On January 17, 2021Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and genetically defined diseases, today reported a full analysis of the final data, including mature overall survival (OS) results, from its global Phase 3 ClarIDHy trial of TIBSOVO (ivosidenib tablets) in patients with previously treated isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma (Press release, Agios Pharmaceuticals, JAN 17, 2021, View Source [SID1234574070]). Data from the study were featured in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO-GI), which is being held virtually January 15-17, 2021.

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The final analysis showed an improvement in the secondary endpoint of OS favoring patients randomized to TIBSOVO compared to those randomized to placebo; however, statistical significance was not reached. The median OS for patients randomized to TIBSOVO was 10.3 months compared to 7.5 months for patients randomized to placebo (hazard ratio [HR]=0.79; 95% CI [0.56–1.12], 1-sided p=0.093). The protocol specified that patients randomized to placebo could cross over to TIBSOVO at the time of disease progression, and a high proportion of patients in the placebo arm (70.5%) crossed over to TIBSOVO. The results of a pre-specified analysis to adjust for crossover, based on the rank-preserving structural failure time (RPSFT) model, showed a median OS for patients in the placebo arm of 5.1 months (HR=0.49, 95% CI 0.34–0.70, 1-sided p<0.0001). The safety profile observed in the study was consistent with previously published data. As previously announced, the study demonstrated a statistically significant improvement in the primary endpoint of progression-free survival (PFS) by independent radiology review.

"The progression-free survival and overall survival data from the ClarIDHy Phase 3 study, coupled with a tolerable safety profile and supportive patient-reported quality-of-life data, demonstrate that TIBSOVO has the potential to be a clinically meaningful treatment option for patients with previously treated IDH1-mutant cholangiocarcinoma, an aggressive cancer with limited effective treatment options," said Andrew Zhu, M.D., Ph.D., director emeritus of liver cancer research at Massachusetts General Hospital, director of Jiahui International Cancer Center and professor of medicine at Harvard Medical School. "Treatment with TIBSOVO resulted in a consistent trend in improved overall survival, despite the high rate of crossover from the placebo arm, and this improvement was further supported by the pre-specified statistical analysis to adjust for the crossover effect. I look forward to the potential of having a new treatment option for my patients with this devastating disease."

"We are extremely pleased with the results of the ClarIDHy Phase 3 study, the first and only randomized Phase 3 trial for IDH1-mutant advanced cholangiocarcinoma, and believe TIBSOVO has demonstrated compelling results for patients facing a grim prognosis who currently have few treatment options," said Chris Bowden, M.D., chief medical officer at Agios. "We will collaborate closely with regulators to advance this potential new oral, non-cytotoxic, targeted treatment option, and we look forward to filing for U.S. approval later this quarter."

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. The primary endpoint of the ClarIDHy trial is progression-free survival (PFS) as evaluated by independent radiology review. Secondary endpoints include investigator-evaluated PFS, safety and tolerability, overall response rate, OS, duration of response, pharmacokinetics, pharmacodynamics and quality of life assessments.

As of the May 31, 2020 data cutoff, 187 patients were randomized, with 126 patients in the TIBSOVO arm and 61 patients in the placebo arm. Forty-three patients randomized to placebo (70.5%) crossed over to open-label TIBSOVO upon radiographic disease progression and unblinding.

Updated Efficacy Data
Efficacy data as of the data cutoff showed:

The median OS for patients in the TIBSOVO arm was 10.3 months compared to 7.5 months for patients in the placebo arm (HR=0.79; 95% CI [0.56–1.12], 1-sided p=0.093).
After adjusting for crossover from placebo to TIBSOVO using the pre-specified analysis of rank-preserving structural failure time (RPSFT), the median OS for patients in the placebo arm was 5.1 months (HR=0.49; 95% CI [0.34–0.70], 1-sided p<0.0001).
The 6-month survival rate for patients in the TIBSOVO arm was 69 percent compared to 57 percent of patients in the placebo arm, not adjusted for crossover.
The 12-month survival rate for patients in the TIBSOVO arm was 43 percent compared to 36 percent for patients in the placebo arm, not adjusted for crossover.
Treatment with TIBSOVO preserved patients’ physical functioning from baseline, as assessed by the EORTC QLQ-C30 questionnaire, whereas patients in the placebo arm experienced decline from baseline at cycle 2, day 1 (2-sided p=0.002) and cycle 3, day 1 (2-sided p=0.004).
Treatment with TIBSOVO improved patients’ pain at cycle 2, day 1 compared to placebo, as assessed by the EORTC QLQ-BIL21 questionnaire (2-sided p=0.039); no difference was observed at cycle 3, day 1.
Neither arm was favored on other pre-specified quality-of-life subscales (QLQ-C30 Appetite Loss and QLQ-BIL21 Pain and Eating).
Updated Safety Data

Grade 3 or above treatment-emergent adverse events (TEAE) were reported in 53 percent of total TIBSOVO patients, which includes patients originally randomized to TIBSOVO and those who crossed over from placebo to TIBSOVO, compared to 37.3 percent of patients on placebo, with the most common being ascites (9.0% total TIBSOVO vs. 6.8% placebo), anemia (7.2% total TIBSOVO vs. 0% placebo) and increased blood bilirubin (5.4% total TIBSOVO vs. 1.7% placebo).
TEAEs leading to discontinuation were more common with placebo compared with total TIBSOVO (8.5% vs. 6.6%).
TEAEs leading to dose reductions (3.0% vs. 0%) and interruptions (30.1% vs. 18.6%) were more common with total TIBSOVO compared with placebo.
The most common TEAEs of any grade for total TIBSOVO were nausea (38.0%), diarrhea (33.1%) and fatigue (28.9%).
Previously Reported Data
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. Results from the trial demonstrated a statistically significant improvement in the primary endpoint of PFS among patients randomized to TIBSOVO compared with placebo patients (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 percent at six months and 22 percent 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.

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.

Agios plans to submit a supplemental new drug application for TIBSOVO in previously treated IDH1-mutant cholangiocarcinoma in the first quarter of 2021.

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 AML 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.