On June 3, 2017 Eli Lilly and Company (NYSE: LLY) reported that results from the Phase 3 MONARCH 2 study showed that abemaciclib, a cyclin-dependent kinase (CDK)4 & 6 inhibitor, in combination with fulvestrant, significantly improved progression-free survival (PFS) compared to treatment with fulvestrant alone in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced breast cancer who have relapsed or progressed after endocrine therapy (median PFS, 16.4 vs. 9.3 months, respectively, HR: 0.553; 95% CI: 0.449, 0.681, P < .0000001) (Press release, Eli Lilly, JUN 3, 2017, View Source [SID1234519366]). The data were presented at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #1000) and simultaneously published online in the Journal of Clinical Oncology.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Metastatic HR+ breast cancer remains a dangerous disease and oncologists are always on the lookout for active new therapies to combat it," said George W. Sledge Jr., M.D., professor of medicine, Stanford University School of Medicine and principal investigator. "I am very impressed with the results from this study. For these patients who progressed on endocrine therapy, there was a significant prolongation of progression-free survival, and more than double the response rate, including an increased rate of complete response."

Patients with measureable disease treated with abemaciclib plus fulvestrant achieved an objective response rate (ORR) of 48.1 percent (3.5% complete response [CR]), compared to 21.3 percent (0% CR) in patients treated with fulvestrant alone. Additionally, abemaciclib plus fulvestrant caused a greater degree of tumor shrinkage than fulvestrant alone.

"One of our goals with the MONARCH clinical development program is not to replicate studies, but rather to further innovate in the field of CDK4 & 6 inhibition and advance potential treatment options for patients wherever they may be in the course of their disease," said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology. "From the single-agent activity seen in MONARCH 1 to the significant MONARCH 2 results shared today, and our ongoing Phase 3 studies, we are committed to working with physicians to evolve treatment expectations for people living with breast cancer."

The global Phase 3, double-blind study was designed to evaluate the efficacy and safety of abemaciclib, in combination with fulvestrant, in patients with advanced (locoregionally recurrent or metastatic) breast cancer. The intent-to-treat population of 669 patients was randomized to receive abemaciclib or placebo orally twice a day on a continuous dosing schedule, given in combination with fulvestrant at its approved dose and schedule, until disease progression. Patients enrolled in the study had experienced disease progression on or within 12 months of receiving endocrine treatment in the neoadjuvant or adjuvant setting or while receiving first-line endocrine therapy for metastatic disease. Patients who had received chemotherapy in the metastatic setting were not eligible for the study. The primary endpoint for MONARCH 2 was PFS.

The most frequent adverse events (AEs) of any grade in the abemaciclib plus fulvestrant arm were diarrhea, neutropenia, nausea, and fatigue. Of these, the reported Grade 3 AEs (abemaciclib vs. placebo arm) were diarrhea (13.4% vs. 0.4%), neutropenia (23.6% vs. 1.3%), nausea (2.7% vs. 0.9%), and fatigue (2.7% vs. 0.4%). No patients in either arm experienced Grade 4 diarrhea, nausea or fatigue, and Grade 4 neutropenia was observed in 2.9 percent versus 0.4 percent of patients in the abemaciclib versus placebo arms, respectively.

Severity and frequency of diarrhea generally decreased following one to two cycles, and was managed with loperamide or dose reduction. The majority (70.1%) of patients in the abemaciclib arm with an AE of diarrhea did not require treatment modification (dose interruption, reduction, or discontinuation), and 2.9 percent of patients discontinued the study drug due to diarrhea.

In addition to the ongoing MONARCH trials, including the newly initiated monarchE adjuvant study, which will assess abemaciclib in patients with high-risk, early breast cancer, Lilly is actively evaluating abemaciclib in lung cancer, pancreatic cancer, and patients with brain metastases.

Notes to Editor

About Advanced Breast Cancer
Breast cancer is the most common cancer in women worldwide with nearly 1.7 million new cases diagnosed in 2012.[1] Advanced breast cancer includes metastatic breast cancer, cancer that has spread from the breast tissue to other parts of the body, and locally or regionally advanced breast cancer, meaning the cancer has grown outside the organ where it started but has not yet spread to other parts of the body.[2] Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic and an estimated six to 10 percent of all new breast cancer cases are initially diagnosed as being metastatic.[3] Survival is lower among women with a more advanced stage at diagnosis: 5-year relative survival is 99 percent for localized disease, 85 percent for regional disease, and 26 percent for metastatic disease. Other factors, such as tumor size, also impact 5-year survival estimates.[4]

About Abemaciclib
In many cancers, uncontrolled cell growth arises from a loss of cell cycle regulation due to increased signaling from CDK4 and CDK6. Abemaciclib (LY2835219) is an investigational, oral cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting cyclin-dependent kinases, CDK4 and CDK6, and was most active against Cyclin D1 and CDK4 in cell-free enzymatic assays. In breast cancer, Cyclin D1/CDK4 has been shown to promote phosphorylation of the retinoblastoma protein (Rb), cell proliferation and tumor growth. In hormone receptor-positive breast cancer cell lines, sustained target inhibition by abemaciclib reduced phosphorylation of Rb, inducing cell cycle arrest.

In 2015, the U.S. Food and Drug Administration granted abemaciclib Breakthrough Therapy Designation based on data from the breast cancer cohort expansion of the company’s Phase 1 trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. In addition to its current MONARCH clinical trials evaluating abemaciclib in breast cancer, a Phase 3 trial of abemaciclib in lung cancer is also underway.

For more information on additional abemaciclib trials, a complete listing can be found on ClinicalTrials.gov (in the search box on the home page, type in "abemaciclib").

About the MONARCH Clinical Trial Program
Lilly is evaluating abemaciclib in the comprehensive MONARCH clinical program, which includes the following studies:

MONARCH 1: a global Phase 2 study evaluating the efficacy and safety of abemaciclib monotherapy in patients with HR+, HER2- advanced breast cancer who had prior endocrine therapy and chemotherapy for metastatic disease.

MONARCH 2: a global Phase 3 study evaluating the efficacy and safety of abemaciclib, in combination with fulvestrant, in patients with HR+, HER2- advanced breast cancer who progressed on endocrine therapy.

MONARCH 3: a global Phase 3 study evaluating the efficacy and safety of abemaciclib, in combination with an aromatase inhibitor, as initial endocrine-based therapy for postmenopausal women with HR+, HER2- advanced breast cancer who have had no prior systemic treatment for advanced disease.

monarcHER: a global Phase 2 study evaluating abemaciclib plus trastuzumab (with or without fulvestrant) in women with HR+, HER2+ advanced breast cancer.

MONARCH plus: a Phase 3 study evaluating the efficacy and safety of abemaciclib, in combination with endocrine therapies, to support registration in China.

neoMONARCH: a Phase 2 study evaluating abemaciclib in the neoadjuvant setting, alone or in combination with the non-steroidal aromatase-inhibitor anastrozole, in postmenopausal women with previously untreated early stage HR+, HER2- breast cancer.

monarchE: a global Phase 3 study evaluating the efficacy and safety of abemaciclib in the adjuvant setting in patients with high-risk, early breast cancer.

On June 3, 2017 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the fields of cancer metabolism and rare genetic diseases, reported updated data from the dose-escalation and expansion cohorts of the Phase 1 study evaluating single agent AG-120 (ivosidenib) in isocitrate dehydrogenase-1 (IDH1) mutant positive cholangiocarcinoma at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 2-6, 2017 in Chicago (Press release, Five Prime Therapeutics, JUN 3, 2017, View Source [SID1234519368]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The durable disease control signal seen with the Phase 1 data, combined with AG-120’s favorable safety profile, are encouraging for patients with advanced IDH1 mutant cholangiocarcinoma who have received multiple prior therapies," said Maeve Lowery, M.D., Memorial Sloan Kettering Cancer Center who presented the study results. "With no approved treatments and few effective options beyond the first line setting in this challenging disease, we look forward to continuing to characterize AG-120’s activity in the Phase 3 ClarIDHy study."

"Consistent with AG-120’s unique mechanism of action and in the context of this heavily pre-treated patient population, we believe durable stable disease is a meaningful measure of clinical benefit," said Chris Bowden, M.D., chief medical officer at Agios. "These data support further development of AG-120 in our ongoing Phase 3 registration-enabling ClarIDHy study, where we aim to confirm the early efficacy signal and evaluate the potential to impact tumor biology."

The ongoing Phase 1 trial is assessing the safety and tolerability of AG-120 in advanced solid tumors, including glioma, cholangiocarcinoma and chondrosarcomas with an IDH1 mutation. Enrollment is now complete for the dose-escalation and expansion cohorts. As of March 10, 2017, 73 patients with IDH1 mutant positive cholangiocarcinoma have been treated with single agent AG-120 in the dose escalation (n=24) and expansion cohorts (n=49). Thirteen patients remain on treatment. AG-120 was administered at the following dose levels and schedules in the dose-escalation cohort: 100 mg twice daily, and 300, 400, 500, 800 and 1200 mg once a day over a 28 day cycle length. In the dose expansion cohort, patients received 500 mg once a day, which was the selected dose for the ongoing Phase 3 ClarIDHy trial. Among the Phase 1 cholangiocarcinoma population, the median age is 60 (ranging from 32-81). Sixty-five patients had intrahepatic cholangiocarcinoma and eight had extrahepatic disease. The median number of prior systemic therapies was two (ranging from one to five) and 97% of patients received a prior gemcitabine-based chemotherapy regimen.

Safety Data

A safety analysis conducted for all 73 treated patients as of the data cut-off demonstrated that AG-120 was well-tolerated with a favorable safety profile in IDH1 mutant positive cholangiocarcinoma patients.

No dose limiting toxicities or treatment-related deaths have been observed.
The majority of adverse events (AEs) reported were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhea and decreased appetite.
Four patients experienced drug-related AEs ≥ grade 3: two at the 500 mg dose level, fatigue (n=1) and blood alkaline phosphatase increases (n=1) and two at the 1200 mg dose level, fatigue (n=1) and blood phosphorous decreases (n=1).
One patient had a dose reduction for a grade 2 AE of worsening leg cramps that was considered to be possibly drug-related.
Efficacy Data

Efficacy data from all 73 treated patients as of the data cut-off showed:

Four patients (5%) experienced a confirmed partial response (one at 300 mg QD and three at 500 mg QD). A partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
Forty-one patients (56%) experienced stable disease.
Landmark analyses of progression free survival at six (PFS6) and 12 months (PFS12) were 38.5% and 20.7% respectively. The median progression free survival (PFS) was 3.8 months (95% CI 3.6, 7.3).
AG-120 treatment inhibited plasma 2-hydroxyglutarate (2-HG) to within levels found in healthy volunteers, and also reduced 2-HG in tumor biopsies, with 2-HG levels in plasma and tumor biopsies showing a positive correlation.
Pathology review of on-study tumor biopsies were conducted in a patient achieving a partial response, which showed morphologic changes suggestive of cellular differentiation which is consistent with the proposed mechanism of action of AG-120.
ClarIDHy Phase 3 Trial

AG-120 (ivosidenib) is currently being evaluated in an ongoing, global, registration-enabling randomized Phase 3 trial known as ClarIDHy, enrolling 186 previously treated IDH1m positive cholangiocarcinoma patients who have documented disease progression following one or two systemic therapies in the advanced setting.

Patients will be randomized 2:1 to receive either single-agent AG-120 500 mg once daily or placebo with crossover to AG-120 permitted at the time of progression.
The primary endpoint of the trial is PFS with secondary endpoints including safety and tolerability, overall response rate, overall survival, duration of response, PK/PD and quality of life assessments.
Assuming a median PFS of 3 months for the control group, the study was designed with 96% power to detect a hazard ratio of 0.5 for PFS (AG-120 vs placebo), with a one-sided alpha of 0.025.
Thermo Fisher Scientific is providing next-generation sequencing to detect IDH1m for all tumor samples as inclusion criteria for enrollment in the study and will develop and commercialize the validated companion diagnostic.
About Cholangiocarcinoma

Cholangiocarcinoma (CC) is a rare cancer of the bile ducts within and outside of the liver. Cases that occur within the liver are known as intrahepatic cholangiocarcinoma (IHCC) and those that occur outside the liver are considered extrahepatic. Mutations in IDH1 occur in 13–15% of CC cases overall and in up to 25% of IHCC cases. Current treatment options for localized disease include surgery, radiation and/or other ablative treatments. There are no approved systemic therapies for cholangiocarcinoma and limited chemotherapy options are available in the advanced setting. Gemcitabine-based chemotherapy is often recommended for newly diagnosed metastatic disease. Progression-free survival (PFS) in patients with advanced biliary cancer receiving second-line chemotherapy is 2–3 months.

On June 3, 2017 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported initial data from the TOPACIO trial of niraparib plus KEYTRUDA (pembrolizumab) and results of a Phase 1 trial of TSR-042 during an investor briefing held in conjunction with the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting (Press release, TESARO, JUN 3, 2017, View Source [SID1234519444]). The Company also provided an update on its commercial businesses in the U.S. and Europe.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"ASCO represents an opportunity to showcase ZEJULA and the potential for it to positively impact the lives of women with recurrent ovarian cancer. Data presented earlier today during the conference further characterize the positive, durable treatment effects of ZEJULA and the clinical benefit in women who have residual disease following treatment with platinum-based chemotherapy. We are excited that the initial data from TOPACIO suggest a potential synergy between niraparib and an anti-PD-1 antibody, and look forward to evaluating this combination further in ovarian cancer and additional tumor types," said Lonnie Moulder, CEO of TESARO. "To date, there has been an overwhelmingly positive response by prescribers, patients and payors related to our U.S. launch and the potential for ZEJULA to benefit women with recurrent ovarian cancer. Our European organization has started filling orders for VARUBY in Germany, with other countries soon to follow. Pre-launch preparations are also underway to support the introduction of ZEJULA in Europe later this year, pending European Commission approval. In the U.S., demand for the oral formulation of VARUBI continues to increase and we look forward to a fourth quarter launch of VARUBI IV to extend our offering for patients who are undergoing emetogenic chemotherapy. Finally, our immuno-oncology programs are advancing at a rapid pace, led by the clinical study of TSR-042, our anti-PD-1 antibody, which we believe will form the basis for a registration of the drug in patients with MSI-H tumors, including endometrial cancer."

TOPACIO Data Demonstrate Activity in Platinum-Resistant Ovarian Cancer
TOPACIO is a Phase 1/2 clinical trial designed to evaluate the preliminary safety and efficacy of niraparib plus KEYTRUDA (pembrolizumab) in patients with recurrent, platinum-resistant ovarian cancer or triple negative breast cancer. Phase 1 of TOPACIO consisted of a dose escalation study to evaluate an oral, once-daily dose of niraparib (200 milligrams or 300 milligrams) plus 200 milligrams of pembrolizumab administered intravenously on day one of each 21-day treatment cycle. Endpoints included tolerability assessments, pharmacokinetic measures, and RECIST response rate.

In the dose escalation phase, a disease control rate of 69% was observed (9 of 13 evaluable patients), including 3 PRs and 1 CR, in patients with platinum-resistant ovarian cancer. The most common grade ≥3 adverse events included thrombocytopenia, anemia and neutropenia. At the recommended Phase 2 dose, one of seven patients experienced grade 3 thrombocytopenia and no significant overlapping toxicities were observed. A dose of 200 milligrams of niraparib once daily was selected for evaluation with pembrolizumab in Phase 2 of this study.

The first expansion cohorts of patients with platinum-resistant ovarian cancer (n=24) and triple-negative breast cancer (n=24) are now fully enrolled, and the second expansion cohorts for each tumor have been opened. Additional data from this trial are anticipated to become available during the second half of 2017.

The TOPACIO trial is being conducted in collaboration with Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc., which is providing support for the trial.

TSR-042 Phase 1 Results Show Anti-PD-1 Activity
The Phase 1 study of TSR-042, TESARO’s anti-PD-1 antibody, is now complete. No dose limiting toxicities were observed. Among the 21 heavily pretreated patients in Part 1 of the study, two had a partial response (PR) and five had stable disease. Adverse events were commensurate with commercially-available anti-PD-1 therapies.

Following the identification of a fixed dose and patient-centric dosing schedule, the ongoing clinical trial of TSR-042 was expanded to enroll patients with metastatic microsatellite instability-high (MSI-H) endometrial cancer who have progressed following one or two prior chemotherapy treatments. During the first 12 weeks of treatment, TSR-042 is administered once every three weeks, followed by administration every six weeks until disease progression. The intent of this study is to support a request for accelerated approval and Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA). The primary endpoints of this trial are overall response rate (ORR) and duration of response, and secondary endpoints include disease control rate, progression free survival (PFS), and overall survival (OS). The addition of cohorts for patients with other tumor types, including those with MSI-H tumors, is also planned. This is the first clinical development program within a broader plan that includes potential label expansion trials of TSR-042 in multiple cancers in combination with ZEJULA, TSR-022, TESARO’s anti-TIM-3 antibody, and TSR-033, TESARO’s anti-LAG-3 antibody.

Niraparib Data Presentations at ASCO (Free ASCO Whitepaper) Demonstrate Positive, Durable Treatment Effect
Three posters describing additional data analyses from the Phase 3 ENGOT-OV16/NOVA trial of niraparib were presented today during the ASCO (Free ASCO Whitepaper) Annual Meeting.

An analysis was performed to assess PFS and safety in patients who enrolled in the NOVA trial after a PR to their last platinum-based chemotherapy. Approximately 50% of all patients who enrolled in this trial entered with a PR, and results demonstrated that niraparib treatment provided significant benefit to these patients, with a treatment effect similar to that observed in the overall study population in both the gBRCAmut cohort (HR=0.24 for patients with a PR vs. HR=0.27 for all patients) and non-gBRCAmut cohort (HR=0.35 for patients with a PR and HR=0.45 for all patients). The safety profile of niraparib-treated patients with a PR was similar to that of the overall study population.

An assessment of platinum resistance status of patients in the NOVA trial was performed to better understand the population of patients that could benefit from treatment with niraparib. Approximately 50% of the patients in the placebo arm of this trial were found to have platinum-resistant disease following their last platinum-based therapy, as defined by progressive disease occurring less than six months following the last dose of chemotherapy. These findings suggest that approximately half of the total NOVA study population had disease that would have been considered platinum-resistant when they began maintenance treatment during the trial. The results of NOVA demonstrate that patients who had developed platinum-resistant disease after their last round of chemotherapy experienced benefit from niraparib maintenance.

Additional analyses of NOVA assessed the longer-term efficacy of niraparib. Across both the gBRCAmut and non-gBRCAmut cohorts, treatment with niraparib increased the probability of PFS at 12, 18 and 24 months from randomization vs. placebo, as demonstrated by Kaplan-Meier estimates. The similarity in results for PFS2 minus PFS1 between niraparib and placebo suggests that niraparib had no decremental effect on the benefit of subsequent therapy.
Robust Demand for ZEJULA Continues
The U.S. launch of ZEJULA is off to a strong start, with more than 800 new patient starts since approval and prescriptions written by over 600 physicians. TESARO introduced ZEJULA in late April, following U.S. FDA approval for use as a maintenance treatment for women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response (CR or PR) to platinum-based chemotherapy. ZEJULA is the only PARP inhibitor to have demonstrated efficacy in patients without BRCA mutations in a randomized, Phase 3 trial and is the only PARP inhibitor to be approved by the FDA that does not require patient selection with a biomarker test. Pre-launch preparations continue in support of a European launch of ZEJULA by year-end 2017, pending European Commission approval. The niraparib early access program, or EAP, has already enrolled a number of patients in Europe, and more patients are anticipated to enter the program.

VARUBY Launches Ongoing in Europe; VARUBI IV PDUFA Date Established in the U.S.
Following the approval of VARUBY (oral formulation) by the European Commission for the prevention of delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults, VARUBY is now available in Germany. In the U.S., the FDA has accepted the Company’s NDA re-submission for rolapitant IV and classified it as a Class 2 resubmission with a Prescription Drug User Fee Act (PDUFA) action date of October 25, 2017. TESARO is committed to bringing the intravenous formulation of VARUBI to physicians and patients to enable additional flexibility and choice of antiemetic regimens.

About ZEJULA (niraparib)
ZEJULA (niraparib) is an oral, once-daily poly(ADP-ribose) polymerase (PARP) 1/2 inhibitor that is indicated in the U.S. for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect.

ZEJULA (niraparib) Select Important Safety Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in patients treated with ZEJULA in all clinical studies. Discontinue ZEJULA if MDS/AML is confirmed. Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with ZEJULA. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time.

Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Based on its mechanism of action, ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for six months after receiving the final dose. Because of the potential for serious adverse reactions in breastfed infants from ZEJULA, advise a lactating woman not to breastfeed during treatment with ZEJULA and for one month after receiving the final dose.

In clinical studies, the most common adverse reactions included: thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, abdominal pain/distension, mucositis/stomatitis, diarrhea, fatigue/asthenia, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash and hypertension.

Please see full Prescribing Information for additional Safety Information at www.zejula.com.

About VARUBI (rolapitant)
VARUBI is a substance P/neurokinin-1 (NK-1) receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. NK-1 receptors are highly concentrated in the brain and bind neurokinin substance P. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies. A Positron Emission Tomography (PET) study with rolapitant in normal, healthy volunteers demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK-1 receptors at high levels for up to 120 hours. VARUBI has a half-life of approximately seven days, which may contribute to the ability of a single dose of VARUBI to cover the entire delayed CINV Phase (25-120 hours). VARUBI is contraindicated in patients receiving thioridazine, a CYP2D6 substrate. The inhibitory effect of a single dose of VARUBI on CYP2D6 lasts at least seven days and may last longer. Avoid use of pimozide; monitor for adverse events if concomitant use with other CYP2D6 substrates with a narrow therapeutic index cannot be avoided. Please see full prescribing information, including additional important safety information, available at View Source

About TSR-042
TSR-042 is a monoclonal antibody targeting PD-1 and was developed as part of the collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drugs targeting PD-1, TIM-3 (TSR-022), and LAG-3 (TSR-033), in addition to a bi-specific antibody drug candidate targeting PD-1/LAG-3.

About Endometrial Cancer
Endometrial cancer is the most common type of uterine cancer, accounting for more than 95 percent of cases. Endometrial cancer develops in the lining of the uterus, called the endometrium. The annual number of new cases of endometrial cancer is estimated at 325,000 worldwide. The most common histologic form is endometrioid adenocarcinoma originating in the glandular tissue, which represents about 75-80% of diagnosed cases. In 2017, SEER1 estimates 61,380 patients will be diagnosed with endometrial cancer, with approximately 30% or 18,414 being stage III/IV patients. Based on genomic characterization studies of endometrial cancer, 20-25% of patients have tumors with a microsatellite instability phenotype (MSI-H)2. Microsatellite instability arises from a failure to repair replication-associated errors due to a defective DNA mismatch repair system. This failure allows persistence of mismatch mutations all over the genome, but especially in regions of repetitive DNA known as microsatellites, leading to increased mutational load that has been demonstrated to improve responses to anti-PD-1 therapies.3,4

On June 3, 2017 ArQule, Inc. (Nasdaq: ARQL) reported that data from a phase 1/2 trial with fibroblast growth factor receptor (FGFR) inhibitor, ARQ 087, presented at ASCO (Free ASCO Whitepaper) demonstrate a meaningful clinical benefit to intrahepatic cholangiocarcinoma (iCCA) patients harboring FGFR2 fusions (Press release, ArQule, JUN 3, 2017, View Source [SID1234519376]). The data show a robust response rate and prolonged duration of therapy for these patients well in excess of that reported for second-line chemotherapy. These data support future development of ARQ 087 as second-line treatment, and a registrational phase 3 trial in iCCA FGFR2 fusion positive patients is planned to begin in the third quarter of 2017. ARQ 087 is a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor (FGFR) family.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The presentation titled "ARQ 087, an oral pan-Fibroblast Growth Factor Receptor (FGFR) inhibitor, in patients with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations" can be viewed at View Source

ARQ 087 Results from Phase 1/2 iCCA Trial Presented at ASCO (Free ASCO Whitepaper)

The data is comprised of 35 iCCA patients harboring FGFR2 genetic alterations, of which 29 patients were FGFR2 fusion positive. All 29 of these patients were evaluable for this data presentation.
The objective response rate for iCCA FGFR2 fusion positive patients was 21% (six partial responses) and the disease control rate was 83% (six partial responses and 18 patients with stable disease). Patients were evaluated using Standard RECIST (Response Evaluation Criteria in Solid Tumors).
Clinical benefit was observed in 72% of FGFR2 fusion positive patients defined as partial response (six patients) and stable disease (15 patients) for at least 16 weeks.
The median duration of therapy observed in iCCA FGFR2 fusion positive patients was 182 days. In these same patients, the median duration of front-line chemotherapy was 119 days.
ARQ 087 showed a manageable safety profile with mostly Grade 1 and 2 adverse events.
Nine patients with FGFR2 fusions are on-going in the trial.
"Clinical evidence is accumulating on the role of FGFR inhibitors in cholangiocarcinoma and other FGFR driven tumors such as urothelial and gastric cancers," said Dr. Brian Schwartz, M.D., Head of Research and Development and Chief Medical Officer at ArQule. "We are encouraged to see that both the response rate and disease control rate were consistent throughout the trial. Patients with iCCA often have a poor prognosis for front-line treatment with chemotherapy, and there are no currently approved second-line therapeutic options."

Patients with advanced iCCA who relapse after first-line multi-agent chemotherapy have limited treatment options with poor prognosis. In recent years, FGFR2 fusions have been recognized as a potential iCCA-specific therapeutic target. The company has been granted orphan drug designation by the U.S. Food and Drug Administration and European Medicines Agency for ARQ 087 in this indication.

About Intrahepatic Cholangiocarcinoma

Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC)1. Depending on the anatomic location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA), and extrahepatic (eCCA). iCCA originates from the intrahepatic biliary ductal system and forms an intrahepatic mass. The average age adjusted incidence rate for iCCA is approximately one in 100,000 per year in the United States and Europe2,3.

About FGFR and ARQ 087

ARQ 087 is a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor ("FGFR") family with demonstrated efficacy in FGFR2 genetic alterations. The FGFR pathway is disrupted in several ways in human cancer, thus providing numerous therapeutic targets for an inhibitor of this pathway. ARQ 087 has demonstrated in vivo inhibition of tumor growth and downstream signaling in tumors whose growth is driven by FGFR.

Signals of single agent activity with this drug were observed in phase 1a testing. Phase 1b expansion cohorts with ARQ 087 include patients with cholangiocarcinoma and adrenocortical tumors, as well as those with FGFR translocations, amplifications and mutations. Clinical development of ARQ 087 advanced into phase 2 for intrahepatic cholangiocarcinoma (iCCA) in patients with FGFR2 fusions following the observation of two confirmed responses in this patient population in the phase 1 portion of the program, and a phase 3 registrational trial is planned to begin in the third quarter of 2017 in this same patient population.

On June 3, 2017 TG Therapeutics (NASDAQ:TGTX) reported positive results from its Phase 3 GENUINE trial of TG-1101 (ublituximab) plus ibrutinib in patients with previously treated high risk Chronic Lymphocytic Leukemia (CLL) (Press release, TG Therapeutics, JUN 3, 2017, View Source [SID1234519447]). Data from this trial was presented today by Dr. Jeff Sharman, Medical Director, Hematology Research, US Oncology in an oral session during the 53rd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Michael S. Weiss, Executive Chairman and Chief Executive Officer of TG Therapeutics stated, "Patients with high-risk CLL have the poorest outcomes on ibrutinib and are in need of a more efficacious treatment. We believe the data presented today demonstrate that the addition of TG-1101 to ibrutinib improves patient outcomes across multiple measures." Mr. Weiss continued, "In addition to increasing the overall number of patients that responded to treatment with ibrutinib, adding TG-1101 to ibrutinib increased the number of patients with bone marrow confirmed CR’s, MRD negativity in peripheral blood, deepened nodal responses, and resulted in fewer patients progressing on therapy. Collectively, we see the consistent pattern of enhanced benefit as providing a compelling case for combining TG-1101 with ibrutinib in these hard to treat patients with high-risk CLL. We look forward to sharing these data with the FDA later this year to discuss filing for accelerated approval. We would like to thank our investigators and their patients for their participation in this important clinical trial."

Highlight’s from this presentation include the following:

Oral Presentation: Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE Phase 3 study

This presentation includes data from the GENUINE Phase 3 trial, a multicenter, randomized trial (NCT02301156), which assessed the efficacy and safety of TG-1101 plus ibrutinib versus ibrutinib alone in patients with high risk CLL. For the trial, high-risk was defined as having any one or more of the following centrally confirmed features: 17p deletion, 11q deletion or p53 mutation. The GENUINE study was designed to demonstrate the value of adding TG-1101, a potent next generation glycoengineered anti-CD20 monoclonal antibody to ibrutinib monotherapy in high-risk CLL, and was powered to show a statistically significant improvement in ORR of 30%, with a minimal absolute detectable difference between the two arms of approximately 20%.

The trial met its primary endpoint, demonstrating a statistically significant improvement in Overall Response Rate (ORR), as assessed by blinded independent central radiology and hematology review by iwCLL (Hallek 2008) criteria, compared to ibrutinib alone in both the Intent to Treat (ITT) population (p=0.001) and Treated population (p < 0.001). Per iwCLL guidelines, all responders required confirmation of response for a minimum duration of 2 months. The ITT population includes all 126 randomized patients (64 in the TG-1101 plus ibrutinib arm and 62 in the ibrutinib alone arm) while the Treated population includes all ITT patients that received at least one dose of either study drug (59 in the TG-1101 plus ibrutinib arm and 58 in the ibrutinib alone arm).

Patient Demographics

One hundred and twenty-six (126) patients were randomized on the GENUINE Phase 3 trial. 100% of patients were high-risk and had either 17p deletion, 11q deletion or p53 mutation. Sixty-four percent (64%) of patients in the TG-1101 plus ibrutinib arm and 66% of patients in the Ibrutinib alone arm had 17p deletion and/or a p53 mutation while 36% and 34% of patients in the TG-1101 plus ibrutinib and ibrutinib alone arms, respectively, had an 11q deletion only. The median age of patients on either arm was 67 years and the median number of prior lines of therapy for either arm was 3.

Safety & Tolerability

One hundred and seventeen (117) patients were evaluable for safety (59 patients in the TG-1101 plus ibrutinib arm, and 58 patients in the ibrutinib alone arm). The combination was well tolerated and, apart from infusion related reactions, the addition of TG-1101 did not appear to alter the safety profile of ibrutinib monotherapy. Neutropenia, occurring in 9% of patients, was the most commonly reported Grade 3/4 Adverse Event (AE) in the combination arm, followed by infusion related reactions and anemia, each reported in 5% of patients. Notably, the majority of infusion related reactions (IRR) were Grade 1 or 2 in severity, with only 5% Grade 3/4 IRR observed. Median follow-up for this study was approximately 11.4 months.

Clinical Activity

Response Rates

TG-1101 plus Ibrutinib Ibrutinib P-value
Treated Population (n) n=59 n=58
Overall Response Rate (ORR) 78 % 45 % P < 0.001
Complete Response (CR) 7 % 0 % NS
MRD-Negative 19%
(n=53) * 2%
(n=53) * P < 0.01

*Patients evaluable for MRD included those enrolled > 4 months prior to data cutoff date of February 15, 2017. MRD analyzed by central lab, 7-color flow cytometry

In addition to the improvements in ORR, CR and MRD-negativity, a trend in improvement of Progression Free Survival (PFS) was observed in the combination arm of TG-1101 plus ibrutinib as compared to ibrutinib alone (Hazard Ratio = 0.559; p=NS).

ABOUT THE PHASE 3 GENUINE STUDY

The Phase 3 GENUINE study is a randomized, open label, multicenter clinical trial to evaluate the safety and efficacy of TG-1101 (ublituximab) plus ibrutinib compared to ibrutinib alone in adult patients with high-risk Chronic Lymphocytic Leukemia (CLL) who received at least one prior therapy for their disease.

The study was conducted at 160 clinical trial sites in the US and Israel and randomized 126 patients. Patients received ibrutinib orally at 420 mg once daily in both arms and in the combination arm those patients also received intravenous infusions of TG-1101 at 900 mg dosed on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6. Patients in the combination arm who had not progressed received quarterly infusions of TG-1101 maintenance at 900 mg.

PRESENTATION DETAILS:

The above referenced presentation is now available on the Publications page, located within the Pipeline section, of the Company’s website at www.tgtherapeutics.com/publications.cfm.