On December 6, 2018 Novocure (NASDAQ:NVCR) reported that the results of a retrospective post-hoc sub-group analysis of its EF-14 phase 3 pivotal trial in newly diagnosed glioblastoma (GBM) have been published in the Journal of Neuro-Oncology (Press release, NovoCure, DEC 6, 2018, View Source [SID1234531931]). The analysis demonstrated that more time on Optune predicted increased survival in patients who received Optune plus temozolomide compared to patients who received temozolomide alone. Optune is a noninvasive, portable medical device that delivers Tumor Treating Fields to people with GBM. Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt cell division, inhibiting tumor growth and causing certain cancer cells to die.

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"The total amount of time the device is worn, also known as monthly Optune usage – or treatment compliance – matters greatly for patients with GBM, one of the most aggressive forms of cancer," said Steven A. Toms, MD, Professor of Neurosurgery and Medicine, and Vice Chair of the Department of Neurosurgery at Lifespan Health System, and the Warren Alpert Medical School of Brown University in Providence, Rhode Island, and author of the article. "Optune plus temozolomide has proven to provide long-term quality survival to patients with newly diagnosed GBM. Therefore, the importance of monthly Optune usage should be reinforced with patients by their health care providers."

Data from this sub-group analysis demonstrated that patients using Optune 50 percent or more of the time had a survival benefit compared to those who used temozolomide alone (n=388/450, OS HR 0.67, 95% CI 0.45–0.99). Patients who used Optune more than 90 percent of the time experienced a median overall survival of 24.9 months (n=43; OS HR 0.52, 95 percent CI 0.35–0.79) and a predicted 5-year survival rate of 29.3 percent versus a median overall survival of 16.0 months and a predicted 5-year survival rate of 4.5 percent for patients who used temozolomide alone. Monthly usage was a predictor of survival, independent of other prognostic factors such as Karnofsky Performance Status, age or MGMT methylation status.

Novocure’s phase 3 pivotal EF-14 trial compared Optune in combination with temozolomide to temozolomide alone in a total of 695 patients with newly diagnosed GBM. The trial was designed to test both progression free survival and overall survival. The trial demonstrated unprecedented five-year survival results in newly diagnosed GBM for those patients treated with Optune in combination with temozolomide. Those patients experienced an extension of overall survival without added systemic toxicity compared to patients treated with temozolomide alone. The data also showed that Optune-treated patients were able to maintain their mental, emotional and physical well-being longer than those treated with temozolomide alone, as measured for up to one year.

On December 6, 2018 Novartis reported additional analysis from the global Phase III SOLAR-1 trial investigating the alpha-specific PI3K inhibitor BYL719 (alpelisib) in combination with fulvestrant in men and postmenopausal women with PIK3CA mutated hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer (Press release, Novartis, DEC 6, 2018, https://www.novartis.com/news/media-releases/novartis-investigational-byl719-alpelisib-plus-fulvestrant-consistently-improved-pfs-patients-pik3ca-mutated-hrher2-advanced-breast-cancer-new-solar-1-analyses [SID1234531929]).

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In SOLAR-1, the addition of BYL719 to fulvestrant nearly doubled median progression-free survival (PFS) in patients with PIK3CA mutated HR+/HER2- advanced breast cancer who progressed on or after an aromatase inhibitor (AI) compared to fulvestrant alone. In this analysis, BYL719 plus fulvestrant also showed consistent clinically meaningful treatment benefit after progression on an AI or after receiving up to one additional line of therapy for advanced breast cancer[1]. These data will be presented today during an oral presentation at the 2018 San Antonio Breast Cancer Symposium (SABCS) (Abstract #GS3-08).

Approximately 40% of patients living with HR+ advanced breast cancer have a PIK3CA mutation, which over activates the PI3K pathway[2]. When activated, the PI3K pathway is associated with tumor growth, resistance to endocrine treatment and a poor overall prognosis[3],[4]. Currently there are no approved treatments for breast cancer that specifically target this mutation.

"PIK3CA mutation is the most common actionable alteration in ER+ breast cancer, so it is encouraging to see a meaningfully prolonged PFS with BYL719 combination therapy in patients with PIK3CA mutated breast cancer who progressed on an aromatase inhibitor and who received up to one additional line of therapy prior to treatment with BYL719 plus fulvestrant," said Dejan Juric, MD, Director, Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center. "With the SOLAR-1 trial results, we can confidently say that identifying and targeting PIK3CA mutations is clinically important as we apply the precision oncology paradigm to breast cancer and continuously look for new treatment solutions to extend the lives of patients with this disease."

BYL719 in combination with fulvestrant consistently improved median PFS in patients with PIK3CA mutated HR+/HER2- advanced breast cancer who progressed within 12 months of AI treatment (mPFS: 11.0 months vs 6.8 months for fulvestrant alone) or received up to one additional line of therapy for advanced breast cancer (mPFS: 10.9 months vs 3.7 months, respectively).

Most adverse events were mild to moderate in severity and generally manageable through dose interruption, dose reductions and medical management. Treatment discontinuation rate due to adverse events in those with a PIK3CA mutation receiving BYL719 plus fulvestrant was 3% compared to 2% for fulvestrant alone. The most frequent all-grade adverse events (>=40%) were hyperglycemia (65% vs 9%), diarrhea (54% vs 11%), nausea (46% vs 20%) and rash (40% vs 6%). The most common grade 3/4 events (>=10%) were hyperglycemia (37% vs <1%) and rash (13% vs <1%)[1].

Mutation status of participants in SOLAR-1 was identified by a clinical trial assay developed by Qiagen*. A significant PFS benefit was observed for BYL719 plus fulvestrant in patients with a PIK3CA mutation regardless of whether the mutation was identified by a tumor tissue test or ctDNA test, suggesting the potential viability of using liquid biopsies to identify PIK3CA mutation status (tissue positive HR=0.65; mPFS 11.0 months; plasma positive HR=0.56; mPFS 10.9 months)[1].

Novartis has entered into agreements with both Qiagen and Foundation Medicine** to develop flexible companion diagnostic solutions for BYL719 that utilize both tumor tissue and plasma sample types.

"Our work to develop an effective PI3K inhibitor started more than two decades ago, and learning from multiple clinical trial experiences, we have been able to advance an investigational targeted therapy for patients with this specific breast cancer," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "SOLAR-1 is the first breast cancer trial to show potential utility of liquid biopsies. We are excited to collaborate with Qiagen and Foundation Medicine on tissue and plasma tests that, if approved, may help oncologists identify patients who could benefit from BYL719 plus fulvestrant."

The SOLAR-1 trial is ongoing to evaluate secondary endpoints, including overall survival and will be presented and discussed in the future. Overall survival (OS) results were immature at the time of data cut-off after 52% of events (HR=0.73; 95% CI 0.48-1.10; p=0.06; median not estimable vs 26.9 months). The prespecified O’Brien-Fleming stopping boundary was not crossed. Discussions with health authorities regarding the SOLAR-1 data have begun.

About SOLAR-1
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying investigational BYL719 in combination with fulvestrant for postmenopausal women with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor[1].

The trial randomized 572 patients. Patients were allocated based on tumor tissue assessment to either a PIK3CA-mutated cohort or a PIK3CA non-mutated cohort. Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with BYL719 (300mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant. Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment[1].

The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with a PIK3CA mutation. Secondary endpoints include but are not limited to overall survival, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety and tolerability[1].

For the primary SOLAR-1 analysis, mutation status was determined by tumor tissue via polymerase chain reaction (PCR) analysis. Plasma ctDNA samples were also collected at baseline as a secondary endpoint. Plasma ctDNA mutation status of participants in SOLAR-1 was identified by an assay developed by Qiagen.

About BYL719 (alpelisib)
BYL719 is an investigational, orally bioavailable, alpha-specific PI3K inhibitor. In breast cancer cell lines harboring PIK3CA mutations, BYL719 has been shown to potentially inhibit the PI3K pathway and have antiproliferative effects. In addition, cancer cell lines with PIK3CA mutations were more sensitive to BYL719 than those without the mutation across a broad range of different cancers[5].

On December 6, 2018 SELLAS Life Sciences Group, Inc. (Nasdaq: SLS) ("SELLAS" or the "Company"), a clinical-stage biopharmaceutical company focused on the development of novel cancer immunotherapies for a broad range of cancer indications, reported additional data on patterns of clinical relapses (including organ or site of recurrence), as well as results from a preplanned secondary efficacy analysis across various predefined subgroups from the prospective, randomized, single-blinded, controlled Phase 2b independent investigator-sponsored clinical trial of the combination of trastuzumab (Herceptin) +/- nelipepimut-S (NeuVax, NPS) targeting HER2 low-expressing breast cancer patient cohorts at the 41st San Antonio Breast Cancer Symposium (SABCS) in San Antonio, TX (Press release, Sellas Life Sciences, DEC 6, 2018, View Source [SID1234531928]).

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These new data show a decrease in the total number of clinically detectable relapses with the combination of NPS + trastuzumab (7.5%) vs. trastuzumab alone (27.3%), p-value 0.004, which represents a 72.5% relative reduction in risk of relapse across time with a median follow up of 26.1 months in favor of the combination arm. Results from a planned analysis (log-rank) of the difference in disease free survival (DFS) outcomes between the two arms of the study in prespecified TNBC patient subgroups (patients who received neoadjuvant chemotherapy, expressed lower HER2, were 51 years or older, or had AJCC 7th Edition stage I/II TNBC), showed a clinically meaningful and statistically significant effect (p-value range: 0.004 – 0.014) in these subgroups in favor of the NPS plus trastuzumab combination arm. There was an average decrease of 84.2% in the relative risk of relapse or death at 24 months across these four subgroups of TNBC patients treated with NPS plus trastuzumab vs trastuzumab alone. The full data are summarized in the table below:

Comparison between NPS + trastuzumab vs. trastuzumab arms
Patient subgroups within the TNBC cohort Hazard Ratio (HR) HR 95% Confidence Interval P-value
(difference in favor of NPS + trastuzumab) Decrease in relative risk of relapse or death at 24 mos. (in favor of NPS + trastuzumab)
Received Neoadjuvant Chemotherapy 0.226 0.063 – 0.815 0.013 78.1%
Harbored BC with HER2 IHC 1+ expression level 0.178 0.038 – 0.837 0.014 81.3%
Aged ≥ 51 years 0.144 0.031 – 0.656 0.004 77.4%
AJCC 7 Stage I/II at diagnosis Incalculable* N/A 0.006 100%
*no DFS events occurred in AJCC 7 stage I/II TNBC patients treated with NPS plus trastuzumab.

"These new data provide insights on the pattern of clinically detectable relapses across various sites/organs, as well as add to our knowledge of the specific potential benefit distribution within the TNBC cohort. The results in four predefined TNBC subgroups inform us of the types of TNBC patients with residual disease after neoadjuvant chemotherapy who may potentially benefit when treated with NPS plus trastuzumab in the adjuvant setting. As previously announced, we are on track to meet with the U.S. Food and Drug Administration this month on the most expeditious and appropriate development path for NPS in TNBC," said Nicholas J. Sarlis, MD, PhD, Executive Vice President and Chief Medical Officer of SELLAS.

"We are very pleased with the results of these new analyses which indicate that the NPS plus trastuzumab combination – when given in the adjuvant setting after frontline therapy – could potentially improve outcomes across specific predefined subgroups of patients with early-stage TNBC, an aggressive subtype of breast cancer. The clinically meaningful and statistically significant decrease in the frequency of clinically detectable relapses – with a median follow-up of over 26 months – indicates a high degree of internal consistency," commented Elizabeth A. Mittendorf, MD, PhD, Rob and Karen Hale Distinguished Chair in Surgical Oncology, Director of Research, Breast Surgical Oncology Brigham and Women’s Hospital, Director, Breast Immuno-Oncology Program Dana-Farber/Brigham and Women’s Cancer Center, and the Principal Investigator of the Phase 2b study. "The data presented today are consistent with the previously reported beneficial effect seen in the TNBC cohort at large and are consistent with the immunobiological mechanism of action of nelipepimut-S."

Herceptin is a registered trademark of Genentech, Inc. and is not a trademark of SELLAS. The manufacturer of this brand is not affiliated with and does not endorse SELLAS or its products.

SABCS Presentation Information

Date and Time: Thursday, December 6, 2018; 8:00 – 10:00 am ET
Poster Session 2: Treatment: Immunotherapy (clinical)
Poster Hall Location: Hall 1
Abstract ID: P2-09-01
Title: Subgroups analysis of a multicenter, prospective, randomized, blinded phase 2b trial of trastuzumab + nelipeptimut-S (NeuVax) vs. trastuzumab for prevention of recurrence in breast cancer patients

About SABCS

The mission of the SABC Symposium (SABCS) is to provide state-of-the-art information on breast cancer research. Since 2007, the SABCS has been jointly sponsored by the Cancer Therapy & Research Center (CTRC) at the University of Texas Health Science Center – San Antonio, the Baylor College of Medicine and the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

On December 6, 2018 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company focused on the development of oncology drug candidates, all of which are based on license agreements with The University of Texas System on behalf of the M.D. Anderson Cancer Center, reported it has filed a request with the U.S. Food and Drug Administration ("FDA") for Orphan Drug Status for its drug candidate WP1066 (Press release, Moleculin, DEC 6, 2018, View Source [SID1234531927]).

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"Clinical progress with WP1066 has been encouraging," commented Walter Klemp, Moleculin’s Chairman and CEO. "Given its potential to address rare and difficult to treat cancers, including glioblastoma, we believe WP1066 is well positioned to qualify for Orphan Drug Status."

The FDA grants orphan drug designation to drugs and biologics that are intended for the treatment of rare diseases that affect fewer than 200,000 people in the U.S. Orphan drug status is intended to facilitate drug development for rare diseases and may provide several benefits to drug developers, including tax credits for qualified clinical trials costs, exemptions from certain FDA application fees, and seven years of market exclusivity upon regulatory product approval.

On December 6, 2018 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in hematology and oncology, reported that data from the Phase 3 RECOVER clinical study was presented during the 2018 San Antonio Breast Cancer Symposium (SABCS) (Press release, Spectrum Pharmaceuticals, DEC 6, 2018, View Source [SID1234531926]). These data confirm the efficacy and safety of ROLONTIS (eflapegrastim) in reducing the Duration of Severe Neutropenia (DSN) in breast cancer patients treated with chemotherapy. ROLONTIS is a novel, long-acting granulocyte colony-stimulating factor (G-CSF) being studied as a treatment for neutropenia in patients undergoing treatment with myelosuppressive cytotoxic chemotherapy.

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"Despite available treatments, neutropenia remains a critical issue for patients undergoing chemotherapy that puts them at risk for developing life threatening infections," said Lee Schwartzberg, MD, FACP, lead investigator, professor of medicine and division chief, hematology/oncology, University of Tennessee Health Science Center, and executive director, UT/West Cancer Center. "The robust data from both Phase 3 studies demonstrate that ROLONTIS has the potential to be a valuable option in the management of neutropenia for patients undergoing treatment with chemotherapeutic agents."

The data released yesterday in a poster presentation from the ROLONTIS Phase 3 RECOVER study (n=237) showed that in Cycle 1, the mean DSN±SD was 0.31±0.688 days for ROLONTIS and 0.39±0.949 days for pegfilgrastim, demonstrating non-inferiority (p<0.0001). The non-inferiority of ROLONTIS for DSN was maintained across all four treatment cycles (all (p<0.0001)). Incidence of severe neutropenia was 20 percent versus 24 percent in the eflapegrastim and pegfilgrastim arms respectively, with a relative risk reduction of 14 percent in favor of eflapegrastim. There were no statistically significant differences on secondary endpoints such as time to absolute neutrophil count (ANC) recovery, depth of ANC nadir, and incidence of febrile neutropenia between treatment arms across all cycles. None of the ≥Grade 3 study drug related adverse events (AE) occurred in >2% of the patients and included hematologic and bone pain related AEs in both arms.

The RECOVER trial is the second ROLONTIS Phase 3 study to meet the primary efficacy endpoint of non-inferiority in mean DSN. Results from ADVANCE, the first ROLONTIS Phase 3 study, were announced at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and presented at the Multinational Association in Supportive Care in Cancer Annual Meeting (MASCC) earlier this year.

"The RECOVER study is the second Phase 3 study to confirm non-inferiority data and comparable safety profile between ROLONTIS and the current standard of care," said Joe Turgeon, chief executive officer of Spectrum Pharmaceuticals. "Data from both studies, which enrolled 643 patients combined, will be used to support the BLA filing which is expected to be submitted by the end of the year. If approved, we look forward to having a unique opportunity to launch and compete in this large market with the first novel G-CSF in more than 15 years."

About RECOVER

The RECOVER study is a Phase 3, randomized, open-label, active-controlled, multicenter study that enrolled 237 breast cancer patients who received docetaxel and cyclophosphamide chemotherapy every 21 days. Patients were randomized in a 1:1 ratio to receive either ROLONTIS (n=118) or pegfilgrastim (n=119). The primary study endpoint was the DSN in Cycle 1 of chemotherapy (absolute neutrophil count [ANC] <0.5×109/L), based on central laboratory assessment of ANC over a 21 day cycle. There were a total of four cycles evaluated in this study. Secondary endpoints included, the DSN in Cycles 2, 3, and 4, time to ANC recovery, depth of ANC nadir and incidence of febrile neutropenia at cycle one. Patients with stage I to stage IIIA breast cancer were treated on day one of each of the four cycles with adjuvant/neo-adjuvant docetaxel and cyclophosphamide. On day two of each cycle, patients received a single subcutaneous dose of either eflapegrastim 13.2 mg/0.6 mL (equivalent to 3.6 mg G-CSF) or pegfilgrastim (6 mg).