The most clinically significant event was cardiac dysfunction, which occurred in 4.7% of patients. A large, open-label, randomized Phase III study (H0648g) in 469 patients with HER2-positive metastatic breast cancer was conducted to evaluate the efficacy of Herceptin in combination with chemotherapy as first-line treatment. Patients who were anthracycline-naïve were randomized to receive either anthracycline plus cyclophosphamide (AC) or Herceptin plus AC. Patients who had received prior anthracyclines in the adjuvant setting were randomized to receive either paclitaxel or Herceptin plus paclitaxel. Patients randomized to Herceptin and chemotherapy measurably benefited in comparison to patients treated with chemotherapy alone in terms of time to disease progression, overall response rate, median duration of response, and survival. As determined by an independent Response Evaluation Committee (REC), Herceptin prolonged median time to disease progression from 4.6 months to 7.4 months (p<0.001), improved the overall response rate (complete and partial responses) from 32% to 50% (p<0.001), and increased median duration of response from 6.1 to 9.1 months (p<0.001). Compared to chemotherapy alone, the addition of Herceptin significantly lowered the incidence of death at one year from 33% to 22% (p=0.008) and increased median overall survival 24% from 20.3 months to 25.1 months (p=0.046). The observed survival advantage remained despite crossover of 66% of patients initially randomized to chemotherapy alone who elected to receive Herceptin upon disease progression (Tripathy et al. 2000). Fever/chills were observed with the initial Herceptin infusion in approximately 25% of patients. Class III or IV cardiac dysfunction was observed in 16% of the Herceptin + AC subgroup; increasing age was an associated risk factor for the development of cardiotoxicity in this treatment cohort. Based on these data, Herceptin was approved by the U.S. Food and Drug Administration (FDA) for use in HER2-overexpressing metastatic breast cancer in combination with paclitaxel for first-line treatment and as a single agent for patients failing prior chemotherapy for metastatic disease. However, current usage patterns of Herceptin indicate that the drug is now being used in a broader array of circumstances than in the CONFIDENTIAL Page 8 of 102 Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 pivotal clinical trials. Since initiation of the pivotal clinical trials, docetaxel has become a commonly used taxane in the treatment of metastatic breast cancer (Chevallier et al. 1995) and new data have emerged on the weekly use of paclitaxel (Akerley et al. 1997). Herceptin has been studied in combination with paclitaxel and docetaxel using a variety of doses and schedules with promising results (Seidman et al. 1999; Nicholson et al.