On November 13, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported the publication of previously presented results from the ExteNET Phase III clinical trial of Puma’s drug neratinib in patients with early stage HER2-positive breast cancer in the journal The Lancet Oncology (Press release, Puma Biotechnology, NOV 13, 2017, View Source [SID1234522009]).

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The article, entitled "Neratinib after trastuzumab-based adjuvant therapy in early stage HER2-positive breast cancer (ExteNET): 5-year analysis of a randomized, double blind, placebo-controlled phase III trial," appears in the November 13th online issue of The Lancet Oncology and will be published in a future print issue of the journal.

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 published online 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 invasive recurrent disease, ductal carcinoma in situ (DCIS), or death for a period of five years after randomization in the trial.

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.

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).

"ExteNET 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. We are pleased that The Lancet Oncology has chosen to publish these results," said Alan H. Auerbach, Chief Executive Officer and President of Puma.

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). No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhea were identified in the analysis. 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.

On November 13, 2017 Mirati Therapeutics, Inc. (Nasdaq: MRTX) (the Company or Mirati), a clinical-stage targeted oncology company, reported that it is reprioritizing its development programs to capitalize on encouraging data and development opportunities in its sitravatinib and KRAS programs (Press release, Mirati, NOV 13, 2017, View Source [SID1234522006]). In addition, the Company announced that it has selected a clinical lead and backup compounds in its KRAS program that potently target KRAS G12C mutations. An Investigational New Drug (IND) Application submission is expected by the fourth quarter of 2018. The Company also announced it will deprioritize further investment in glesatinib and will pursue opportunities to partner the program. The reallocation of resources will support the acceleration and expansion of the sitravatinib and KRAS programs and is expected to provide funding for operations into late 2019.

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"We are very encouraged by the early results from our sitravatinib immuno-oncology program. The combination of sitravatinib and nivolumab has demonstrated durable responses and prolonged stable disease in patients with non-small cell lung cancer that have documented progression on prior checkpoint therapy. This is a patient population with poor prognosis and limited treatment options. We are focusing on accelerating this promising opportunity with sitravatinib and advancing our potentially first-in-class KRAS program, both of which address large underserved patient populations with significant market potential," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer.

Program updates the Company expects to provide in 2018 include:
•
Phase 2 data from the immuno-oncology combination of sitravatinib and nivolumab in patients with checkpoint refractory non-small cell lung cancer (NSCLC) by mid-2018.
•
Advancement of the potentially first-in-class KRAS G12C inhibitor program to an IND submission by the fourth quarter of 2018.
•
Phase 1b proof-of-concept data from the study of sitravatinib as a single agent in genetically selected patients with NSCLC and other solid tumors by mid-2018.

•
Phase 2 data from the immuno-oncology combination of mocetinostat and durvalumab in patients with checkpoint refractory NSCLC in the first quarter of 2018.

Mirati’s Development Programs

Sitravatinib

Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being tested in combination with the anti-PD-1 checkpoint inhibitor, nivolumab (OPDIVO), in NSCLC patients who have experienced documented disease progression following treatment with a checkpoint inhibitor. The majority of NSCLC patients either do not respond to checkpoint therapy or experience disease progression following treatment. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.

As previously reported at the IASLC 18th World Conference on Lung Cancer, initial data from the ongoing Phase 2 study of sitravatinib in combination with nivolumab included three confirmed Partial Responses (PRs) in the first 11 evaluable patients. Eight of these patients exhibited tumor reduction. Seven patients (including all three patients with PRs) remained on study, with treatment duration ranging from four months to 10.5 months. These initial results are encouraging and may extend to other tumor types, including renal cell, bladder and liver cancer, where checkpoint inhibitors have demonstrated efficacy that may potentially be expanded by combining with sitravatinib. The Company plans to provide an update on the first two stages of this trial in up to 34 patients by mid-2018.

Sitravatinib is also being evaluated as a single agent in a Phase 1b expansion trial enrolling patients whose tumors harbor CBL, CHR4Q12 and RET genetic alterations in NSCLC and other tumor types. In the ongoing Phase 1b study of sitravatinib as a single agent, an objective response with tumor reduction of 77% was observed in the first evaluable NSCLC patient with a CBL mutation. The Company continues to enroll patients in this trial to confirm this early promising activity and will provide a further update across all cohorts by mid-2018.

KRAS Program Advancing Towards IND in 2018

The Company has selected a clinical lead and backup compounds for advancement to IND in its potential first-in-class KRAS program. The KRAS program emerged from a joint drug discovery collaboration with Array BioPharma, where over 100 co-crystal structures provided critical insight toward the design of potent and selective KRAS inhibitors. The clinical lead and backups are orally-available small molecule inhibitors of KRAS G12C mutations, with potencies of 1 to 20 nM (cellular IC50) and selectivity of greater than 1,000-fold for target inhibition in tumor cells harboring KRAS G12C mutations compared with cells exhibiting wild-type KRAS. In addition, the clinical lead and backups demonstrated complete regression of KRAS G12C-positive tumors implanted in mice. IND-enabling preclinical studies are underway, and an IND submission is expected by the fourth quarter of 2018, with early clinical proof-of-concept anticipated in 2019.

Historically, KRAS has been extremely difficult to directly inhibit due to its high affinity for GTP, and its lack of a defined binding pocket. Tumors characterized by KRAS mutations are commonly associated with poor prognosis and resistance to therapy. KRAS G12C driver mutations occur in approximately 14% of NSCLC adenocarcinoma patients and 5% of colorectal cancer patients, who

have few treatment options. The Company’s KRAS program has the potential to be the first direct inhibitor of this important and challenging tumor driver mutation.

Mocetinostat

Mocetinostat is a selective Class I and IV HDAC inhibitor. Inhibition of histone acetylation is predicted to enhance the recognition of tumor cells by anti-tumor T cells and reverse immunosuppressive factors in the tumor microenvironment. The Company is conducting a Phase 2 study of mocetinostat in combination with durvalumab (IMFINZI) in NSCLC patients who have experienced disease progression after prior treatment with checkpoint inhibitor therapy. Patients are stratified into two cohorts based upon their best response to prior checkpoint therapy. Stage 1 of the study is currently enrolling nine patients in each cohort. As previously reported, one cohort has already met the prespecified criteria for expansion into stage 2 with at least one confirmed partial response. The Company will provide an update on this trial in the first quarter of 2018.

Glesatinib
Glesatinib has demonstrated clinical activity and acceptable tolerability in MET-altered NSCLC patients. However, in light of superior investment opportunities in its pipeline, the Company will suspend further investment in glesatinib and will pursue opportunities to partner the program. The Company intends to present glesatinib data at a future medical conference.

LSD1 Preclinical Program
The Company has elected to suspend further development of its preclinical LSD1 inhibitor program as part of its reprioritization. In light of superior investment opportunities in its pipeline, the Company will seek a partner to continue development of the program.

On November 13, 2017 Celsion Corporation (NASDAQ:CLSN), an oncology drug development company, reported the submission of its Phase I/II clinical trial protocol to the U.S. Food and Drug Administration (FDA) for GEN-1, the Company’s DNA-based immunotherapy for the localized treatment of ovarian cancer (Press release, Celsion, NOV 13, 2017, View Source [SID1234521999]). The protocol, developed in conjunction with guidance from the Company’s Medical Advisory Board, is designed with a single dose escalation to evaluate the safety and biological activity of GEN-1 at 100mg/m² in newly diagnosed Stage III/IV ovarian cancer patients, followed by a continuation at the selected dose in Phase II in a 90 patient 1 to 1 randomized study. GEN-1 has demonstrated encouraging safety and efficacy data in a recently completed dose escalating Phase IB trial in combination with neoadjuvant chemotherapy, the standard of care for patients newly diagnosed with ovarian cancer. Concurrently with neoadjuvant chemotherapy, enrolled patients received escalating weekly doses of GEN-1, from levels beginning at 36mg/m², to 47mg/m², 61mg/m² and 79mg/m² weekly for 8 treatments in total, followed by interval debulking surgery.

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"GEN-1 is designed to locally activate IL-12 production which can recruit and stimulate the patient’s immune system to attack and destroy cancer," stated Dr. Nicolas Borys, Celsion’s senior vice president and chief medical officer. "In preclinical and multiple Phase I clinical studies performed to date, GEN-1 has demonstrated good safety and impressive immune system stimulation and clinical activity. This trial will evaluate its value as an adjuvant to current standard of care in newly diagnosed Stage III/IV ovarian cancer patients with a relatively healthy immune system. We look forward to initiating the study in the first half of 2018."
The Phase I/II study builds on the highly promising clinical and translational research data for the recently completed Phase IB dose-escalating OVATION Study. This next Phase I/II study will have a dose escalating phase to 100 mg/m² to identify a safe and tolerable dose of GEN-1 while maximizing an immune response. The study protocol was unanimously supported by an expert medical advisory board and lead investigators from the Phase IB OVATION Study and is summarized below:

Open label, 1:1 randomized design

Enrollment up to 90 patients with Stage III/IV ovarian cancer patients at ten U.S. centers
Primary endpoint of improvement in progression-free survival (PFS) comparing GEN-1 with neoadjuvant chemotherapy versus neoadjuvant chemotherapy alone.

PFS for patients treated per protocol in the Phase IB OVATION Study continues to be followed. Of the eight patients who received GEN-1 treatment over one year ago (cohort 1 – 3) and are being followed, only three patients’ cancer has progressed. This compares favorably to the historical median progression-free survival of 12 months for newly-diagnosed patients with Stage III and IV ovarian cancer that undergo neoadjuvant chemotherapy followed by interval debulking surgery. Of the remaining five patients who have been on the OVATION Study for over one year, their median PFS as of October 31, 2017 is 18.8 months with the longest progression-free patient at 24 months.

The protocol has been submitted to the FDA for its 30 day review and comment period. Pending this review, the Company expects to initiate enrollment of the Phase I portion of the study in the first half of 2018. The Company expects to have the study 50% enrolled by the end of 2018. Due to the open label design, clinical data will be disclosed throughout the execution of the trial as it is released by the study’s investigators.

"GEN-1 holds the potential of tremendous promise as a cancer treatment in the rapidly emerging area of immuno-oncology. Unlike the toxicities, poor tolerability, and poor pharmacokinetics of systemically administered recombinant IL-12, the beauty of GEN-1 is that it inspires secretion of highly-tolerable endogenous IL-12," said Michael H. Tardugno, Celsion’s chairman, president and chief executive officer. "Designed in consultation with leading thought leaders, this Phase I/II trial is expected to define an optimal dose, demonstrate GEN-1’s clinical benefit when compared with current standard of care, and provide insights on powering for a registration program as the candidate progresses through development."

About GEN-1 Immunotherapy

GEN-1, designed using Celsion’s proprietary TheraPlas platform technology, is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anti-cancer immunity acting through the induction of T-lymphocyte and natural killer (NK) cell proliferation. The Company has previously reported positive safety and encouraging Phase I results with GEN-1 given as monotherapy in patients with peritoneally metastasized ovarian cancer, and recently completed a Phase Ib trial of GEN-1 in combination with PEGylated doxorubicin in patients with platinum-resistant ovarian cancer.

On November 13, 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 the initiation of two new global pivotal clinical trials of BGB-3111, an investigational Bruton’s Tyrosine Kinase (BTK) inhibitor, including a Phase 3 trial of BGB-3111 in previously untreated patients with CLL/SLL and a pivotal Phase 2 trial of BGB-3111 in combination with GAZYVA (obinutuzumab) in patients with relapsed or refractory FL (Press release, BeiGene, NOV 13, 2017, View Source;p=RssLanding&cat=news&id=2316623 [SID1234521996]). Along with a global Phase 3 trial comparing BGB-3111 to ibrutinib in Waldenström’s macroglobulinemia (WM), initiated in early 2017, BGB-3111 is now being evaluated in global pivotal trials in three distinct indications. Additionally, BGB-3111 is being evaluated in a broad pivotal clinical development program in China, including ongoing pivotal Phase 2 trials in MCL, CLL, and WM, which was initiated in August 2017. BeiGene also announced today that enrollment in the pivotal Phase 2 trial of BGB-3111 in China in MCL patients was completed in September 2017.

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"The initiation of two additional pivotal trials expands our global registration-directed clinical development of BGB-3111 to additional indications, including patients with follicular lymphoma, a common B cell malignancy for which BTK inhibitors are not yet approved. We look forward to continuing the development of BGB-3111 as a potentially best-in-class BTK inhibitor for patients worldwide who suffer from hematological malignancies," commented John V. Oyler, Founder, Chief Executive Officer, and Chairman of BeiGene.

"We believe that these two new pivotal trials are supported by our growing clinical experience with BGB-3111, in which over 600 patients have been dosed to date. With the newly initiated Phase 3 CLL/SLL trial, we aim to investigate whether BGB-3111 could be an effective treatment option for a broad population of CLL/SLL patients requiring initial treatment. The initiation of the pivotal trial in follicular lymphoma is an effort to determine whether the combination of BGB-3111 and obinutuzumab represents an effective treatment option for a high-unmet-need population of relapsed or refractory patients to potentially support the pursuit of accelerated or conditional approval of this regimen," commented Jane Huang, M.D., Chief Medical Officer, Hematology.

Trial Design

The Phase 3 trial in CLL/SLL is designed to compare BGB-3111 to BR and will be conducted in North America, Europe, Australia, New Zealand, and Asia. The study will enroll previously untreated CLL/SLL patients ineligible for intensive chemo-immunotherapy (i.e., fludarabine, cyclophosphamide, and rituximab), who will be divided into two cohorts. The first cohort is designed to include 420 patients without a 17p deletion (del17p), who will be randomized in a 1:1 ratio to receive either BGB-3111 until progression or six cycles of BR. Crossover will be allowed in the BR arm upon progression. The primary endpoint will be progression-free survival (PFS), and secondary endpoints include overall response rate (ORR), duration of response (DOR), overall survival (OS), and patient-reported outcomes. Patients with del17p will be enrolled in a second cohort to receive BGB-3111 until progression and will be assessed for response and safety.

The pivotal Phase 2 trial in FL is designed to evaluate BGB-3111 in combination with obinutuzumab in patients who have had at least two prior lines of therapy and who progressed within 12 months of their last treatment or were refractory to their last treatment. The primary endpoint will be ORR and obinutuzumab monotherapy will be included as a comparator, in order to evaluate the contribution of BGB-3111. The trial is expected to enroll approximately 210 patients in North America, Europe, Australia, and New Zealand who will be randomized 2:1 to receive either BGB-3111 with obinutuzumab or obinutuzumab alone. Patients in the obinutuzumab arm will have the option to add BGB-3111 after 12 months if a response has not been achieved. Secondary endpoints of the study include DOR, PFS, OS, and time to response.

About BGB-3111

BGB-3111 is a potent and highly selective investigational small molecule inhibitor of BTK. BGB-3111 has demonstrated higher selectivity against BTK than ibrutinib, a BTK inhibitor currently approved by the U.S. Food and Drug Administration and the European Medicines Agency, based on biochemical assays, higher exposure than ibrutinib based on their respective Phase 1 experience in separate trials, and sustained 24-hour BTK occupancy in both the peripheral blood and lymph node compartments.

On November 13, 2017 Arcus Biosciences, a clinical-stage biotechnology company focused on the discovery and development of innovative cancer immunotherapies, reported the completion of a $107 million Series C financing (Press release, Arcus Biosciences, NOV 13, 2017, View Source [SID1234521995]). This financing brings the total equity capital that the company has raised since its inception in 2015 to $227 million.

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The proceeds from this financing will be used for the advancement of Arcus’s clinical programs for AB928, a first-in-class dual adenosine receptor antagonist, and AB122, a PD-1 antibody. Earlier this month, Arcus initiated a phase 1 trial of AB928 in healthy volunteers and Arcus plans to initiate a phase 1/2 trial of AB928 in combination with AB122 in cancer patients during the first half of 2018. Also in November, Arcus initiated a phase 1 trial of AB122 in cancer patients in Australia. Data from the AB122 trial will be available in 2018 and Arcus plans to evaluate AB122 in combination with its other product candidates, in addition to AB928, in the future. The proceeds raised will also allow Arcus to advance at least two additional product candidates into clinical development, including AB680, a first-in-class small molecule CD73 inhibitor, and AB154, a TIGIT antibody.

The financing was led by GV (formerly Google Ventures), with participation from new investors, including Wellington Management Company LLP, EcoR1 Capital, BVF Partners L.P., Decheng Capital, Hillhouse, Aisling Capital and entities affiliated with Leerink Partners. Arcus’s existing investors, including The Column Group, Foresite Capital, Invus Opportunities, DROIA, Celgene Corporation and Taiho Ventures, also participated in the financing.

"We are extremely pleased to add several outstanding investors with significant expertise in biotechnology to our investor group," said Terry Rosen, Ph.D., CEO of Arcus Biosciences. "We have been assembling a team of staff, investors, leadership and advisors with a highly aligned long-term vision to create, develop and commercialize innovative cancer immunotherapies that may offer a meaningful benefit to patients over existing treatments. These new investors share this vision, and we are thrilled to add their expertise, leadership and commitment to our team."