On September 8, 2017 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported preliminary clinical data from an ongoing Phase 1/2 trial of its investigational PARP inhibitor BGB-290 in patients with advanced solid tumors at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain (Press release, BeiGene, SEP 8, 2017, View Source [SID1234520433]). The data are on display in a poster and are scheduled to be further reviewed during a poster discussion session. The clinical data suggest that BGB-290 was generally well tolerated in patients with advanced solid tumors, with an overall response rate of 33% in 39 evaluable patients with epithelial ovarian cancer (EOC) or other associated tumors and 43% in 23 patients with mutant BRCA status.

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"BGB-290 continues to demonstrate promising anti-tumor activity in preliminary data from the Phase 1/2 trial. Objective responses were observed, with three patients achieving a complete response among 39 evaluable patients with epithelial ovarian or associated cancers," said Jason Lickliter, MBBS FRACP, Chief Medical Officer of Nucleus Network, Melbourne, Australia and coordinating principal investigator of the trial.

"BGB-290 was generally well tolerated, and all observed treatment-related adverse events were grade 3 or lower in severity. In addition to the trial from which data were presented at ESMO (Free ESMO Whitepaper), we continue to enroll patients in our Phase 1 monotherapy trial in China and our global Phase 1 trial in combination with BGB-A317, our PD-1 antibody. We also recently initiated two global combination trials of BGB-290 with temozolomide in solid tumors and with radiation and/or temozolomide in glioblastoma, respectively. We look forward to moving BGB-290 into late-stage development," commented Amy Peterson, MD, Chief Medical Officer, Immuno-oncology at BeiGene.

Summary of Results from an Ongoing Phase 1/2 Trial

The multi-center, open-label Phase 1/2 trial of BGB-290 is being conducted in Australia in patients with advanced solid tumors. The Phase 1 dose-escalation and dose-finding component identified the recommended Phase 2 dose to be 60 mg twice daily (BID). Once-daily dosing will also be evaluated. The ongoing Phase 2 component has two parts: the first part is investigating the safety, tolerability, and antitumor activity of BGB-290 in disease-specific dose-expansion cohorts, and the second part is investigating the effects of food on the pharmacokinetic profile of a single dose of BGB-290. Data presented at ESMO (Free ESMO Whitepaper) include patients from both the Phase 1 and 2 components of the trial.

As of June 1, 2017, 68 patients were enrolled in the trial, with 45 patients in the Phase 1 component, and 23 patients in the Phase 2 component, including eight patients in the food effect sub-study. The median duration of therapy for all patients was 79 days (range 1–926 days). At the time of the data cutoff, 20 patients remained on treatment.

The safety analysis suggested that BGB-290 was generally well tolerated in patients with advanced solid tumors. Adverse events (AEs) assessed to be related to treatment occurred in 78% of patients and were all grade 3 or lower in severity. The most common treatment-related AEs (≥10% of patients) were nausea (56%), fatigue (40%), anemia (25%), vomiting (21%), diarrhea (21%), decreased appetite (15%), and neutropenia or neutrophil count decrease (12%). Serious AEs (SAEs) occurred in 46% of patients, and SAEs considered related to treatment and occurring in more than one patient included two cases each of nausea and anemia. Four patients discontinued treatment due to treatment-emergent AEs. Four patients had a treatment-emergent AE with a fatal outcome, none were assessed as related to treatment, all were associated with disease progression.

At the time of the data cutoff, the efficacy-evaluable population per RECIST 1.1 criteria (measurable disease at baseline and at least one post-baseline tumor assessment) included 39 patients with EOC or associated tumors (i.e., fallopian tube or primary peritoneal cancers). Among this group, there were three confirmed complete responses (CRs), 10 confirmed partial responses (PRs), and 21 cases of stable disease (SD). Of the 23 evaluable patients with EOC or other associated tumors known to be BRCA-mutated, there were three CRs, seven PRs, and 10 cases of SD. Complete and partial responses were observed in patients known to be platinum-resistant as well as patients with platinum-sensitive disease.

About BGB-290

BGB-290 is a potent and highly selective inhibitor of PARP1 and PARP2 with pharmacological properties such as brain penetration and PARP–DNA complex trapping demonstrated in preclinical models. BGB-290 is currently in global clinical development as a monotherapy and in combination with other agents for a variety of solid tumor malignancies.

On September 8, 2017 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported that an interim analysis of its ongoing, randomized Phase 2 trial showed that NY-ESO-1+ soft tissue sarcoma (STS) patients receiving the combination of CMB305 and Genentech’s checkpoint inhibitor, atezolizumab (TECENTRIQ), experienced greater clinical benefit and immune response than those receiving atezolizumab alone (Press release, Immune Design, SEP 8, 2017, View Source [SID1234520432]). The data will be presented in a poster discussion session at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress, September 8-12, 2017 in Madrid, Spain.

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This fully enrolled trial is evaluating the safety, immunogenicity and efficacy of CMB305 in combination with atezolizumab (C+A, n=45), or atezolizumab alone (A, n=43), in a total of 88 patients with locally advanced, relapsed, or metastatic NY-ESO-1+ synovial sarcoma or myxoid/round-cell liposarcoma. Data to be presented at ESMO (Free ESMO Whitepaper) summarize patients evaluated in an interim analysis in a data cut as of July 21, 2017, with analysis divided into two groups: pre-specified interim analysis (n=36) and full study population (n=88).

Patient Characteristics:

Patients receiving CMB305 plus atezolizumab have more advanced disease than those receiving atezolizumab alone, including:

Metastatic Disease: 98% (C+A) vs. 79% (A)
≥2 prior lines of systemic anti-cancer therapy: 61% (C+A) vs. 49% (A)
≥2 lesions at time of study entry: 96% (C+A) vs. 84% (A)
Grade 3 disease at diagnosis: 47% (C+A) vs. 33% (A)
Greater Clinical Benefit with Combination of CMB305 and Atezolizumab:

Interim analysis data (n=36) show that patients receiving CMB305 plus atezolizumab experienced greater clinical benefit than those receiving atezolizumab alone.

Disease Control Rate (Partial Responses (PR) + Stable Disease (SD)): 61%, including 1 PR (C+A) vs. 28% with no PRs (A)
Median Progression Free Survival (PFS): 2.6 months (C+A) vs. 1.4 months (A)
Time to Next Treatment (TTNT): 9 months (C+A) vs. 6.3 months (A)
Overall survival: as of the collection date, overall survival data are immature (median duration of observation is less than six months); Immune Design intends to present survival data in 2018 once all patients approach at least one year of follow up.
In the full study population (n=88), the trend of greater clinical benefit on the combination arm remains consistent for the entire patient population:

Disease Control Rate: 57% (3 PRs total, 1 unconfirmed) (C+A) vs. 38% (0 responses) (A)
More Robust Immune Response with Combination of CMB305 and Atezolizumab:

Patients in the full study population (n=88) who received the combination of CMB305 and atezolizumab demonstrated stronger anti-NY-ESO-1 immune responses compared to those receiving atezolizumab alone (samples evaluable from (n=60/88)), including:

Induced anti-NY-ESO-1 T cells: 52% (C+A) vs. 17% (A)
Induced anti-NY-ESO-1 antibodies: 52% (C+A) vs. 0% (A)
Induced antigen spreading: 19% (C+A) vs. 0% (A)
Biomarker Analysis Shows Continued Link Between Induced Immune Response and Clinical Benefit:

In an exploratory analysis, a trend towards improved overall survival was observed in patients with an induced immune response (T cells or antibodies) who received CMB305 plus atezolizumab.

Induced anti-NY-ESO-1 T cells: 78% reduction in mortality rate, as compared to patients without induced T cells [HR=0.22, log-rank p value=0.043]
Induced anti-NY-ESO-1 antibodies: 87% reduction in mortality rate, as compared to patients without induced antibodies [HR=0.13, log-rank p value=0.025]
This trend of improved overall survival in patients with induced immune response was not observed in the atezolizumab-only arm.
In addition, pretreatment tumor biopsies available from 70 patients show both an absent or very low level of PD-L1 expression and CD8 T cell infiltration, further supporting that these subtypes of STS are "cold" tumors.

Positive Safety Profile with Combination of CMB305 and Atezolizumab:

This combination was observed to be well tolerated, and there were no new safety signals in either arm.

"We believe the greater clinical benefit and more robust immune response shown in the combination study arm supports the hypothesis that the combination of an appropriately-designed, next-generation cancer vaccine such as CMB305 with a checkpoint inhibitor is important to produce clinical benefit in a cold tumor such as STS, where checkpoint inhibitors otherwise may have limited efficacy," said Carlos Paya, M.D., Ph.D., President and Chief Executive Officer of Immune Design. "In addition, we are pleased to observe the trend towards longer overall survival in patients with an induced anti-NY-ESO-1 immune response, further supporting the positive CMB305 monotherapy data we presented at ASCO (Free ASCO Whitepaper) in June."

Atezolizumab is a monoclonal antibody being developed by Genentech, a member of the Roche Group, and is designed to target and bind to a protein called PD-L1 (programmed death ligand-1). The trial is being conducted pursuant to a clinical collaboration with Genentech. TECENTRIQ is a registered trademark of Genentech.

The ESMO (Free ESMO Whitepaper) Poster Discussion session presentation details are as follows:

A Phase 2 Study of CMB305 and Atezolizumab in NY-ESO-1+ Soft Tissue Sarcoma: Interim Analysis of Immunogenicity, Tumor Control and Survival

Abstract # 1480PD
Session Title: Sarcoma Poster Discussion Session
Date: Monday, Sept. 11, 2017
Time: 11 a.m. — 12:30 p.m.
Location: Bilbao Auditorium
Poster Presenter: Dr. Sant Chawla
Poster Discussant: Dr. Robert Maki

About CMB305

CMB305 is a prime-boost vaccine approach against NY-ESO-1-expressing tumors, designed to generate an integrated, anti-NY-ESO-1 immune response in vivo via a targeted, specific interaction with dendritic cells, a mechanism of action Immune Design believes differs from traditional cancer vaccines. CMB305 is being evaluated in soft tissue sarcoma patients in ongoing Phase 1 monotherapy and Phase 2 combination studies. Immune Design has received Orphan Drug Designation for CMB305 from the U.S. Food and Drug Administration (FDA) for the treatment of soft tissue sarcoma, as well as from the FDA and European Medicines Agency for each of the components of CMB305 for the treatment of soft tissue sarcoma.

On September 8, 2017 Array BioPharma (Nasdaq: ARRY) and Pierre Fabre reported safety results and initial clinical activity from the safety lead-in of the Phase 3 BEACON CRC study evaluating binimetinib, a MEK inhibitor, encorafenib, a BRAF inhibitor and Erbitux (cetuximab), an anti-EGFR antibody, in patients with BRAF-mutant colorectal cancer (CRC) whose disease has progressed after one or two prior regimens in the metastatic setting (Press release, Array BioPharma, SEP 8, 2017, View Source [SID1234520426]). BRAF-mutant CRC represents a difficult-to-treat subtype of colorectal cancer that impacts 10 to 15% of CRC patients. These data were presented as an e-poster on September 8 at the 2017 European Society for Medical Oncology Congress in Madrid, Spain (Abstract No. #517P).

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As of August 9, 2017, 30 patients were treated in the safety lead-in and received the triplet combination of binimetinib, encorafenib and cetuximab (BINI 45 mg twice daily, ENCO 300 mg daily and CETUX per label). Out of the 30 patients, 29 had a BRAFV600E mutation. Microsatellite instability-high (MSI-H) (resulting from defective DNA mismatch repair) was detected in only one patient. The triplet demonstrated good tolerability, supporting initiation of the randomized portion of the study. In addition, promising initial clinical activity was observed, with a confirmed overall response rate (ORR) of 41%, including a complete response, in patients with the BRAFV600E mutation, a group of patients with historically poor outcomes. The observed ORR was 59% in the 17 patients with the BRAFV600E mutation with only one prior therapy. Out of 28 patients with both a BRAFV600E mutation and a post-baseline assessment, 27 showed tumor regression.

"The BRAF mutation carries a very poor prognosis for patients with advanced colorectal cancer, and is particularly unresponsive after first-line therapy," said Scott Kopetz, M.D., Ph.D., FACP, Associate Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "In the safety lead-in, the triplet combination showed impressive results with a confirmed overall response rate of 41%. Several patients also showed prolonged stable disease, with 76% of patients overall continuing on therapy after a median duration of exposure of 5.6 months. These results are unprecedented for this patient population based on existing standards of care."

In the safety lead-in, the triplet combination was generally well-tolerated. The most common grade 3 or 4 adverse events (AEs) seen in at least 10% of patients were nausea (10%), vomiting (10%), increased blood creatine kinase (10%) and urinary tract infection (10%). Three patients discontinued treatment due to AEs with only one considered related to treatment. At the time of the analysis, 76% of patients remain on study treatment after a median duration of treatment of 5.6 months (range 1.0 – 9.3 months).

With these encouraging results, Array continues to enroll the randomized portion of the BEACON CRC study, assessing the efficacy of encorafenib in combination with cetuximab with or without binimetinib compared to cetuximab and irinotecan-based therapy.

"There has been a long-standing need to find improved treatment options for patients with BRAF-mutant colorectal cancer, and we are encouraged that data from the safety lead-in show binimetinib, encorafenib and cetuximab may have this potential," said Axel Grothey, M.D., Professor of Oncology, Mayo Clinic College of Medicine and Science. "We hope these promising findings, with the impressive response rates, including a complete response, and early signs of durability, will bring us one step closer to addressing this high unmet medical need."

ARRAY INVESTOR RECEPTION AND WEBCAST: Array will host an investor reception during ESMO (Free ESMO Whitepaper) 2017 where key opinion leaders in the colorectal cancer field, including Dr. Scott Kopetz, M.D. Anderson and Dr. Axel Grothey, Mayo Clinic, who will give presentations covering the BRAF-mutant colorectal cancer landscape and data from the BEACON CRC safety lead-in. The presentations will be webcast (live and replay), for those who wish to participate remotely.

Date:
Saturday, September 9, 2017
Time:
4:00-6:00 PM CEST (10:00 am – 12-noon EDT)
Location:
Neuvo Boston Hotel, Madrid, Spain
RSVP:
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About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Of these, nearly 750,000 were diagnosed in men, and 614,000 in women. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. In the U.S. alone, an estimated 135,430 patients will be diagnosed with cancer of the colon or rectum in 2017, and approximately 50,000 are estimated to die of their disease. [1] In the United States, BRAF mutations are estimated to occur in 10% to 15% of patients with colorectal cancer and represent a poor prognosis for these patients.[2-5] Based on recent prospective historical data, the prevalence of MSI-H in tumors from patients with metastatic BRAF-mutant CRC ranged from 14% in a recent Phase 1b/2 trial (NCT01719380) (Array, data on file) and 18% a recent Southwestern Oncology Group (SWOG) randomized phase 2 study.[6]

About Binimetinib and Encorafenib
MEK and BRAF are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as melanoma, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor and encorafenib is a late-stage small molecule BRAF inhibitor, both of which target key enzymes in this pathway. Binimetinib and encorafenib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial.

BEACON CRC was initiated based on results from a Phase 2 study which included the combination of encorafenib and cetuximab in 50 patients with advanced BRAF-mutant CRC. These results were presented at the 2016 ASCO (Free ASCO Whitepaper) annual meeting. In this arm, median overall survival for these patients exceeded one year, which is more than double several separate historical standard of care published benchmarks for this population. [7-12] The objective response rate (ORR) was 22%; historical published benchmarks in this patient population using standard of care regimens range between 4% to 8%. [10-13]

On July 5, 2017, Array announced that it submitted two NDAs to the FDA to support use of the combination of binimetinib 45 mg twice daily and encorafenib 450 mg once daily (COMBO450) for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. Array completed its NDA submissions based on findings from the pivotal Phase 3 COLUMBUS trial. In addition, Array’s European partner, Pierre Fabre, announced on August 28, 2017 that the European Medicines Agency (EMA) has validated the review of the Marketing Authorization Applications for binimetininb and encorafenib.

Binimetinib and encorafenib are investigational medicines and are not currently approved in any country.

Array BioPharma retains exclusive rights to binimetinib and encorafenib in key markets including the U.S., Canada and Israel. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. The BEACON CRC trial is being conducted with support from Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

On September 8, 2017 Seattle Genetics, Inc. (NASDAQ: SGEN) reported that preliminary clinical data for tisotumab vedotin from a Genmab-sponsored phase 1/2 clinical trial (GEN701) are being featured in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress being held September 8-12, 2017 in Madrid, Spain (Press release, Seattle Genetics, SEP 8, 2017, View Source [SID1234520425]). Additional data from the trial will also be presented in a poster session. Tisotumab vedotin is an antibody-drug conjugate (ADC) targeting tissue factor, which is expressed on a broad range of solid tumors. Among patients with cervical cancer treated in the trial, tisotumab vedotin demonstrated an encouraging response rate and manageable safety profile. Tisotumab vedotin is being co-developed by Seattle Genetics and Genmab. The companies are evaluating next steps in the development of tisotumab vedotin for cervical cancer. The GEN701 study is ongoing and further data, including other solid tumor indications, will be published at a later date.

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"These encouraging data reinforce our recent decision to exercise our option to co-develop tisotumab vedotin with Genmab, thereby adding another clinical-stage solid tumor ADC program to our pipeline with a potentially rapid registrational pathway," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "In the recurrent cervical cancer setting, there is no standard of care and response rates are limited, underscoring the unmet need. Beyond cervical cancer, we believe tisotumab vedotin may have therapeutic potential in other solid tumors, and we are collaborating with Genmab to advance this program to benefit patients."

A Phase IIA Study of Tisotumab Vedotin (HuMax-TF-ADC) in Patients with Relapsed, Recurrent and/or Metastatic Cervical Cancer (Abstract #931, oral presentation on Friday, September 8, 2017 at 5:00 p.m. CET)

Tisotumab vedotin was evaluated in a phase 1/2 two-part trial conducted by Genmab. Part 1 assessed escalating single-agent doses ranging from 0.3 to 2.2 milligrams per kilogram (mg/kg) administered every three weeks in a variety of solid tumors. Part 2 consisted of disease-specific expansion cohorts at the recommended dose of 2.0 mg/kg. Data were reported from an expansion cohort of 34 patients with relapsed, recurrent and/or metastatic cervical cancer with a median age of 43 years. Of these patients, 91 percent had received prior treatment with a platinum and/or taxane-based chemotherapy regimen and 71 percent had received prior bevacizumab (Avastin). Key findings include:

Of the 34 patients evaluable for response, 11 patients (32 percent) achieved a response. Fifty percent of patients achieved clinical benefit after 12 weeks.
Median duration of confirmed responses was 8.3 months. Three responders remained on study.
The most common adverse events of any grade were conjunctivitis (50 percent), epistaxis, fatigue and alopecia (47 percent each) and nausea (44 percent).
The most common grade 3 or higher adverse events were vomiting (15 percent) and fatigue, nausea and abdominal pain (9 percent each).
Ocular events of any grade occurred in 53 percent of patients, including three percent with grade 3 or higher. The most common ocular event was conjunctivitis, which was substantially reduced through the introduction of a mitigation plan that involved a prophylactic steroid, lubricating eye drops and cooling eye masks worn during treatment infusion, as well as stricter dose adjustment guidance.
The part 2 portion of the clinical trial is ongoing in multiple solid tumors, including ovarian, prostate, bladder, esophageal and endometrial.
Additional data from the Part 1 dose escalation portion of the trial will be featured in a poster session on Sunday, September 10, 2017: A Phase I/II Safety Study of Tisotumab Vedotin (HuMax-TF-ADC) in Patients with Solid Tumors (Abstract #1148).

More information about the GEN701 clinical trial is available by visiting www.clinicaltrials.gov.

About Cervical Cancer

Cervical cancer originates in the cells lining the cervix, which is the lower part of the uterus. Routine medical examinations and the human papillomavirus (HPV) vaccine have had a positive impact on the incidence of cervical cancer in the developed world. However, even in developed countries, many women do not receive routine medical care or the HPV vaccine, resulting in an unmet medical need particularly for recurrent/metastatic disease. Standard therapies for recurrent/metastatic cervical cancer generally result in response rates of less than 15 percent and a median overall survival of 6 to 8 months.

About Tisotumab Vedotin

Tisotumab vedotin is an antibody-drug conjugate (ADC) composed of a human antibody that binds to tissue factor (TF) and Seattle Genetics ADC technology that utilizes a cleavable linker and the cytotoxic drug monomethyl auristatin E (MMAE). TF is a protein involved in tumor signaling and angiogenesis. Based on its high expression on many solid tumors and its rapid internalization, TF was selected as a target for an ADC approach. Tisotumab vedotin is in phase 1/2 clinical studies for solid tumors.

On September 8, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported the presentation of positive results from the Phase III clinical trial of Puma’s drug neratinib for the extended adjuvant treatment of early stage HER2-positive breast cancer following trastuzumab-based therapy (ExteNET trial) in a proffered paper oral session at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain (Press release, Puma Biotechnology, SEP 8, 2017, View Source [SID1234520424]). Neratinib was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets.

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The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

The ExteNET trial is a double-blind, placebo-controlled, Phase III trial of neratinib versus placebo after adjuvant treatment with trastuzumab (Herceptin) in patients with early stage HER2-positive breast cancer. The predefined 5-year invasive disease free survival (iDFS) analysis as a follow-up to the primary 2-year iDFS analysis of the Phase III ExteNET trial was presented today.

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 (DCIS), or death for a period of five years after randomization in the trial.

The patient characteristics in the trial were well balanced between the neratinib and placebo arms of the trial. For the 1,420 patients in the neratinib arm of the trial, 1,085 (76.4%) were node positive while of the 1,420 patients in the placebo arm of the trial, 1,084 (76.3%) were node positive. Additionally, in the neratinib arm of the trial, 816 patients (57.5%) were hormone receptor positive, and in the placebo arm of the trial, 815 patients (57.4%) were hormone receptor positive. The median time from the last trastuzumab dose to entry into the trial was 4.4 months for the neratinib-treated patients and 4.6 months for the placebo-treated patients.

The primary endpoint of the trial was invasive disease free survival (iDFS). The results of the trial demonstrated that after a median follow up of 5.2 years, treatment with neratinib resulted in a 27% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.73, p = 0.008). The 5-year iDFS rate for the neratinib arm was 90.2% and the 5-year iDFS rate for the placebo arm was 87.7%.

The secondary endpoint of the trial was invasive disease free survival including ductal carcinoma in situ (iDFS-DCIS). The results of the trial demonstrated that treatment with neratinib resulted in a 29% reduction of risk of disease recurrence including DCIS or death versus placebo (hazard ratio = 0.71, p = 0.004). The 5-year iDFS-DCIS rate for the neratinib arm was 89.7% and the 5-year iDFS-DCIS rate for the placebo arm was 86.8%.

For the pre-defined subgroup of patients with hormone receptor positive disease, the results of the trial demonstrated that treatment with neratinib resulted in a 40% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.60, p = 0.002). The 5-year iDFS rate for the neratinib arm was 91.2% and the 5-year iDFS rate for the placebo arm was 86.8%. For the pre-defined subgroup of patients with hormone receptor negative disease, the results of the trial demonstrated that treatment with neratinib resulted in a hazard ratio of 0.95 (p = 0.762).

The safety results were unchanged from the primary 2-year iDFS analysis of the study that showed the most frequently observed adverse event for the neratinib-treated patients was diarrhea, with approximately 39.9% of the neratinib-treated patients experiencing grade 3 or higher diarrhea (1 patient (0.1%) had grade 4 diarrhea). Patients who received neratinib in this trial did not receive any prophylaxis with antidiarrheal agents to prevent the neratinib-related diarrhea. Puma is currently running the ongoing CONTROL trial to investigate the use of loperamide-based prophylaxis to reduce the incidence of grade 3 or higher diarrhea in patients with early stage HER2-positive breast cancer who have completed adjuvant trastuzumab-based treatment. The most recently reported clinical data from CONTROL in June 2017 demonstrated that the use of loperamide-based prophylaxis reduced the rate of grade 3 diarrhea with neratinib, with grade 3 diarrhea rates ranging from 8-31% when loperamide-based prophylaxis was used.

"While the use of trastuzumab in the adjuvant setting has led to a reduction in the risk of disease recurrence in patients with early stage HER2-positive breast cancer, there continues to remain a need for further reductions in the risk of disease recurrence," said Professor Miguel Martin, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERONC, GEICAM, Universidad Complutense in Madrid, Spain. "The longer term follow up results of the ExteNET study demonstrate that we may be able to provide this type of improvement with neratinib to further help the patients with this disease."

"We are very pleased with the results of the 5-year follow up for the ExteNET trial with neratinib. This represents the first trial with a HER2 targeted agent that has shown a benefit in the extended adjuvant setting, which we believe provides a meaningful point of differentiation for neratinib in the treatment of HER2-positive breast cancer," said Alan H. Auerbach, Chief Executive Officer and President of Puma."

About HER2-Positive Breast Cancer

Approximately 20% to 25% of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

IMPORTANT SAFETY INFORMATION

NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information for additional safety information.

The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at www.NERLYNX.com or 1-855-816-5421.