On November 16, 2016 Pfizer Inc. (NYSE:PFE) reported that detailed results from the Phase 3 PALOMA-2 trial were published in The New England Journal of Medicine (Press release, Pfizer, NOV 16, 2016, View Source [SID1234516660]).

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These data, presented at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June, further demonstrate the clinical benefit of IBRANCE (palbociclib) as initial therapy for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) metastatic breast cancer. The PALOMA-2 study showed the combination of IBRANCE and letrozole extended progression-free survival (PFS), or the amount of time before tumor growth, by more than 10 months compared with letrozole plus placebo. Further, the study demonstrated that the median PFS of the IBRANCE and letrozole combination exceeded two years – making it the first and only treatment for this population of women to do so in a randomized Phase 3 study.1

"The median PFS of more than two years observed in this study is unprecedented for this patient population," said Veronique Dieras, M.D., medical oncologist and head of clinical research, Clinical Investigational Unit Chef de Service Recherche Clinique, Unité d’Investigation Clinique Department of Medical Oncology, Institut Curie, Paris, France. "Building on the Phase 2 PALOMA-1 data, the results of PALOMA-2 provide additional evidence that the combination of IBRANCE and letrozole is a meaningful advancement for these women."

"Since its accelerated approval in 2015, IBRANCE in combination with letrozole has become a standard of care for the treatment of post-menopausal women with ER+, HER2- advanced or metastatic breast cancer," said Hope Rugo, M.D., professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. "We now have seen consistent results across three randomized trials in which the addition of IBRANCE to an endocrine therapy significantly prolonged PFS compared to the endocrine therapy alone."

In the trial, median PFS for women treated with IBRANCE plus letrozole was 24.8 months (95% CI, 22.1-not estimable) compared with 14.5 months (95% CI, 12.9-17.1) for women treated with letrozole plus placebo (HR=0.58 [95% CI, 0.46-0.72], p<0.001), a 42% reduction in the risk of disease progression.

"IBRANCE has raised the bar for new treatments in hormone-receptor positive advanced breast cancer. The results of this Phase 3 trial add to the growing body of clinical data in support of IBRANCE and translates into hope for patients," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "We look forward to sharing the full PALOMA-2 data with global regulatory authorities with the goal of making IBRANCE available to more women around the world. Pfizer is proud of being a leader in the development of innovative therapies like IBRANCE that make a meaningful difference in patients’ lives."

Safety results were consistent with PALOMA-1 and no major unexpected safety findings were observed. The most common grade 3/4 adverse events with IBRANCE plus letrozole versus placebo plus letrozole were neutropenia (66.4% vs 1.4%), leukopenia (24.8% vs 0%), infections (6.5% vs 3.2%) and anemia (5.4% vs 1.8%). Febrile neutropenia was reported in 1.8% of patients in the IBRANCE plus letrozole group and none of the patients in the placebo plus letrozole group. For more information, please see Important Safety Information for IBRANCE below.2

IBRANCE first was approved by the U.S. Food and Drug Administration (FDA) in February 2015 and is indicated for the treatment of hormone receptor positive (HR+), HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine-based therapy in postmenopausal women.2 The indication in combination with letrozole was approved under accelerated approval based on PFS results from the Phase 2 PALOMA-1 study. As stated at the time of the approval, continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, the double-blind, Phase 3 PALOMA-2 study.2 A supplemental New Drug Application to support the conversion of the accelerated approval to regular approval based on the results of PALOMA-2 has been submitted to the FDA.

IBRANCE also is approved in the U.S. for the treatment of HR+, HER2-advanced or metastatic breast cancer in combination with fulvestrant in women with disease progression following endocrine therapy based on results from the Phase 3 PALOMA-3 study.2

Since the initial approval in February 2015, more than 40,000 women have been prescribed IBRANCE by more than 8,500 prescribers in the U.S.

As previously disclosed, the European Commission has approved IBRANCE for the treatment of women with HR+, HER2- locally advanced or metastatic breast cancer. The approval is for IBRANCE to be used in combination with an aromatase inhibitor. The approval also covers the use of IBRANCE in combination with fulvestrant in women who have received prior endocrine therapy. In total, IBRANCE is approved in more than 50 countries.

About PALOMA-2

PALOMA-2 is a randomized (2:1), multicenter, multinational, double-blind Phase 3 study designed to assess the PFS of IBRANCE (125 mg orally once daily for three out of four weeks in repeated cycles) in combination with letrozole (2.5 mg once daily continuously) versus letrozole plus placebo as a first-line treatment for postmenopausal women with ER+, HER2- metastatic breast cancer. PALOMA-2 evaluated a total of 666 women from 186 global sites in 17 countries.

The full prescribing information for IBRANCE can be found at www.pfizer.com.

About IBRANCE (palbociclib) 125 mg capsules

IBRANCE is the first and only FDA approved oral inhibitor of CDKs 4 and 6,2 which are key regulators of the cell cycle that trigger cellular progression.3,4 In the U.S., IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.2 The indication in combination with letrozole is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, PALOMA-2.2

Important IBRANCE (palbociclib) Safety Information from the U.S. Prescribing Information

Neutropenia was the most frequently reported adverse reaction in PALOMA-1 (75%) and PALOMA-3 (83%). In PALOMA-1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in PALOMA-1 (5%) and in patients treated with IBRANCE plus fulvestrant in PALOMA-3 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-1 of IBRANCE plus letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-1 reported at a higher incidence in the IBRANCE plus letrozole group vs the letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (4%) and diarrhea (2%).

Lab abnormalities occurring in PALOMA-1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased WBC (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-3 reported at a higher incidence in the IBRANCE plus fulvestrant group vs the fulvestrant plus placebo group included neutropenia (66% vs 1%) and leukopenia (31% vs 2%). The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Lab abnormalities occurring in PALOMA-3 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

On November 16, 2016 GTx, Inc. (Nasdaq: GTXI) reported the achievement of the Stage 1 milestone for the 18 mg cohort of its Phase 2 clinical trial of enobosarm (GTx-024) to treat women with advanced, estrogen receptor positive (ER+), androgen receptor positive (AR+) breast cancer. A pre-defined number of patients demonstrated clinical benefit per protocol to allow the clinical trial to advance to the second and final stage of the trial (Stage 2) for the 18 mg cohort. In September, GTx announced that it had achieved the Stage 1 milestone for the 9 mg cohort of the clinical trial, and that it was enrolling patients in the second and final stage for that dose group. The Company anticipates reporting Stage 1 data from the 9 mg dose group in December 2016.

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"The demonstration of clinical benefit among a pre-defined number of evaluable patients in Stage 1 of both the 9 mg and 18 mg cohorts of our ER+/AR+ breast cancer study continues to validate our belief that enobosarm may provide a new hormonal approach to the treatment of this advanced breast cancer," said Robert J. Wills, Ph.D., Executive Chairman of GTx. "We look forward to reporting top-line data from Stage 1 of the 9 mg cohort in the study later this year."

About the Phase 2 Clinical Trial in ER+/AR+ Breast Cancer

The open-label, multi-center, multinational Phase 2 clinical trial (NCT02463032) will assess the efficacy and safety of orally administered enobosarm in up to 88 evaluable patients with metastatic or locally advanced, ER+/AR+ breast cancer. Patients will receive orally-administered enobosarm (9 mg or 18 mg) daily for up to 24 months. The two dose cohorts in the trial will be treated independently for the purpose of assessing efficacy. The first stage of evaluation will be assessed among the first 18 evaluable patients for each cohort. If at least 3 of 18 patients achieve clinical benefit at week 24, then the trial will proceed to the second stage of enrollment for that cohort to assess clinical benefit in a total of 44 evaluable patients per arm. Clinical benefit is defined as a complete response, partial response, or stable disease, as measured by Response Evaluation Criteria in Solid Tumors (RECIST) at 24 weeks. The lead investigator for the trial is Dr. Beth Overmoyer from the Dana Farber Cancer Institute and the Harvard Medical School.

About enobosarm

Enobosarm, a selective androgen receptor modulator (SARM), has been evaluated in 24 completed or ongoing clinical trials enrolling over 1,500 subjects, of which approximately 1000 subjects were treated with enobosarm at doses ranging from 0.1 mg to 100 mg. At all evaluated dose levels, enobosarm was observed to be generally safe and well tolerated.

Previously, enobosarm 9 mg has been tested in a Phase 2, proof of concept clinical trial of 22 postmenopausal women with ER+ metastatic breast cancer who have previously responded to endocrine therapy. Seventeen of the 22 patients were confirmed to be AR+, and 6 of those 17 patients demonstrated clinical benefit at six months. In total, 7 patients (one patient with indeterminate AR status) achieved clinical benefit at six months. The results also demonstrated that, after a median duration on study of 81 days, 41 percent of all patients (9/22) achieved clinical benefit as best response and also had increased PSA which appears to be an indicator of AR activity. Enobosarm was well tolerated. The most common adverse events reported were pain, fatigue, nausea, hot flash/night sweats, and arthralgia.

About ER+/AR+ Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women, and one in eight women will develop invasive breast cancer in their lifetime. In 2012, 1.7 million women world-wide were diagnosed with breast cancer, and there were 6.3 million women alive who had been diagnosed with breast cancer in the previous five years. Clinical assessment of breast cancer provides for routine characterization of receptor status, including the presence or absence of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) in the tumor tissue. Receptor status is used to assess metastatic potential as well as to guide treatment decisions. The majority of breast cancers are considered hormone receptor positive (expressing ER or progesterone receptor). Approximately 70 percent of women in the U.S. with breast cancer have ER+ tumors, and 75 to 90 percent of these cancers are also AR+.

Estrogen promotes the growth of breast cancers that are hormone receptor positive. Therefore, treatment is directed at blocking the effects of estrogen on the breast cancer either through blocking the estrogen receptor or minimizing the production of estrogen. This endocrine therapy is the cornerstone of treatment for the majority of women with hormone receptor positive advanced breast cancer and is the preferred initial treatment over alternative approaches such as chemotherapy, due to its efficacy and favorable safety profile. Patients who respond to one endocrine therapy are likely to respond to subsequent hormonal therapies. Therefore, the standard of care for women with hormone receptor positive breast cancer typically involves the sequencing of endocrine agents until intolerance or development of resistance occurs, or metastatic progression necessitates a transition to chemotherapy.

Enobosarm may offer an alternate hormonal approach for the treatment of endocrine sensitive advanced breast cancer prior to the introduction of chemotherapy.

On November 16, 2016 Bristol-Myers Squibb Company (NYSE:BMY) and Enterome, a pioneer in the development of pharmaceuticals and diagnostics based on the gut microbiome, reported that they have entered into an Immuno-Oncology focused collaboration agreement for the discovery and development of microbiome-derived biomarkers, drug targets and bioactive molecules to be developed as potential companion diagnostics and therapeutics for cancer (Press release, Bristol-Myers Squibb, NOV 16, 2016, View Source [SID1234516620]). Additionally, the collaboration will seek to identify novel microbiome-derived biomarkers in an effort to improve clinical outcomes for patients treated with Bristol-Myers Squibb’s Immuno-Oncology portfolio.

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The collaboration will combine Bristol-Myers Squibb’s expertise in the discovery and development of novel immunotherapies with Enterome’s proprietary metagenomic technology platform and leadership in the rapidly advancing science of the gut microbiome to support the discovery of novel immunotherapy agents and biomarkers. There is a growing body of scientific evidence to suggest that the gut microbiome plays an important role in modulating mechanisms of response and resistance to cancer immunotherapies. Changes in a host’s immune system driven by the gut microbiome can be exploited to identify specific targets and bioactive compounds with the potential to augment anti-cancer immune responses.

"We continue to pursue the full potential of Immuno-Oncology by applying rapidly evolving science, technology and research to our strong foundation in harnessing the immune system to fight cancer," said Carl Decicco, Ph.D., head of discovery at Bristol-Myers Squibb. "Business development has been integral in partnering external innovation with our internal R&D expertise and capabilities. Enterome’s focus on target identification and validation along with their significant experience in microbiome research can help to advance our goal to improve outcomes for patients treated with immunotherapies."

"We are delighted to collaborate with Bristol-Myers Squibb to help advance the field of Immuno-Oncology," said Pierre Belichard, chief executive officer at Enterome. "The exciting combination of Bristol-Myers Squibb’s extensive capabilities in Immuno-Oncology with our expertise in identifying novel targets and molecules derived from the gut microbiome is highly complementary, and offers a unique opportunity to develop a new generation of cancer drugs and diagnostics."

Under the terms of the agreement, Bristol-Myers Squibb will be granted exclusive rights to intellectual property and therapies generated during the collaboration. Enterome will receive an upfront payment of $15 million for access to its technology plus R&D funding. Enterome is also eligible to receive preclinical and clinical milestone payments for each licensed therapeutic candidate plus royalties on net sales. Enterome is eligible for additional milestone payments in relation to new diagnostic products discovered and developed during the collaboration. Further details of the agreement were not disclosed.

About the Microbiome and Immuno-Oncology

In the past decade, an explosion of research in the microbiome field has revealed a remarkable symbiotic relationship between the gut bacteria and its human host, enhancing biotech companies’ interest in manipulating this relationship to improve human health. Scientists have shown that the gut microbiome plays an important role in regulating metabolism, influencing the chemistry in the brain, acting as a barrier to pathogens and regulating the immune system. In the cancer context, recent publications have demonstrated the role of the intestinal microbiome in mediating immune activation in response to chemotherapeutic agents. New cancer immunotherapies have improved outcomes in cancer patients and their combination with microbiome-based therapeutics may help to boost the immune system and potentially lead to improved outcomes in more patients.