On September 21, 2020 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted cancer therapeutics and utilizing a cost efficient, CRO-independent product development platform to partner with ex-U.S. companies to develop and commercialize innovative products in the U.S., reported updated clinical data from the pivotal trial of envafolimab in MSI-H/dMMR cancer patients that were recently presented by the Company’s corporate partners, 3D Medicines and Alphamab Oncology (Press release, Tracon Pharmaceuticals, SEP 21, 2020, View Source [SID1234565418]).

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!

In a presentation highlighting updated clinical results at the Chinese Society of Clinical Oncology (CSCO) 2020 Virtual Scientific Program entitled, "Subcutaneous Injection of PD-L1 Antibody Envafolimab (KN035) in Advanced Tumors with Mismatch-Repair Deficiency," single agent envafolimab was shown to have a 32% confirmed objective response rate (ORR) by central radiographic review of 41 patients with MSI-H/dMMR colorectal cancer (CRC) who failed a fluoropyrimidine, oxaliplatin and irinotecan, and had at least two on-study tumor assessments. Duration of response (DOR) was greater than or equal to 12 months in 75% of patients and overall survival (OS) was greater than or equal to 12 months in 65% of patients. The ORR in the overall population (N=103) was 43%, DOR was greater than or equal to 12 months in 92% of patients and OS was greater than or equal to 12 months in 75% of patients. Envafolimab demonstrated good tolerability and safety and there continued to be no infusion-related reactions.

Earlier data from this trial were presented by 3D Medicines and Alphamab Oncology at ASCO (Free ASCO Whitepaper) 2020, in a presentation entitled, "Envafolimab (KN035) in Advanced Tumors with Mismatch-Repair Deficiency," at which time single agent envafolimab was shown to have a 28% confirmed ORR by central radiographic review in 39 patients with MSI-H/dMMR CRC who failed a fluoropyrimidine, oxaliplatin and irinotecan, and had at least two on-study tumor assessments. The trial enrolled 103 patients with MSI-H CRC, GC or with dMMR in other advanced solid tumors at clinical sites in China, in an open label format with efficacy endpoints, including the primary endpoint of confirmed ORR determined by independent central review. MSI-H/dMMR status was assessed centrally for CRC and GC and locally for other tumors.

The confirmed ORR in MSI-H/dMMR colorectal cancer patients treated with envafolimab who failed a fluoropyrimidine, oxaliplatin and irinotecan reported at CSCO 2020 of 32% is similar to the 28% confirmed ORR reported in the Opdivo package insert in MSI-H/dMMR colorectal cancer patients who failed a fluoropyrimidine, oxaliplatin, and irinotecan, and the 27.9% confirmed ORR reported for Keytruda in MSI-H/dMMR CRC patients who failed a fluoropyrimidine, oxaliplatin and irinotecan seen in cohort A of the pivotal KEYNOTE-164 trial.

"The CSCO 2020 data provide further clinical evidence that envafolimab’s activity is similar to that of Opdivo and Keytruda in MSI-H/dMMR cancer. Also impressive is the durability of response at 12 months," said James Freddo, M.D., TRACON Chief Medical Officer. "Given the 4% ORR reported in the pivotal study of Votrient, the only approved therapy for refractory UPS and MFS, and the demonstrated efficacy of immune checkpoint

4350 La Jolla Village Drive ● Suite 800 ● San Diego, California 92122 ● P: 858.550.0780 ● F: 858.550.0786

URL: www.traconpharma.com

inhibitors in these populations, we believe the clinical results of our ENVASARC pivotal trial, if positive, could position envafolimab as a transformative new standard of care for sarcoma patients. Moreover, the elimination of PD-L1 associated infusion-related reactions observed to date and the convenience provided by envafolimab as the only subcutaneously administered PD-L1 inhibitor currently being studied in registrational trials, could provide significant benefits for clinicians and their patients."

About ENVASARC

Key elements for the planned ENVASARC pivotal trial include:

Multi-center, open-label, randomized, non-comparative, parallel cohort study at approximately 25 top cancer centers in the United States.

Eligible patients will have undifferentiated pleomorphic sarcoma (UPS) or myxofibrosarcoma (MFS) and received one or two prior cancer therapies, but no prior immune checkpoint inhibitor therapy.

Planned total enrollment of 160 patients, with 80 patients enrolled into cohort A of treatment with single agent envafolimab and 80 patients enrolled in cohort B of treatment with envafolimab and Yervoy.

Primary endpoint of confirmed ORR with duration of response a key secondary endpoint.

Open-label format with blinded independent central review of efficacy endpoint data.

About Envafolimab

Envafolimab (KN035), a novel, single-domain antibody against PD-L1, is the first subcutaneously administered PD-(L)1 inhibitor to be studied in registrational trials. Envafolimab is currently dosing in a Phase 2 registration trial as a single agent in MSI-H/dMMR advanced solid tumor patients and a Phase 3 registration trial in combination with gemcitabine and oxaliplatin in advanced biliary tract cancer patients in China. 3D Medicines and Alphamab Oncology, TRACON’s corporate partners for this program, plan to submit a BLA to the NMPA in China for envafolimab in 2020 based on the ORR in MSI-H/dMMR advanced solid tumor patients. The confirmed ORR in MSI-H/dMMR colorectal cancer patients treated with envafolimab who failed a fluoropyrimidine, oxaliplatin and irinotecan reported at CSCO 2020 was 32%, which was similar to the 28% confirmed ORR reported in the Opdivo package insert in MSI-H/dMMR colorectal cancer patients who failed a fluoropyrimidine, oxaliplatin, and irinotecan and the 27.9% confirmed ORR reported for Keytruda in MSI-H/dMMR CRC patients who failed a fluoropyrimidine, oxaliplatin and irinotecan in cohort A of KEYNOTE-164.

On September 21, 2020 Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, and BeiGene, Ltd., (Nasdaq:BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative medicines worldwide, reported that the first patient has been dosed in the DisTinGuish study, a Phase 2a clinical trial evaluating Leap’s investigational anti-Dickkopf-1 antibody (DKK1), DKN-01, in combination with tislelizumab, BeiGene’s anti-PD-1 antibody, with or without chemotherapy, in patients with gastric or gastroesophageal junction cancer (G/GEJ) (Press release, Leap Therapeutics, SEP 21, 2020, View Source [SID1234565416]).

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!

"Dosing of the first patient in the DisTinGuish study is a key milestone for the DKN-01 development program," said Cynthia Sirard, M.D., Chief Medical Officer of Leap Therapeutics. "We are excited to have the opportunity to combine DKN-01 with tislelizumab due to the promising signals in a DKK1 biomarker-defined population of esophagogastric cancer patients. We look forward to working closely alongside BeiGene to evaluate this potential new combination therapy for a patient population with a high global unmet medical need."

The DisTinGuish trial (NCT04363801) is a Phase 2a, nonrandomized, open-label, multicenter study of DKN-01 in combination with tislelizumab with or without chemotherapy as first-line or second-line therapy in adult patients with inoperable, locally advanced G/GEJ adenocarcinoma. The study, which will be conducted in two parts, is expected to enroll up to 72 patients.

Part A will enroll up to 24 patients with G/GEJ adenocarcinoma who have received no prior systemic treatment in the locally advanced/metastatic setting (first-line treatment), and Part B will enroll up to 48 patients with previously treated, inoperable, locally advanced or metastatic DKK1-high G/GEJ adenocarcinoma (second-line treatment). The study is designed to evaluate safety, tolerability, and efficacy of the combination therapy of intravenous DKN-01 and tislelizumab ± CAPOX (capecitabine + oxaliplatin) in G/GEJ adenocarcinoma patients. Treatment will be conducted in repeating 21-day cycles until the patient meets pre-established criteria for discontinuation or is no longer deriving clinical benefit. Part A and Part B of the study will be conducted concurrently.

Leap is conducting this combination study in the United States as part of an exclusive option and license agreement with BeiGene for the development of DKN-01 in Asia (excluding Japan), Australia and New Zealand. Leap retains exclusive rights for the development, manufacturing and commercialization of DKN-01 for the rest of the world.

About DKN-01

DKN-01 is a humanized monoclonal antibody that binds to and blocks the activity of the Dickkopf-1 (DKK1) protein, a modulator of Wnt/Beta-catenin signaling, a signaling pathway frequently implicated in tumorigenesis and suppressing the immune system. DKK1 has an important role in tumor cell signaling and in mediating an immuno-suppressive tumor microenvironment through enhancing the activity of myeloid-derived suppressor cells and downregulating NK ligands on tumor cells. DKN-01 has received Orphan Drug Designation for the treatment of gastric and gastroesophageal junction cancer from the U.S. Food and Drug Administration.

About Tislelizumab

Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is approved by the China National Medical Products Administration (NMPA) as a treatment for patients with classical Hodgkin’s lymphoma who received at least two prior therapies and for patients with locally advanced or metastatic urothelial carcinoma (UC) with PD-L1 high expression whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In addition, three supplemental new drug applications (sNDAs) for tislelizumab have been accepted by the Center for Drug Evaluation (CDE) of the NMPA and are under review – for first-line treatment of patients with advanced squamous non-small cell lung cancer (NSCLC) in combination with chemotherapy, for first-line treatment of patients with advanced non-squamous NSCLC in combination with chemotherapy, and for previously treated unresectable hepatocellular carcinoma.

Tislelizumab is not approved for use outside of China.

About gastric / gastroesophageal junction cancer

Gastric adenocarcinoma (gastric cancer) remains one of the most common and deadly cancers worldwide, especially among older malesi. Based on GLOBOCAN 2018 data, stomach cancer is the 5th most common neoplasm and the 3rd most deadly cancer, with an estimated 783,000 deaths globally in 2018i. Ninety-five percent of cancers of the stomach are adenocarcinomas i. Gastric cancer incidence and mortality are highly variable by region and highly dependent on diet and Helicobacter pylori infectioni. The gastroesophageal junction (GEJ) is the area where the esophagus and stomach join together. Given its anatomic location, GEJ adenocarcinomas have often been grouped together with either esophageal or gastric cancers in clinical trials.

On September 21, 2020 MacroGenics, Inc. (Nasdaq: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported that a $15 million milestone payment has been triggered under its exclusive global collaboration and license agreement with Incyte for retifanlimab (MGA012), an investigational anti-PD-1 monoclonal antibody designed by MacroGenics and licensed to Incyte (as INCMGA00012) (Press release, MacroGenics, SEP 21, 2020, View Source [SID1234565415]). The milestone was triggered by the initiation of the Phase 3 POD1UM-304 clinical trial, evaluating the efficacy and safety of retifanlimab with platinum-based chemotherapy in patients with metastatic squamous and non-squamous non-small cell lung cancer (NSCLC).

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!

MacroGenics and Incyte have each established multiple development programs for retifanlimab, evaluating the anti-PD-1 molecule either as monotherapy or in combination with other agents. Incyte is conducting clinical trials that are potentially registration-enabling for patients with metastatic NSCLC, squamous carcinoma of the anal canal (SCAC), MSI-high endometrial cancer, Merkel cell carcinoma, and MacroGenics is conducting a potentially registration-enabling study in HER2-positive gastric cancer.

"Anti-PD-1 therapy has become a mainstay in cancer treatment across multiple tumor types, and we are excited to see our Incyte partnership continue to advance the development of retifanlimab across a broad set of monotherapy and combination regimens," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "We look forward to continued progress on this program over the coming months."

Under the collaboration agreement with Incyte, MacroGenics is eligible to receive up to a total of $390 million in potential remaining development and regulatory milestones and up to $330 million in potential commercial milestones. If retifanlimab is approved and commercialized, MacroGenics would be eligible to receive royalties, tiered from 15 to 24 percent, on future worldwide net sales of the molecule.

On September 21, 2020 Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage biotechnology developing allogeneic CAR T and in vivo gene correction therapies with its ARCUS genome editing platform, and SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported they have entered into a clinical trial collaboration agreement. Per the agreement, PBCAR269A, Precision BioSciences’ wholly-owned investigational allogeneic chimeric antigen receptor (CAR) T cell therapy candidate targeting B-cell maturation antigen (BCMA), will be evaluated in combination with nirogacestat, SpringWorks’ investigational gamma secretase inhibitor (GSI), in patients with relapsed or refractory multiple myeloma (Press release, Precision Biosciences, SEP 21, 2020, View Source [SID1234565414]).

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!

"Based on recent clinical data using GSIs in combination with BCMA-targeted therapies, it is exciting to combine these agents in patients who have a need for better therapies," said Nina Shah, M.D., study Principal Investigator and Associate Professor in the Department of Medicine at the University of California, San Francisco. "I look forward to the data generated from this investigational study to see if PBCAR269A plus nirogacestat improves clinical outcomes in patients with multiple myeloma."

Gamma secretase inhibition has been shown preclinically to enhance the activity of BCMA-targeted therapies by preventing the cleavage and shedding of BCMA from the surface of myeloma cells, which increases the cell surface density of BCMA and reduces levels of soluble BCMA. Via this mechanism, nirogacestat may enhance the activity of BCMA-targeted therapies.1 Emerging clinical data also suggest that a GSI may increase antitumor efficacy of BCMA-targeted autologous CAR T therapy in patients with relapsed or refractory multiple myeloma.2,3

"In June, we initiated our Phase 1/2a clinical trial of PBCAR269A, which targets BCMA for the treatment of relapsed or refractory multiple myeloma and has demonstrated anti-tumor activity in preclinical disease models," said Chris Heery, M.D., Chief Medical Officer at Precision BioSciences. "Preclinical data from our own program as well as others have suggested the importance of gamma secretase inhibition to unlock the full potential of BCMA targeted therapies. We look forward to further evaluating this in the clinic."

Under the terms of the agreement, Precision BioSciences will assume all development costs of the expanded Phase 1/2a study of PBCAR269A to include nirogacestat and evaluate the safety and preliminary clinical activity of the combination therapy. Precision BioSciences and SpringWorks will form a joint development committee to oversee the clinical study, which is expected to commence in the first half of 2021, pending discussions with regulators.

Exhibit 99.1

"Patients with multiple myeloma are in great need of treatment advances," said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. "We continue to believe that nirogacestat has the potential to become a cornerstone of BCMA combination therapy for these patients and are pleased to work with Precision BioSciences and their leading group of scientific advisors and clinical investigators to evaluate the combination of our gamma secretase inhibitor with their ‘off-the-shelf’ CAR T therapy."

About PBCAR269A

PBCAR269A is an allogeneic BCMA-targeted CAR T cell therapy candidate being evaluated for the safety and preliminary clinical activity in a Phase 1/2a multicenter, nonrandomized, open-label, parallel assignment, single-dose, dose-escalation, and dose-expansion study of adults with relapsed or refractory multiple myeloma. The starting dose of PBCAR269A is 6 x 105 CAR T cells/kg body weight with subsequent cohorts receiving escalating doses to a maximum dose of 6 x 106 CAR T cells/kg body weight.

PBCAR269A is the company’s third CAR T candidate to advance to the clinic and is part of a pipeline of cell-phenotype optimized allogeneic CAR T therapies derived from healthy donors and then modified via a simultaneous TCR knock-out and CAR T knock-in step with the Company’s proprietary ARCUS genome editing technology. Precision BioSciences optimizes its CAR T therapy candidates for immune cell expansion in the body by maintaining a high proportion of naïve and central memory CAR T cells.

The U.S. Food and Drug Administration (FDA) recently granted Fast Track Designation to PBCAR269A for the treatment of relapsed or refractory multiple myeloma for which the FDA previously granted Orphan Drug Designation. The PBCAR269A clinical trial will be conducted at multiple U.S. sites. For more information, visit www.clinicaltrials.gov, study identifier number NCT04171843.

About Nirogacestat

Nirogacestat is an investigational, oral, selective, small molecule, gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth.

In addition, gamma secretase has been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain, or ECD, from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has four collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies and a bispecific antibody. In addition, SpringWorks and Fred Hutchinson Cancer Research Center have entered into a sponsored research agreement to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA directed therapies using a variety of preclinical and patient-derived multiple myeloma models developed by researchers at Fred Hutch.

Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors (June 2018) and from the European Commission for the treatment of soft tissue sarcoma (September 2019). The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis (November 2018 and August 2019).

On September 21, 2020 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported the results of the final overall survival (OS) analysis from its global Phase 3 ClarIDHy trial of TIBSOVO (ivosidenib tablets) in previously treated cholangiocarcinoma patients with an isocitrate dehydrogenase 1 (IDH1) mutation (Press release, Agios Pharmaceuticals, SEP 21, 2020, View Source [SID1234565409]). A consistent trend in improved OS was observed in patients treated with TIBSOVO compared to those randomized to placebo, but was not statistically significant. The OS endpoint can be affected by crossover, so these results should be taken in the context of the large proportion (70%) of patients in the placebo arm who crossed over to receive TIBSOVO following radiographic disease progression; additional analyses performed to take crossover into account further support that TIBSOVO may improve OS. The safety profile observed in the study was consistent with previously published data. OS was a secondary endpoint in the ClarIDHy study; as previously announced, the study met its primary endpoint of progression-free survival (HR 0.37, p-value < 0.0001).

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!

"Advanced cholangiocarcinoma is a rapidly progressing, aggressive disease with a grim prognosis for patients," said Chris Bowden, M.D., chief medical officer at Agios. "The data from the ClarIDHy Phase 3 study show that treatment with TIBSOVO has the potential to lengthen time to disease progression and have a clinically meaningful impact on life expectancy for patients with IDH1-mutant cholangiocarcinoma. We will collaborate closely with regulators to advance this potential new oral, targeted treatment option for patients."

"We are tremendously grateful to the patients who participated in this study," continued Dr. Bowden. "Part of their legacy is their commitment to contributing to medical advances on behalf of others who will face this devastating disease and who currently have limited treatment options."

The company plans to submit a supplemental new drug application for TIBSOVO in previously treated IDH1-mutant cholangiocarcinoma in the first quarter of 2021 and intends to work closely with regulators on next steps. A full analysis of the ClarIDHy OS data will be submitted for presentation at a future medical meeting.

ClarIDHy Phase 3 Trial
The ClarIDHy trial is a global, randomized Phase 3 trial in previously treated IDH1-mutant cholangiocarcinoma patients who have documented disease progression following one or two systemic therapies in the advanced setting. Patients were randomized 2:1 to receive either single-agent TIBSOVO 500 mg once daily or placebo with crossover to TIBSOVO permitted at the time of documented radiographic progression per RECIST 1.1. As of the May 30, 2020 data cutoff, 185 patients were randomized, with 124 patients in the TIBSOVO arm and 61 patients in the placebo arm. Forty-three patients randomized to placebo (70%) crossed over to open-label TIBSOVO upon radiographic disease progression and unblinding.

The primary endpoint of the ClarIDHy trial is progression-free survival (PFS) as evaluated by independent radiology review. Results from the trial demonstrated a statistically significant improvement in PFS among patients randomized to TIBSOVO compared with placebo patients (hazard ratio [HR] 0.37; 95% CI 0.25 – 0.54, p<0.0001), with a median PFS of 2.7 months in the TIBSOVO arm versus a median PFS of 1.4 months in the placebo arm. The estimated PFS rate was 32% at six months and 22% at 12 months for patients randomized to TIBSOVO, while no patients randomized to placebo were free from progression or death beyond six months as of the data cut-off. Secondary endpoints include investigator-evaluated PFS, safety and tolerability, overall response rate, overall survival, duration of response, pharmacokinetics, pharmacodynamics and quality of life assessments.

Data from the study were previously presented at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper), held in September 2019 in Barcelona, Spain, and published in The Lancet Oncology on May 13, 2020. Based on these data, the National Comprehensive Cancer Network (NCCN) guidelines, the French National Treatment Guidelines for Biliary Cancer and the Italian Clinical Practice Guidelines on Cholangiocarcinoma were updated to recommend treatment with TIBSOVO for patients with advanced previously treated IDH1-mutant cholangiocarcinoma.

TIBSOVO is not approved in any country for the treatment of patients with previously treated advanced IDH1-mutant cholangiocarcinoma.

About Cholangiocarcinoma
Cholangiocarcinoma 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. IDH1 mutations occur in approximately 10% of cholangiocarcinoma cases. Current treatment options for localized disease include surgery, radiation and/or other ablative treatments. There are no approved systemic therapies for IDH1-mutated cholangiocarcinoma and limited chemotherapy options are available in the advanced setting. Gemcitabine-based chemotherapy is often recommended for newly diagnosed advanced or metastatic disease.

About TIBSOVO (ivosidenib)
TIBSOVO is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:

Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
Adult patients with relapsed or refractory AML.
IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions including laboratory abnormalities (≥20%) were hemoglobin decreased (60%), fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline phosphatase increased (30%), mucositis (28%), aspartate aminotransferase increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged (24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).
In patients with newly diagnosed AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
In patients with relapsed or refractory AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.
Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.
Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.