appetite (16.1% vs. 8.5%). Most adverse events were mild-to-moderate in severity. There were no pulmonary embolisms or other venous thromboembolic events reported in either arm.Results from the Phase 2 Study of MM-121 in Combination with Paclitaxel in Neoadjuvant ER/PR+, HER2 Negative Breast Cancer: This randomized, open-label Phase 2 study was designed to compare the pathologic complete response (pCR) rate in ER/PR+ breast cancer patients (n=99) treated in the neoadjuvant setting with MM-121 in combination with paclitaxel followed by doxorubicin and cyclophosphamide, with the pCR rate in patients receiving paclitaxel alone followed by doxorubicin and cyclophosphamide. Patients who received the combination of MM-121 and paclitaxel achieved a pCR rate of 10.8% (95% CI [5.3; 20.6]) compared to 3.3% (95% CI [0.6; 16.7]) for the control arm. There was no formal quantitative endpoint specified for this study. Extensive translational analysis is ongoing based on serial biopsies and will be reported in the future.Overall, similar frequencies were reported for adverse events of any grade between the treatment and control arms, with no unexpected toxicities experienced and no increase in serious adverse events(Grade 3 or worse adverse events were 55.2% on treatment arm vs. 53.1% on control arm). Increased frequencies for individual adverse events on the treatment arm were reported for diarrhea (82.1% vs. 34.4%), rash (41.8% vs. 15.6%), stomatitis (22.4% vs. 6.3%), and hypokalemia (29.9% vs. 6.3%). Most adverse events were mild-to-moderate in severity. In general, venous thromboembolic events were observed more frequently on the control arm (9.4%, including events of deep vein thrombosis and jugular thrombosis) than on the treatment arm (1.5%, one event of pulmonary embolism).
