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Forty Seven, Inc. Announces Proof-of-Concept Data from Two Clinical Trials of 5F9 In Patients with Advanced Solid Tumors and non-Hodgkin’s Lymphoma

On June 3, 2018 Forty Seven, Inc., a clinical-stage, immuno-oncology company focused on developing therapies to activate macrophages in the fight against cancer, reported proof-of-concept data from two separate clinical trials of 5F9: an ongoing Phase 1b/2 trial evaluating 5F9 in combination with rituximab in patients with relapsed/refractory non-Hodgkin’s lymphoma (r/r NHL) and a Phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) trial in patients with advanced solid tumors (Press release, Forty Seven, JUN 3, 2018, View Source [SID1234527178]). 5F9 is a monoclonal antibody against CD47, which is designed to block the "don’t eat me" signal used by cancer cells to avoid being ingested by macrophages. The data are being presented in two oral presentations at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois, June 1-5, 2018.

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"We are pleased to present the first-in-human data for 5F9, which support our belief in the value of harnessing macrophages to fight difficult-to-treat cancers, and help validate our molecule selection strategy and the potential of our proprietary prime-maintenance dosing regimen to overcome the toxicity limitations of previously tested anti-CD47 antibodies," said Chris Takimoto, M.D., Ph.D., F.A.C.P., Chief Medical Officer of Forty Seven, Inc. "Together, the data presented at ASCO (Free ASCO Whitepaper) reveal an encouraging clinical profile for 5F9, suggesting that blocking CD47 can render difficult-to-treat tumors susceptible to phagocytosis. We are particularly encouraged by the evidence of anti-tumor activity observed in patients with r/r NHL and advanced, relapsed ovarian cancer, who are refractory to, or unfit for, existing therapeutic options. We are committed to exploring 5F9’s full potential and are now advancing a broad clinical development program at the recommended priming and Phase 2 dose and schedule, including multiple trials across a range of tumors and treatment modalities."

Data from the Phase 1b Portion of the Ongoing Phase 1b/2 Trial of 5F9 in Combination with Rituximab in r/r NHL

Forty Seven’s Phase 1b/2 trial is designed to evaluate 5F9 in combination with rituximab in patients with r/r NHL, including patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In the Phase 1b portion of the trial, patients received a 1 mg/kg priming dose of 5F9 to mitigate on-target anemia, followed by full doses of rituximab and escalating doses of 5F9, ranging from 10 mg/kg once weekly to 30 mg/kg once weekly. As of the data cutoff of April 2018, 22 patients had been treated across all dose groups in the Phase 1b portion of the trial, including 15 patients with DLBCL and seven patients with FL. Before dosing, 95% of patients were considered refractory to a prior rituximab regimen and the median number of prior therapies was four (ranging from two to 10).

Safety Data: As of the data cutoff date of April 2018, 5F9 was observed to be generally well-tolerated at all doses and the maximum tolerated dose was not defined with 5F9 dosing up to 30 mg/kg. The majority of adverse events (AEs) reported by investigators were Grade 1 or 2 and the most common treatment-related AEs were expected CD47-mechansim-based effects on red blood cells (RBC), which led to a temporary and reversible anemia. Other commonly reported AEs reported included chills, headache, infusion-related reaction and pyrexia. Only one patient discontinued due to an AE.

Clinical Data: As of the data cutoff date, 22 patients across all dose groups were evaluable for response assessment, including 15 patients with DLBCL and seven patients with FL. PET/CT imaging was used to measure clinical activity by the Lugano criteria, which include measures of tumor size and metabolic activity. Across all 22 evaluable patients, the data showed an objective response rate (ORR) of 50% and a complete response rate (CR) of 36%.

In DLBCL, the ORR was 40%, with 33% of patients achieving a CR.
In FL, the ORR was 71%, with 43% of patients achieving a CR.
Among all responding patients, only one patient has subsequently progressed with a median follow-up of over six months. A median duration of response has not been reached for either the DLBCL or FL patient populations, with a median follow-up of 6.2 months and 8.1 months for DLBCL and FL patients, respectively.

"Despite recent advancements, there remains a paucity of safe and effective therapies for patients with r/r NHL, especially for patients who are ineligible for transplantation or new cell therapies," said Sonali Smith, M.D., Elwood V. Jensen Professor in Medicine, an investigator for the study. "These preliminary data suggest that 5F9 may offer patients with DLBCL and FL a new treatment option that is both safe and easy to administer, and that can rapidly induce benefit, with a majority of responding patients showing clinical activity at first assessment with several complete remissions, despite being refractory to multiple prior regimens. I am excited to continue evaluating 5F9 in the Phase 2 portion of this trial, as we learn more about the clinical utility of this potentially transformative agent."

Data from the Phase 1 PK and PD Trial Evaluating 5F9 as a Single-Agent in Advanced Solid Tumors

Forty Seven’s Phase 1 trial was designed to evaluate the safety and tolerability of 5F9 and to define a recommended dose and schedule. A total of 62 patients were treated in the Phase 1 trial. This included 11 patients treated in Part A at four escalating priming doses (ranging from 0.1 mg/kg to 3 mg/kg once weekly); 14 patients treated in Part B at a priming dose of 1 mg/kg and three escalating maintenance doses (ranging from 3 mg/kg to 20 mg/kg once weekly); 15 patients treated in a tumor biopsy cohort at a priming dose of 1 mg/kg and a maintenance dose of 20 mg/kg; and 22 patients treated in Part C at a priming dose of 1 mg/kg and three escalating loading and maintenance doses (ranging from 20 mg/kg to 45 mg/kg once weekly). The treated patients had advanced tumors including colorectal, ovarian, salivary, breast and other solid tumors and were heavily pre-treated, with a median of five prior systemic treatments.

PK and PD: In Part A, 1 mg/kg was identified as the optimal priming dose sufficient to saturate CD47 on RBCs and trigger a compensatory reticulocytosis to mitigate the expected anemia due to the removal of older RBCs. PK data showed that 5F9 can overcome the CD47 antigen sink at doses of 10 mg/kg or higher, with free plasma drug levels exceeding the expected therapeutic range based on preclinical results. PK data at saturating dose levels also showed a mean half-life of approximately 13 days, supporting a maintenance dose once every two weeks. The Recommended Phase 2 Dose (RP2D) has been defined as a 1 mg/kg priming dose, followed by 30 mg/kg once weekly for three weeks, followed by a maintenance dose of 30 mg/kg every two weeks.

Safety Data: 5F9 was observed to be generally well-tolerated at all doses and the maximum tolerated dose was not defined up to 45 mg/kg. The majority of AEs reported by investigators were Grade 1 or 2. The most common treatment-related AEs were expected CD47-mechanism-based effects on RBC, including a predictable and frequently transient anemia that was successfully mitigated by Forty Seven’s priming and maintenance dosing regimen. Other frequently reported treatment-related AEs included infusion-site reactions, headache, fatigue, chills, fever and nausea, which were generally mild-to-moderate in severity and easily managed.

Clinical Data: Preliminary evidence of anti-tumor activity with single-agent 5F9 was observed in the study:

In ovarian cancer, two patients had a confirmed partial response (PR) by RECIST 1.1 criteria. Both patients were treated at weekly maintenance doses of 20 mg/kg and were heavily pre-treated, having failed at least six previous treatment regimens. One of these patients had a durable PR of more than six months.
"I am particularly encouraged by the single-agent activity of 5F9 in patients with advanced, relapsed ovarian cancer, especially for women with platinum-resistant tumors who are less responsive to other therapies," said Amita Patnaik, M.D., FRCPC, Co-Director of Clinical Research at South Texas Accelerated Research Therapeutics and an investigator for this study. "These early clinical responses for 5F9 as a single agent, coupled with strong preclinical data, support Forty Seven’s combination strategy in ovarian cancer, including the recently initiated Phase 1b trial combining 5F9 with the anti-PD-L1 inhibitor, avelumab, under the Company’s existing collaboration with Merck KGaA."

About 5F9:

5F9 is a monoclonal antibody against CD47 that is designed to interfere with recognition of CD47 by the SIRPα receptor on macrophages, thus blocking the "don’t eat me" signal used by cancer cells to avoid being ingested by macrophages. Forty Seven, Inc. is initially developing 5F9, an investigational medicine, for the treatment of patients with solid tumors, acute myeloid leukemia, non-Hodgkin’s lymphoma and colorectal cancer. 5F9 has been granted Fast Track designation by the U.S. Food and Drug Administration for the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma, two forms of B-cell non-Hodgkin’s lymphoma.

FibroGen Presents Clinical Results of Pamrevlumab Treatment in Patients with Locally Advanced Unresectable Pancreatic Cancer at ASCO 2018 Annual Meeting

On June 3, 2018 FibroGen, Inc. (NASDAQ: FGEN), a biopharmaceutical company, reported Phase 1/2 clinical trial results of pamrevlumab in combination with standard-of-care chemotherapy in patients with locally advanced unresectable pancreatic cancer (LAPC) (Press release, FibroGen, JUN 3, 2018, View Source [SID1234527124]). . Principal investigator Vincent J. Picozzi, Jr., M.D., Director, Pancreas Center of Excellence, Virginia Mason Cancer & Digestive Diseases Institutes, presented the results in a discussion poster session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. Pamrevlumab is a proprietary first-in-class antibody targeting connective tissue growth factor (CTGF) under development for the treatment of fibrosis and fibroproliferative disorders.

"These are some of the most exciting clinical trial results in locally advanced pancreatic cancer I have seen since I began treating pancreatic cancer patients," said Dr. Picozzi. "The data suggest that pamrevlumab in combination with chemotherapy has the potential to become a neoadjuvant treatment regimen for locally advanced unresectable pancreatic cancer patients that has not existed before."

Patients with locally advanced pancreatic cancer (without metastasis) tend to have a poor prognosis with a median survival of 9–18 months. In patients who have undergone resection of their tumor, median survival and five-year survival rates have been reported to be higher than those without resection. Therefore, treatment to achieve a surgical resection in this patient population is a meaningful treatment goal to potentially achieve a favorable overall survival outcome.

In this open-label, randomized Phase 1/2 study, pamrevlumab was administered in combination with standard-of-care chemotherapy (gemcitabine and nab-paclitaxel) and compared to treatment with chemotherapy alone in patients with locally advanced pancreatic ductal adenocarcinoma, who were not eligible for surgical resection based on histology, computerized tomography (CT) scans, and laparoscopy criteria, prior to randomization. Upon completion of the six months of study drug treatment, patients underwent surgical eligibility assessment based on pre-specified objective criteria. The study enrolled 37 patients: 24 received pamrevlumab + chemotherapy: 13 received chemotherapy alone.

At ASCO (Free ASCO Whitepaper) 2018, FibroGen reported that a higher proportion of patients whose tumor was previously considered unresectable became eligible for resection (based on protocol pre-specified post-treatment surgical eligibility criteria) after receiving pamrevlumab and chemotherapy than after receiving chemotherapy alone (at the end of 6 months of treatment), 70.8% vs. 15.4%. For those patients who met these surgical resection eligibility criteria at post-treatment assessment, individual patient condition and circumstance contributed to whether resection subsequently occurred. A higher proportion of pamrevlumab-treated patients achieved surgical resection than those received chemotherapy alone, 33.3% vs. 7.7%.

In the study, patients were followed for survival after evaluation for eligibility for resection and, when applicable, after resection. Patients who had successful resections in this study had a statistically significant longer median survival benefit as compared to patients who did not undergo resection, 40 months vs.18.6 months (p=0.0141), as of May, 2018. FibroGen is continuing to monitor study patients for survival.

"Patients with unresectable locally advanced pancreatic cancer are in need of an innovative and effective treatment with the potential to transform non-operable cancer into resectable disease," said Elias Kouchakji, M.D., Senior Vice President, Clinical Development and Drug Safety. "The updated clinical results we are reporting at ASCO (Free ASCO Whitepaper) suggest that pamrevlumab may improve the treatment outcomes for patients who are currently deemed unresectable."

About Locally Advanced Pancreatic Cancer

In locally advanced pancreatic cancer (LAPC), tumors typically encase structures, particularly blood vessels that are closely associated with the pancreas such as the superior mesenteric artery and superior mesenteric vein. Involvement of the cancer around these blood vessels precludes surgical removal of the tumor. Approximately 80% of newly diagnosed LAPC patients are classified as having unresectable disease, and patients with unresectable LAPC have a median survival only slightly better than that of patients with metastatic pancreatic cancer. Patients with resectable cancer whose tumors are surgically removed have a much better prognosis, with median survival of approximately 23 months, and some patients being cured.

About Pamrevlumab

Pamrevlumab is a first-in-class antibody developed by FibroGen to inhibit the activity of connective tissue growth factor (CTGF), a common factor in fibrotic and proliferative disorders characterized by persistent and excessive scarring that can lead to organ dysfunction and failure. Pamrevlumab is advancing towards Phase 3 clinical development for the treatment of idiopathic pulmonary fibrosis (IPF) and pancreatic cancer, and has been granted Orphan Drug Designation (ODD) in each of these indications, and is currently in a Phase 2 trial for Duchenne muscular dystrophy (DMD). Pamrevlumab recently received Fast Track designation from the U.S. Food and Drug Administration for the treatment of patients with locally advanced unresectable pancreatic cancer. Pamrevlumab has demonstrated a good safety and tolerability profile in multiple Phase 2 trials conducted to date. For information about pamrevlumab studies currently recruiting patients, please visit www.clinicaltrials.gov.

Clovis Oncology and Immunomedics Announce Planned Clinical Collaboration to Study Combination Therapies in Metastatic Triple-Negative Breast and Urothelial Cancers

On June 3, 2018 Clovis Oncology, Inc. (NASDAQ:CLVS) and Immunomedics, Inc., (NASDAQ:IMMU) reported their intent to enter into a clinical collaboration to investigate the combination of Clovis’ Rubraca (rucaparib), a poly (ADP ribose) polymerase inhibitor (PARPi), and Immunomedics’ lead antibody-drug conjugate (ADC) product candidate, sacituzumab govitecan, as a treatment of patients with metastatic triple-negative breast cancer (mTNBC) and metastatic urothelial cancer (mUC) (Press release, Clovis Oncology, JUN 3, 2018, View Source [SID1234527115]). The planned phase 1/2 study will include an initial safety cohort followed by expansion cohorts in each of mTNBC and mUC.

"We look forward to entering this important co-development partnership with Clovis, one of the leading innovative biotech companies, to fully leverage the scientific expertise of both companies and expand the potential for two very active agents," said Usama Malik, Chief Business Officer of Immunomedics. "There is synergy between PARPi and sacituzumab govitecan in preclinical models regardless of BRCA mutation status. This partnership will hopefully provide clinical validation for this exciting concept and bring new treatment options to disease settings with high unmet medical need."

"We are very pleased to partner with Immunomedics and are very enthusiastic about the potential synergy between rucaparib and sacituzumab govitecan," said Patrick J. Mahaffy, President and Chief Executive Officer of Clovis Oncology. "Our plan to initiate new combination studies with Immunomedics further expands our clinical development efforts in both advanced breast and bladder cancers, where there is tremendous need for new treatment options."

In preclinical studies, the combination of sacituzumab govitecan and rucaparib in TNBC cell lines in vitro resulted in synergistic growth inhibition regardless of BRCA1/2 status. In addition, the combination of sacituzumab govitecan and a PARPi also demonstrated significant antitumor effects above that observed with monotherapy in BRCA wild-type and mutant animal models of TNBC.1

"There is an opportunity to develop new treatment options for patients in the mTNBC and mUC space through our planned collaboration with Clovis Oncology, as well as potentially pursuing other indications in the future," stated Dr. Robert Iannone, Head of Research & Development and Chief Medical Officer of Immunomedics. "We are excited by the prospect that our unique ADC in combination with rucaparib could help fill a gap in treatment for cancer patients who have few available options."

Reference

Cardillo TM, Sharkey RM, Rossi DL, et al. Synthetic lethality exploitation by an anti-Trop-2-SN-38 antibody-drug conjugate, IMMU-132, plus PARP inhibitors in BRCA1/2-wild-type triple-negative breast cancer. Clin Cancer Res. 2017 Jul 1;23(13):3405-3415.
About Sacituzumab Govitecan

Sacituzumab govitecan, Immunomedics’ most advanced product candidate, is a novel, first-in-class antibody-drug conjugate (ADC). It is currently under review by the U.S. Food and Drug Administration for accelerated approval as a treatment of patients with triple-negative breast cancer who previously received at least two prior therapies for metastatic disease. If approved, sacituzumab govitecan would be the first and only ADC approved for the treatment of metastatic triple negative breast cancer.

About Rubraca

Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian, metastatic castration-resistant prostate, and bladder cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway. Clovis holds worldwide rights for Rubraca. Rubraca is an unlicensed medical product outside of the U.S. and EU.

Rubraca U.S. FDA Approved Indications and Important Safety Information
Rubraca is indicated as monotherapy 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.

Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long term follow-up. Of these, 5 occurred during treatment or during the 28 day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents.

Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).

Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose (see Dosage and Administration (2.2) in full Prescribing Information) and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%).

Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1-4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%), and decrease in lymphocytes (29%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1-4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%), and decrease in absolute neutrophil count (35%).

Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.

Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.

Click here for full Prescribing Information and additional Important Safety Information.

Erdafitinib Phase 2 Study Results Show Promise in the Treatment of Metastatic Urothelial Cancer

On June 3, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported findings today from a Phase 2 study that showed treatment with erdafitinib resulted in durable responses in patients with metastatic or surgically unresectable urothelial cancer (mUC) and fibroblast growth factor receptor alterations (FGFRalt) (Press release, Johnson & Johnson, JUN 3, 2018, View Source [SID1234527110]). This is a patient population with high unmet need based on poor outcomes when treated with available therapies. Erdafitinib is a once-daily pan-FGFR inhibitor.1 FGFRs are cell proteins that, if altered, can contribute to the development of cancer.1 Alterations occur in approximately 20 percent of mUC patients.1 The results were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting in Chicago (Abstract #4503) and have been selected for the Best of ASCO (Free ASCO Whitepaper) Meetings.1

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"I am very encouraged by these Phase 2 data showing that erdafitinib had promising response rates and progression-free survival in a patient population with such high unmet need," said Dr. Yohann Loriot, Senior Consultant, Department of Cancer Medicine & INSERM, Institut Gustave Roussy, University of Paris Sud, Villejuif, France. "Currently there are no targeted therapies approved for specific subsets of patients with urothelial cancer who have genetic alterations. While immune checkpoint inhibitors have led to improvements in outcomes for these patients, we are still finding that many patients do not respond to treatment."

BLC2001 (NCT02365597) is a multicentre, open-label Phase 2 study evaluating the efficacy and safety of erdafitinib in the treatment of adult patients with locally advanced or metastatic urothelial cancer, whose tumours have certain FGFR alterations.1 Ninety-nine patients were treated with an optimised dosing schedule using pharmacodynamically guided dose up-titration: a starting dose of erdafitinib at 8 mg daily, with the possibility to increase the dose to 9 mg daily based on serum phosphate levels.2 Twelve percent of patients were chemo-naïve, 89 percent of patients had received one or more lines of therapy, 43 percent of patients had received two or more prior lines of therapy, and 78 percent of patients had visceral metastases.2 There was a 40 percent confirmed overall response rate1 (RECIST 1.1;* 3% Complete Response, 37% Partial Response), a median progression-free survival of 5.5 months and median overall survival of 13.8 months.2 In patients who experienced grade 3 adverse events (AEs), the most common were, stomatitis (9%) and diarrhoea (4%).1 Seven patients discontinued due to treatment-related AEs.2

"These study results are very promising, particularly as this is an area of high unmet need with patients who otherwise have very limited treatment options remaining. We hope that the response rates shown by erdafitinib could eventually give patients with metastatic or surgically unresectable urothelial cancer a new treatment option," said Dr Ivo Winiger-Candolfi, Europe, Middle East and Africa (EMEA) Oncology Therapeutic Area Lead, Janssen. "The successful development of new oncology therapies, such as erdafitinib, is an example of our precision medicine approach: providing the right patient, with the right treatment, at the right time. We recognise that every patient is unique and that by accounting for individual differences in people’s genes, environments and lifestyles, we can optimise the therapeutic benefit for particular groups of patients. We look forward to understanding the potential efficacy and broader safety profile of erdafitinib in both Phase 3 development as well as in combination with anti-PD1 therapy."

*RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumors which is a standard way to measure how well a cancer patient responds to treatment and is based on whether tumours shrink, stay the same, or get bigger.3

About Urothelial Cancer

Europe has among the highest incidence rates of bladder cancer in the world and mortality rates for men are by far the highest recorded worldwide.4 It is the fifth most frequently diagnosed cancer in the EU, with about 124,000 new cases each year for both sexes.5 The majority (90%) of bladder cancer consists of urothelial carcinoma in Western Europe.6 Urothelial bladder cancer starts in the bladder lining (urothelial cells or transitional cells) and can be non-invasive or invasive.7 For patients with metastatic disease, outcomes can be poor due to the often rapid progression of the tumour and the lack of efficacious treatments.8 The relative five-year survival rate for patients with metastatic disease is five percent.9

About erdafitinib

Erdafitinib is a once-daily oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor being evaluated by Janssen Research & Development in Phase 2 and 3 clinical trials in patients with advanced urothelial cancer.10 FGFRs are a family of receptor tyrosine kinases which may be upregulated in various tumour cell types and may be involved in tumour cell proliferation, tumour angiogenesis and tumour cell survival.11 In 2008, Janssen entered into an exclusive worldwide license and collaboration agreement with Astex Therapeutics Ltd. to develop and commercialise erdafitinib.

Erdafitinib received Breakthrough Therapy Designation from the U.S. Food and Drug Administration in March 2018.12 The aim is to move towards regulatory submission with the Phase 2 data and continue to pursue erdafitinib in Phase 3 clinical development, as well as in combination with anti-PD-1 therapy.

Third Novartis Phase III trial shows Kisqali® combination therapy significantly improves PFS in HR+/HER2- advanced breast cancer

On June 3, 2018 Novartis reported positive results from the third Phase III trial of Kisqali (ribociclib) in advanced or metastatic breast cancer. MONALEESA-3 showed Kisqali plus fulvestrant significantly prolonged progression-free survival (PFS) compared to fulvestrant alone in postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer (Press release, Novartis, JUN 3, 2018, View Source [SID1234527099]). MONALEESA-3 is the largest phase III trial to evaluate efficacy and safety of a CDK4/6 inhibitor plus fulvestrant in multiple advanced breast cancer patient populations – first-line and second-line settings[1]. These data will be presented today as an oral presentation at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract #1000) and published simultaneously in the Journal of Clinical Oncology.

Kisqali in combination with fulvestrant demonstrated a median PFS of 20.5 months (95% CI: 18.5-23.5 months) compared to 12.8 months (95% CI: 10.9-16.3 months) for fulvestrant alone (HR=0.593; 95% CI: 0.480-0.732; p=.00000041) across both treatment arms. The median PFS for the subgroup of patients receiving Kisqali plus fulvestrant in the first-line setting, including only de novo patients and those whose disease relapsed >12 months since end of neo(adjuvant) endocrine therapy, was not reached compared to 18.3 months for fulvestrant alone (HR=0.577; 95% CI: 0.415-0.802). In patients receiving treatment in the second-line setting, or those who relapsed <12 months since end of neo(adjuvant) endocrine therapy, the median PFS was 14.6 months compared to 9.1 months for fulvestrant alone (HR=0.565; 95% CI: 0.428-0.744)[1].

"The MONALEESA-3 results in patients treated in this first-line setting were particularly significant. Nearly 70% of women who received ribociclib plus fulvestrant in this setting were estimated to remain progression-free at the median follow-up of 16.5 months," said Dennis J. Slamon, MD, Director of Clinical/Translational Research, University of California, Los Angeles Jonsson Comprehensive Cancer Center. "In the advanced breast cancer setting, it is important to ensure we provide patients with treatment options that increase time to disease progression while also maintaining quality of life."

Fifty percent of the women in MONALEESA-3 had lung and/or liver metastases and showed a consistent treatment benefit compared with the overall population. Follow-up to measure overall survival is ongoing as these data remain immature[1].

"MONALEESA-3 data add to the robust body of evidence demonstrating the broad potential of Kisqali to treat pre- and postmenopausal women living with advanced breast cancer in various endocrine combinations and multiple lines of therapy," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "These results along with the other MONALEESA studies build a compelling case that Kisqali combination therapy should be a cornerstone of first-line treatment of HR+/HER2- advanced breast cancer."

No new safety signals were observed in the MONALEESA-3 trial; adverse events were generally consistent with those observed in MONALEESA-2[1]. The discontinuation rate due to adverse events was 8.5% for Kisqali plus fulvestrant compared to 4.1% for fulvestrant alone[1]. The most common (>=5%) grade 3/4 adverse events in patients receiving Kisqali plus fulvestrant compared to fulvestrant alone were neutropenia (53.4% vs 0%) and leukopenia (14.1% vs 0%)[1].

Additional Kisqali data are being presented at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting. Further results from MONALEESA-7 showed consistent treatment benefit among premenopausal women with HR+/HER2- advanced breast cancer regardless of prior chemotherapy treatment in the advanced setting (Abstract #1047)[2]. Initial safety data from the CompLEEment-1 trial demonstrated a consistent safety profile for Kisqali in a patient population more reflective of those seen in a real-world setting (Abstract #1056)[3]. Lastly, biomarker data from MONALEESA-2 showed that clinical benefit of Kisqali was consistent across gene expression subgroups with a trend toward greater Kisqali benefit in the high versus low ESR1 expression and low versus high RTK expression subgroups (Abstract #1022)[4].

Novartis is in discussion with the US Food and Drug Administration (FDA) with respect to a supplemental New Drug Application (sNDA), seeking approval of Kisqali plus fulvestrant for the treatment of postmenopausal women with HR+/HER2- advanced breast cancer.

About MONALEESA-3
MONALEESA-3 is a Phase III randomized, double-blind, placebo-controlled study evaluating Kisqali in combination with fulvestrant compared to fulvestrant alone for the treatment of postmenopausal women with HR+/HER2- advanced breast cancer who received no prior or only one line of prior endocrine therapy for advanced disease. A total of 726 people were randomized in the trial, including first-line patients comprised of 367 women who were treatment-naïve and 345 who had received up to one line of prior endocrine therapy for advanced disease. Patients were randomized (2:1) to receive Kisqali plus fulvestrant or fulvestrant alone. Randomization was stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first-line versus second-line).

About Kisqali (ribociclib)
Kisqali 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, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali was approved by the US Food and Drug Administration in March 2017 and by the European Commission in August 2017, as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor based on findings from the pivotal MONALEESA-2 trial. Kisqali is not currently approved for use in combination with fulvestrant or in premenopausal women.

Kisqali is approved for use in 59 countries around the world, including the United States and European Union member states. Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About the Kisqali Clinical Trial Program
With more than 2,000 patients enrolled in current trials, the MONALEESA program is the largest industry sponsored Phase III clinical program researching a CDK4/6 inhibitor in HR+/HER2- advanced breast cancer. In addition to MONALEESA-3, there are three other Phase III trials evaluating Kisqali combination therapy.

MONALEESA-7 is a Phase III randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of Kisqali in combination with tamoxifen or a non-steroidal aromatase inhibitor plus goserelin versus tamoxifen or an aromatase inhibitor plus goserelin, in premenopausal or perimenopausal women with HR+/HER2- advanced breast cancer who had not previously received endocrine therapy for advanced disease.

MONALEESA-2 is a Phase III global registration trial evaluating Kisqali 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.

CompLEEment-1 is an open-label, multicenter, Phase IIIb study evaluating the safety and efficacy of Kisqali plus letrozole in pre- or postmenopausal women and men with HR+/HER2- advanced breast cancer who have not received prior hormonal therapy for advanced disease.

More information about these studies can be found at www.ClinicalTrials.gov.

About Novartis in Advanced Breast Cancer
For more than 30 years, Novartis has been tackling breast cancer with superior science, great collaboration and a passion for transforming patient care. With one of the most diverse breast cancer pipelines and one of the largest numbers of breast cancer compounds in development, Novartis leads the industry in discovery of new therapies and combinations, especially in HR+ advanced breast cancer, the most common form of the disease.

Important Safety Information from the Kisqali EU SmPC
The most common ADRs and the most common grade 3/4 ADRs (reported at a frequency >=20% and >=2% respectively) for which the frequency for Kisqali plus letrozole exceeds the frequency for placebo plus letrozole were blood and lymphatic system disorders (including abnormally low neutrophil and white blood cell count), headache, back pain, nausea, fatigue, diarrhea, vomiting, constipation, hair loss and rash and abnormally low levels of neutrophils or white blood cells, abnormal liver function tests (increased alanine and aspartate aminotransferase), abnormally low lymphocyte count, low levels of phosphate, vomiting, nausea, fatigue and back pain, respectively. Low levels of neutrophils was the most commonly seen severe adverse event; fever in addition to a low neutrophil count was reported in 1.5% of patients.

Kisqali can cause serious side effects such as a significant decrease in neutrophil count, abnormal liver function tests and may have an effect on the electrical activity of the heart known as QT/QTc interval prolongation, which could lead to disturbances in heart rhythm. As a precaution, patients should have complete blood counts, liver function, and serum electrolyte levels measured prior to starting treatment as well as during treatment with Kisqali. Patients should also have their heart activity checked before and monitored during treatment.

The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease.

The use of Kisqali with medicinal products known to prolong QTc interval or strong CYP3A4 inhibitors should be avoided as this may lead to prolongation of the QT/QTc interval. If treatment with a strong CYP3A4 inhibitor cannot be avoided, the Kisqali dose should be reduced. Concomitant administration with other medicines that could affect cardiac repolarization or prolong the QT/QTc interval should be taken into account prior to and during treatment with Kisqali. Patients taking sensitive CYP3A4 substrates with narrow therapeutic index should use caution because of the increased risk of adverse events that may occur if these medications are co-administered with Kisqali.

Kisqali contains soya lecithin and therefore it should not be taken by patients who are allergic to peanut or soya.

Animal studies suggest that Kisqali may cause fetal harm in pregnant women. Therefore, as a precaution, women of childbearing potential should use effective contraception while receiving Kisqali during treatment and up to 21 days after stopping treatment. Women should not breast feed for at least 21 days after the last dose of Kisqali. Kisqali may affect fertility in males.

Please see full Prescribing Information for Kisqali, available at www.kisqali.com.

Disclaimer
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