On July 21, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported updated results from the Phase III clinical trial of Puma’s investigational drug PB272 (neratinib) for the extended adjuvant treatment of HER2-positive early stage breast cancer (ExteNET trial) (Press release, Puma Biotechnology, JUL 21, 2016, View Source [SID:1234513986]). The ExteNET trial is a double-blind, placebo-controlled, Phase III trial of neratinib versus placebo after adjuvant treatment with trastuzumab (Herceptin) in women with early stage HER2-positive breast cancer.

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The ExteNET trial randomized 2,840 patients in 41 countries with early-stage HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab. After completion of adjuvant treatment with trastuzumab, patients were randomized to receive extended adjuvant treatment with either neratinib or placebo for a period of one year. Patients were then followed for recurrent disease, ductal carcinoma in situ, or death for a period of two years after randomization in the trial. The primary endpoint of the trial was invasive disease free survival (DFS). The results of the trial demonstrated that treatment with neratinib resulted in a 33% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.67, p = 0.009). The 2-year invasive DFS rate for the neratinib arm was 93.9% and the 2-year invasive DFS rate for the placebo arm was 91.6%. These results were previously reported at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting and updated results, including interim 3-year invasive DFS data, were presented at the 2015 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS).

As part of the data analysis for the New Drug Application (NDA) filing in the United States and the Marketing Authorisation Application (MAA) submission in Europe, an updated analysis that included an interim 5-year invasive DFS analysis was performed. This data analysis was performed in order to examine the durability of treatment effect beyond the 2-year data included in the primary analysis. This interim analysis was not a pre-planned analysis in the statistical analysis plan for the trial. For the primary endpoint of the trial, invasive DFS, the 5-year interim results of the trial demonstrated that treatment with neratinib resulted in a 26% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.74, p = 0.017). The 5-year interim invasive DFS rate for the neratinib arm was 90.4% and the 5-year interim invasive DFS rate for the placebo arm was 87.9%. Additional updated results for the 3-year invasive DFS rate and 4-year invasive DFS rate are shown in the table below:


DFS for Intent to Treat (ITT) Population
3-Year DFS 4-Year DFS 5-Year Interim DFS
Neratinib 92.5% 91.4% 90.4%
Placebo 90.3% 89.2% 87.9%
Absolute invasive DFS
Difference 2.2% 2.2% 2.5%

As an inclusion criteria for the ExteNET trial, patients needed to have tumors that were HER2 positive using local assessment. In addition, as a pre-defined subgroup in the trial, patients had centralized HER2 testing performed on their tumor as well. To date, centralized HER2 testing has been performed on 2,140 (75%) of the patients in the ExteNET trial, and further central testing on available samples is currently ongoing. For the 1,777 patients whose tumors were HER2 positive by central confirmation, the interim results of the trial demonstrated that treatment with neratinib resulted in a 30% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.70, p = 0.026). The 5-year interim invasive DFS rate for the centrally confirmed patients in the neratinib arm was 90.8% and the 5-year interim invasive DFS rate for the centrally confirmed patients in the placebo arm was 88.1%.

For the pre-defined subgroup of 1,631 patients with hormone receptor positive disease, the interim results of the trial demonstrated that treatment with neratinib resulted in a 41% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.59, p = 0.002). The 5-year interim invasive DFS rate for the neratinib arm was 91.7% and the 5-year interim invasive DFS rate for the placebo arm was 86.9%. Additional updated results for the 3-year invasive DFS rate and 4-year invasive DFS rate are shown in the table below:


DFS for Hormone Receptor Positive (HR-positive) Population
3-Year DFS 4-Year DFS 5-Year Interim DFS
Neratinib 93.8% 92.9% 91.7%
Placebo 89.9% 88.6% 86.9%
Absolute invasive DFS
Difference 3.9% 4.3% 4.8%

"We are very pleased with the interim 5-year invasive DFS results from the ExteNET trial with neratinib," said Alan H. Auerbach, Chief Executive Officer and President of Puma. "We believe these results support the long term clinical benefit of neratinib in the extended adjuvant treatment of patients with early stage HER2-positive breast cancer who have completed prior trastuzumab-based adjuvant therapy. We look forward to obtaining the full 5-year DFS data, which we anticipate will be available in 2017."

On July 21, 2016 Mylan N.V. (NASDAQ, TASE: MYL) and Biocon Ltd. (BSE code: 532523, NSE: BIOCON) reported that the European Medicines Agency (EMA) has accepted for review, Mylan’s Marketing Authorization Application (MAA) for our proposed biosimilar Pegfilgrastim, which is used to reduce the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) (Press release, Mylan, JUL 21, 2016, View Source [SID:1234513985]).

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Mylan and Biocon, who have co-developed the proposed biosimilar, received EMA’s acceptance of the submission for review. In addition to analytical, functional and pre-clinical data, the application includes clinical data from pivotal Pharmacokinetic / Pharmacodynamic (PK / PD) and confirmatory efficacy, safety and immunogenicity studies completed earlier in 2016. The results from the studies are expected to be presented at the prestigious European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress to be held in Copenhagen in Oct. 2016.

Arun Chandavarkar, CEO and Joint Managing Director, Biocon, said: "The regulatory submission of biosimilar Pegfilgrastim with the EMA by our partner Mylan marks another significant milestone in our journey to develop affordable biologics for cancer patients. Once approved, this product will enable enhanced access to a cost-effective alternative for patients undergoing chemotherapy in the EU. We are committed to bring a diversified portfolio of high-quality, life-enhancing biosimilars to patients globally."
Mylan President Rajiv Malik commented: "We continue to make great progress across our biosimilars portfolio, which represents one of the industry’s largest and most diversified portfolios in development. This milestone in our Pegfilgrastim program represents yet another important step in bringing more affordable versions of these critical products to market, with Europe representing an exciting opportunity for Mylan in this area."

Pegfilgrastim is prescribed for cancer patients to help them with some of the side-effects of their treatment. It reduces the duration of neutropenia (low levels of neutrophils, a type of white blood cell that fights infections) and the incidence of febrile neutropenia (neutropenia with fever) that are a result of their chemotherapy treatment.
Biocon and Mylan are exclusive partners on a broad portfolio of biosimilars and generic insulin analogs. The proposed biosimilar Pegfilgrastim is one of the six biologic products co-developed by Mylan and Biocon for the global marketplace. Mylan has exclusive commercialization rights for the proposed biosimilar Pegfilgrastim in the U.S., Canada, Japan, Australia, New Zealand and in the European Union and European Free Trade Association countries. Biocon has co-exclusive commercialization rights with Mylan for the product in the rest of the world.

On July 21, 2016 Mateon Therapeutics, Inc. (Nasdaq:MATN), a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, reported that the first patient has been enrolled into the Phase 2 portion of the PAZOFOS Study (Press release, Mateon Therapeutics, JUL 21, 2016, View Source [SID:1234513984]). The PAZOFOS Study is a Phase 1b/2 clinical trial in patients with recurrent ovarian cancer that will assess the efficacy and safety of the combination of Mateon’s investigational drug CA4P plus Novartis’ approved tyrosine kinase inhibitor pazopanib (Votrient) compared to pazopanib alone. The primary outcome measure of the Phase 2 portion of the study is progression free survival measured by RECIST; secondary endpoints include safety, overall survival, objective response rate and relevant biomarkers. The study is designed to enroll 128 patients at ten sites in the United Kingdom.

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"The advancement of the PAZOFOS Study into the Phase 2 portion is an important milestone for the continued development of CA4P," stated William D. Schwieterman, M.D., President and Chief Executive Officer of Mateon. "There are a number of parallels between the PAZOFOS Study and the completed GOG-0186I Study, each in recurrent ovarian cancer and evaluating CA4P in combination with an established anti-angiogenic agent. We believe combination vascular targeted therapy with a VDA and an anti-angiogenic has the potential to be a powerful approach to fight cancer, and we look forward to receiving data on this trial as it becomes available."

PAZOFOS is sponsored by The Christie NHS Foundation Trust and coordinated by the Manchester Academic Health Science Centre, Trials Coordination Unit (MAHSC-CTU) with additional support from The University of Manchester, the Royal Marsden NHS Foundation Trust and Mount Vernon Cancer Centre (portion of the East and North Hertfordshire NHS Trust). CA4P and pazopanib are being provided by Mateon and Novartis, respectively.

On July 21, 2016 Amgen (NASDAQ:AMGN) and Allergan plc (NYSE:AGN) reported results from a Phase 3 study evaluating efficacy and safety of ABP 980 compared with trastuzumab in patients with human epidermal growth factor receptor 2-positive (HER2-positive) early breast cancer (Press release, Amgen, JUL 21, 2016, View Source [SID:1234513982]). The results ruled out inferiority compared to trastuzumab but could not rule out superiority based on its primary efficacy endpoint of the difference of the percentage of patients with a pathologic complete response (pCR). The primary endpoint had a prespecified equivalence margin of +/- 13 percent and the observed upper end of the confidence interval was 13.4 percent.

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Overall, adverse events were comparable between ABP 980 and trastuzumab. In the neoadjuvant phase of the study, which included chemotherapy, there were more serious adverse events reported in the ABP 980 group, the majority of which were reported by the investigators as unlikely related to investigational product. In the adjuvant phase of the study, which did not include chemotherapy, serious adverse events were comparable between treatment groups. The overall results also showed comparable immunogenicity.

"We believe this study confirms no clinically meaningful differences between ABP 980 and trastuzumab, and we look forward to continued discussions with regulatory authorities," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Biosimilars are approved based on the analytical, nonclinical and clinical data, and we believe that the totality of the evidence we’ve generated supports ABP 980 as highly similar to the reference product."

"These results provide significant clinical evidence that ABP 980 could be an important biosimilar treatment option for patients with HER2-positive early breast cancer," said David Nicholson, chief research and development officer, Allergan. "Allergan is committed to the continued development of ABP 980 and other biosimilars that provide safe, high-quality and effective therapies in key disease areas."

ABP 980 is being developed as a biosimilar to trastuzumab, a recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody which targets HER2. Trastuzumab is approved in many regions for the treatment of HER2-positive early breast cancer, metastatic breast cancer and metastatic gastric cancer.

Amgen and Allergan are collaborating on the development and commercialization of four oncology biosimilars. Amgen has a total of nine biosimilars in development. Allergan is also independently developing biosimilars.

Study Design
This above referenced Phase 3 study was a randomized, multicenter, double-blinded, active-controlled study (study number 20120283) that evaluated safety and efficacy of ABP 980 compared to trastuzumab in adult female patients with HER2-positive early breast cancer. There were 725 patients randomized, with 364 patients in the ABP 980 group and 361 patients in the trastuzumab group.

In the neoadjuvant phase, enrolled patients received run-in chemotherapy consisting of epirubicin and cyclophosphamide (EC) every three weeks (Q3W) for four cycles. Once run-in chemotherapy was completed, patients with adequate cardiac function were randomized 1:1 to receive investigational product (ABP 980 or trastuzumab), plus paclitaxel, Q3W for four cycles. Surgery (breast and sentinel node or axillary lymph node resection) was complete three to seven weeks after the last dose of investigational product in the neoadjuvant phase, and pCR was analyzed.

In the adjuvant phase, following surgery, patients received investigational product (ABP 980 or trastuzumab) Q3W for up to one year from the first day of investigational product administered in the neoadjuvant phase. Patients who received ABP 980 during the neoadjuvant phase continued to receive ABP 980 Q3W for the adjuvant phase. Patients who received trastuzumab during the neoadjuvant phase received either ABP 980 or trastuzumab Q3W for the adjuvant phase. The allocation to a treatment group during the neoadjuvant or adjuvant phase occurred at randomization.

The primary analysis was conducted when the last patient completed the surgery following the neoadjuvant therapy. Clinical equivalence was assessed by comparing the confidence interval of the risk difference and risk ratio of the pCR in breast tissue and axillary lymph nodes with the prespecified equivalence margins. The final analysis of safety will be conducted when the last patient has completed their last study assessment in the adjuvant phase.

About HER2-Positive Early Breast Cancer
HER2-positive early breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells.1 Approximately 20 percent of all breast cancers are HER2-positive.2 Breast cancer is the second leading cause of cancer death among women and each year it is estimated that over 230,000 women in the United States will be diagnosed.3 HER2-positive breast cancers tend to grow and spread more aggressively than HER2-negative breast cancers.1

About ABP 980
ABP 980 is being developed as a biosimilar to trastuzumab, a recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody approved in many regions for the treatment of HER2-overexpressing early breast cancer, metastatic breast cancer and metastatic gastric cancer. The active ingredient of ABP 980 is a humanized monoclonal antibody which has the same amino acid sequence as trastuzumab. ABP 980 has the same pharmaceutical dosage form and strength as trastuzumab (US) and trastuzumab (EU).