On December 9, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported results of a large head-to-head study comparing the efficacy of six tests used to predict the recurrence of breast cancer (Press release, Myriad Genetics, DEC 9, 2016, View Source [SID1234517014]). A key finding was that EndoPredict (EPclin), a second-generation test, was superior to Oncotype Dx (RS), a first-generation test, in predicting the long-term recurrence of breast cancer. The results are being featured today in a podium presentation at the 2016 San Antonio Breast Cancer Symposium (SABCS) in San Antonio, Texas.

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"In this important study, EndoPredict more accurately predicted the risk of breast cancer recurrence than the first-generation Oncotype Dx test, particularly in years five to 10 following surgery when half of breast cancer recurrences will happen," said Johnathan Lancaster, M.D., Ph.D., chief medical officer, Myriad Genetic Laboratories. "Clinicians can consider using EndoPredict to identify patients who can forgo chemotherapy with confidence, knowing they have a low risk of recurrence over 10 years."

Podium Presentation
Title: Comprehensive comparison of prognostic signatures for breast cancer in TransATAC.
Presenter: Ivana Sestak, Ph.D.
Date: Friday, Dec.9, 2016: 4:15 p.m. CT.
Location: S6-05; General Session 6 – Hall 3.

This study was led by scientists at the Institute of Cancer Research in London. The analysis included 818 women with ER+/HER2- breast cancer (591 node-negative; 227 node-positive) from the TransATAC study and compared the power of six predictive signatures, including: clinical treatment score, immunohistochemical markers, Oncotype Dx recurrence score (RS), breast cancer index (BCI), Prosigna and EndoPredict (EPClin). Distant recurrence of breast cancer was the primary endpoint and the median follow-up period was 10 years.

Overall, each of the three second-generation tests evaluated (breast cancer index, Prosigna and EndoPredict) outperformed Oncotype Dx in this cohort in predicting the recurrence of breast cancer in both node-negative and node-positive patients across both zero to 10 and five to 10 years post-surgery. In a head-to-head comparison between EndoPredict and Oncotype Dx in this study:

EndoPredict offered more predictive power than Oncotype Dx across zero to 10 years.
The data show that the likelihood ratio (LRx2, a common measure of predictive power) for EndoPredict was almost double that of Oncotype Dx in node-negative patients (EndoPredict: LRX2= 40.6; Oncotype: LRX2=22.8) and was five times higher in node-positive patients (EndoPredict: LRX2= 35.6; Oncotype: LRX2=6.4).

EndoPredict had superior predictive power over Oncotype Dx between five to 10 years.
The likelihood ratio for EndoPredict was seven times higher than for Oncotype Dx in node-negative patients (EndoPredict: LRX2= 24.0; Oncotype: LRX2=3.4) and 13 times higher in node-positive patients (EndoPredict: LRX2= 14.9; Oncotype: LRX2=1.1). Importantly, the likelihood ratio for Oncotype DX failed to achieve statistical significance in predicting cancer recurrence in years five to 10 for either node-positive or node-negative patients, indicating an inability to predict distant recurrence over the five to 10 year timeframe.

EndoPredict was superior in classifying node-positive patients as low-risk compared to Oncotype Dx.
Node-positive patients classified as low risk by EndoPredict had a substantially lower 10-year recurrence rate (5.6 percent) than patients classified as low risk by Oncotype Dx (26.2 percent) as well as a lower five to 10 year recurrence rate (3.3 percent for EndoPredict vs 17.9 percent for Oncotype Dx).
"Myriad is committed to research that improves care for patients with breast cancer. Patients at high risk of cancer recurrence are candidates for adjuvant chemotherapy after surgery, while those at low risk can be spared chemotherapy and the side effects," said Lancaster. "We believe EndoPredict will help clinicians and patients understand the risk of breast cancer recurrence and identify more patients who can safely forgo chemotherapy. Additionally, EndoPredict does not contain an intermediate risk category and each patient receives a clear test result, allowing oncologists to confidently develop their treatment plan."

The TransATAC study, in part, was previously published in the Journal of the National Cancer Institute (View Source). The current presentation at SABCS expands on that article and provides a comprehensive comparison of prognostic signatures for breast cancer. Follow Myriad on Twitter via @MyriadGenetics and stay informed about symposium news and updates by using the hashtag #SABCS16.

On December 9, 2016 Novartis reported additional analyses from the Phase III MONALEESA-2 study that show LEE011 (ribociclib) plus letrozole significantly prolonged progression-free survival (PFS) across pre-planned patient subgroups with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer, including post-menopausal women diagnosed de novo, those with visceral liver and lung metastases, and those with bone-only disease[1],[2] (Press release, Novartis, DEC 9, 2016, View Source [SID1234517015]).

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These findings demonstrate the strength of LEE011 plus letrozole in the first-line setting, showing that treatment benefit was evident across all patient subgroups regardless of their disease burden or tumor location, including those patients with aggressive disease. Data will be presented today at the San Antonio Breast Cancer Symposium (SABCS) (Abstracts P4-22-05 and P4-22-16).

"Results from the de novo subgroup of women in the MONALEESA-2 trial establish ribociclib in combination with letrozole as a meaningful treatment option in the first-line setting for this patient population," said Joyce O’Shaughnessy, MD, Co-Chair, Breast Cancer Research, Texas Oncology-Baylor Charles A. Sammons Cancer Center. "These de novo patients are often diagnosed initially with advanced breast cancer that has already metastasized, so it is critical to start them with treatments that extend time until disease progression."

"Breast cancer that has metastasized to areas such as the liver or lungs can often be more challenging to effectively treat with current standards of care," said Howard A. Burris, MD, President, Clinical Operations and Chief Medical Officer, Sarah Cannon. "We have been encouraged by the MONALEESA-2 results because treatment benefit was observed regardless of the number of metastatic sites and was maintained across all subgroups taking ribociclib plus letrozole. Our observations indicate that this novel therapy may be a promising treatment option for many patients living with advanced forms of breast cancer."

First-line ribociclib + letrozole in patients with de novo HR+, HER2- advanced breast cancer: A subgroup analysis of the MONALEESA-2 trial (Abstract P4-22-05)
A predefined subgroup analysis of the MONALEESA-2 trial evaluated the safety and efficacy of LEE011 plus letrozole versus letrozole alone in 227 patients with de novo advanced breast cancer, defined as disease found to be metastatic at the time of first diagnosis[1]. Because de novo disease has not been previously treated with systemic treatment for early-stage breast cancer, tumors may exhibit a different disease biology, which could result in varied responses compared to patients who experienced recurrence[1]. In patients with de novo advanced breast cancer, LEE011 plus letrozole reduced the risk of disease progression or death by 55% over letrozole alone (HR=0.448 [95% CI: 0.267-0.750])[1]. The 12-month PFS rate was 82% in the LEE011 plus letrozole arm compared to 66% with letrozole alone.

Consistent with the overall study population, most adverse events were mild to moderate in severity, identified early through routine monitoring, and generally managed through dose interruption and reduction[1]. The most common grade 3/4 adverse events (>=15% of patients with de novo advanced breast cancer; LEE011 plus letrozole vs. letrozole alone) were neutropenia (55.3% vs. 0.9%) and leukopenia (21.1% vs. 0%)[1].

First-line ribociclib + letrozole in patients with HR+, HER2- advanced breast cancer presenting with visceral metastases or bone-only disease: A subgroup analysis of the MONALEESA-2 trial (Abstract P4-22-16)
In separate predefined subgroups, 393 patients with advanced breast cancer with visceral metastases and 147 patients with bone-only disease were evaluated as part of the MONALEESA-2 trial. Those with visceral metastases have metastatic growth at the site of the lung or liver, and typically have a poorer prognosis than patients with non-visceral disease[2]. Results of these analyses show that first-line LEE011 plus letrozole was well tolerated and reduced the risk of disease progression or death by 47% (patients with visceral disease: HR=0.535 [95% CI: 0.385-0.742]) and by 31% (patients with bone-only disease: HR=0.690 [95% CI: 0.381-1.249]) respectively[2]. Treatment benefit with LEE011 in combination with letrozole was observed regardless of the number of metastatic sites and (HR=0.607 (95% CI: 0.437-0.845) among patients with less than 3 metastases; HR=0.456 (95% CI: 0.298-0.700) among patients with 3 or more metastases)[2].

Among patients with visceral metastases the most frequent grade 3/4 adverse events (>=20% of patients; LEE011 plus letrozole vs. letrozole alone) were neutropenia (64.0% vs 1%) and leukopenia (20.8% vs 0.5%)[2]. Among patients with bone-only disease the most frequent grade 3/4 adverse events (>=20% of patients; LEE011 plus letrozole vs. letrozole alone) were neutropenia (53.6% vs 1.3%) and leukopenia (23.2% vs 1.3%)[2].

"These additional results from the MONALEESA-2 study are very promising for women with HR+ advanced breast cancer," said Bruno Strigini, CEO, Novartis Oncology. "We believe LEE011 could significantly benefit a broad range of women as an initial treatment for metastatic breast cancer and look forward to working with global health authorities to bring this new treatment to patients."

The MONALEESA-2 study is ongoing to evaluate secondary endpoints, including overall survival. LEE011 received Breakthrough Therapy designation from the US Food and Drug Administration (FDA) in August 2016 and Priority Review in October 2016.

About LEE011 (ribociclib)
LEE011 (ribociclib) is a selective cyclin dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated in a cell, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring cancer cells do not grow uncontrollably.

LEE011 is not approved for any indication in any market at this time. LEE011 was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About the MONALEESA Clinical Trial Program
Novartis is continuing to assess LEE011 through the robust MONALEESA (Mammary ONcology Assessment of LEE011’s Efficacy and SAfety) clinical trial program, which includes MONALEESA-2, MONALEESA-3, and MONALEESA-7. These trials are evaluating LEE011 in multiple endocrine therapy combinations across a broad range of patients, including men and premenopausal women.

MONALEESA-2 is a Phase III randomized, double blind, placebo controlled, multicenter global registration trial to evaluate the safety and efficacy of LEE011 in combination with letrozole compared to letrozole alone in postmenopausal women with HR+/HER2- advanced breast cancer who received no prior therapy for their advanced breast cancer[3].

The trial randomized 668 patients in a 1:1 ratio stratified by the presence of liver and/or lung metastases at 223 clinical trial sites globally[3]. Patients received LEE011 600 mg/daily (three weeks on and one week off), or placebo, in combination with letrozole 2.5 mg/daily.

The primary endpoint of the trial was PFS[3]. Secondary endpoints included: overall survival, overall response rate, clinical benefit rate, health-related quality of life, safety and tolerability[3].

In MONALEESA-2, the most common grade 3/4 (most severe) adverse events were as follows for LEE011 plus letrozole compared to letrozole alone: neutropenia (60% vs 1%), leukopenia (21% vs 1%), elevated alanine aminotransferase (9% vs 1%), lymphopenia (7% vs 1%) and elevated aspartate aminotransferase (6% vs 1%)[1]. The most common all-grade adverse events (>=35% of patients in either arm, regardless of relationship to study treatment) were as follows for LEE011 plus letrozole compared to letrozole alone: neutropenia (74% vs 5%), nausea (52% vs 29%), infections (50% vs 42%), fatigue (37% vs 30%), and diarrhea (35% vs 22%)[1]. Nausea, infections, fatigue, and diarrhea were mostly grade 1 or 2[1].

The MONALEESA-3 trial is a phase III trial evaluating LEE011 in combination with fulvestrant compared to fulvestrant alone in men and post-menopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy.

MONALEESA-7, the largest phase III trial of a CDK4/6 inhibitor in this patient population, is investigating LEE011 in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in pre-menopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy. Both MONALEESA-3 and MONALEESA-7 are fully enrolled.

About Advanced Breast Cancer
Up to one-third of patients with early-stage breast cancer will subsequently develop metastatic disease[4]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[5]. Advanced breast cancer comprises metastatic breast cancer (stage 4) and locally advanced breast cancer (stage 3)[5]. Survival rates for women living with advanced breast cancer are lower than those for women with earlier stage disease. The 5-year relative survival rate for stage 3 breast cancer is approximately 72%, while metastatic (stage 4) breast cancer has a 5-year relative survival rate of approximately 22%[6].

Myovant Sciences has filed a 10-Q – Quarterly report [Sections 13 or 15(d)] with the U.S. Securities and Exchange Commission (Filing, 10-Q, Myovant Sciences, 2017, DEC 9, 2016, View Source [SID1234522023]).

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On December 9, 2016 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that the company will host a live conference call and webcast on Monday, December 12, 2016 at 8:30 a.m. EST (5:30 a.m. PST) to discuss recent CB-839 clinical data presentations at the San Antonio Breast Cancer Symposium, the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium, and other recent corporate highlights and business developments (Press release, Calithera Biosciences, DEC 9, 2016, View Source;p=RssLanding&cat=news&id=2228746 [SID1234517011]).

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The live audio webcast can be accessed via the Investor section of the Company’s website at www.calithera.com. The conference call can be accessed by dialing (855) 783-2599 (domestic) or (631) 485-4877 (international) and refer to conference ID 36690670. Please log in approximately 5-10 minutes before the event to ensure a timely connection. The archived webcast will remain available for replay on Calithera’s website for 30 days.

On December 8, 2016 PellePharm, a clinical-stage biopharmaceutical company committed to developing patidegib, a topical hedgehog inhibitor to treat basal cell carcinomas (BCCs), including those in Gorlin Syndrome, a devastating orphan disease, reported its launch with financing from BridgeBio Pharma (Press release, BridgeBio, DEC 8, 2016, View Source [SID1234527852]). This financing supports the development of topical patidegib through the completion of two phase 2 clinical trials that are underway, including a clinical trial in Gorlin Syndrome that just completed enrollment. In addition, the company has a drawable pool of capital from BridgeBio Pharma that enables it to finance future clinical trials through registration.

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PellePharm was founded by a team of globally recognized experts in dermatology, oncology and hedgehog signaling and is managed by a team of industry experts. The company is dedicated to finding an effective therapy to manage the extensive tumor burden in Gorlin Syndrome, a rare genetic disease that causes patients to develop multiple BCCs. Gorlin Syndrome affects about 10,000 people in the United States and 15,000 people in the European Union. The disease results from a mutation in a tumor-suppressor gene, which acts as the primary inhibitor of the hedgehog signaling pathway. PellePharm’s founders developed a topical gel formulation of a proprietary hedgehog inhibitor that it exclusively licensed from Infinity Pharmaceuticals to help mitigate certain adverse events observed with oral hedgehog inhibitors.

"It made sense that a potent inhibitor of the hedgehog pathway should provide a therapeutic benefit for patients suffering from Gorlin Syndrome, but we needed an approach that would allow us to target the disease at its source without eliciting harmful toxicity reactions," said Ervin Epstein, M.D., co-founder of PellePharm. "We are hopeful that patidegib will provide the balance of targeted treatment without the adverse events associated with oral formulations."

PellePharm’s approach attracted the attention of industry veterans Mark de Souza, Ph.D. and Karl Beutner, M.D., Ph.D. who joined the team. "It’s not often that you find a program as attractive as PellePharm’s patidegib," said de Souza, executive chairman of PellePharm. "This investigational treatment has the potential to address a very high unmet need among patients with Gorlin Syndrome, whose current standard of care is to undergo multiple surgeries each year to manage their symptoms. We know that hedgehog pathway inhibitors have therapeutic potential for this condition, and we believe PellePharm’s topical formulation may offer a truly effective treatment option for these patients."

PellePharm is currently conducting two double-blinded, placebo-controlled, randomized, phase 2 clinical trials that are evaluating the safety, tolerability and effect of topical patidegib on both pre-existing tumors and the frequency of the development of new tumors. A U.K.-based study is evaluating 18 patients with Gorlin syndrome to determine whether the product shrinks the tumors present at the beginning of the study and reduces the number of new tumors that develop during the trial. A U.S.-based study is evaluating 36 patients with sporadic BCCs to determine whether tumor diameter decreases after 12 weeks of treatment. Both studies also will evaluate safety and tolerability, as well as a biomarker (GLI-1) of hedgehog signaling. Enrollment in the U.K. trial is complete and topline data is expected in the second quarter of 2017.

"PellePharm is really at the intersection of precision oncology and monogenic dermatology – these are the types of assets we look for at BridgeBio Pharma," said Frank McCormick, investment committee member of BridgeBio Pharma and board member of PellePharm. "Gorlin Syndrome is a well-researched disease that can be treated directly at its source. We have had the privilege of knowing the founding and operating team of PellePharm for years and look forward to working with them to bring patidegib to patients in need."

Founders and Scientific Advisory Board Members
PellePharm was founded by a group of globally recognized experts in dermatology, oncology and hedgehog signaling who continue to lend expertise and counsel to the PellePharm management team. Founders and scientific advisory board members include:

Philip Beachy, Ph.D., professor of biochemistry and developmental biology, Stanford University
Ervin Epstein, M.D., senior scientist, Children’s Hospital of Oakland Research Institute
Jean Tang, M.D., Ph.D., associate professor of dermatology, Stanford University
About Basal Cell Carcinomas (BCCs) and Gorlin Syndrome
Basal cell carcinomas (BCCs) are a type of skin cancer that begins when one of the skin cells spontaneously develops a mutation in its DNA, usually due to UV radiation (sunlight, tanning lamps). They commonly occur in sun-exposed areas like the face and neck and generally in people of European descent with lighter skin and in the elderly and in people with chronic sun exposure. There are more than four million BCCs diagnosed in the United States each year. BCCs are usually treated with surgery, which can leave disfiguring scars.

Gorlin Syndrome, also known as nevoid basal cell carcinoma syndrome, is a rare genetic disease where patients develop many BCCs. Patients with Gorlin Syndrome have heritable mutations in the tumor suppressor gene encoding Patched1 (PTCH1), which acts as the primary inhibitor of the hedgehog signaling pathway; this leads to hundreds of BCCs, especially on the face and sun-exposed areas. The standard of care is surgery, as there are no FDA-approved drugs for Gorlin Syndrome. Individuals who have severe Gorlin Syndrome have as many as 30 surgeries per year, many of which can be scarring.