TIBSOVO® Improves Survival in IDH1 Mutated Advanced Cholangiocarcinoma

SUMMARY: Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia (AML) and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic Cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

TIBSOVO® (Ivosidenib) is an oral, targeted, small-molecule inhibitor of mutant IDH1. The FDA in July, 2018, approved TIBSOVO® for adult patients with relapsed or refractory AML with a susceptible IDH1 mutation. A previously published Phase I study demonstrated the safety and activity of TIBSOVO® in patients with IDH1 mutated advanced Cholangiocarcinoma.MOA-of-Ivosidenib

ClarIDHy is an international, randomized, double-blind, Phase III study, in which 187 previously treated patients with advanced Cholangiocarcinoma with an IDH1 mutation were randomly assigned 2:1 to receive TIBSOVO® 500 mg orally once daily (N=126) or matched placebo (N=61). All patients had advanced unresectable Cholangiocarcinoma. The median age was 62 years, 91% had intrahepatic Cholangiocarcinoma, 93% of patients had metastatic disease and 47% had received two prior therapies. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Safety, Objective Response Rate (ORR) and Overall Survival (OS). Crossover from placebo to TIBSOVO® was permitted upon radiographic disease progression.

This study met its Primary endpoint and the median PFS was 2.7 months for patients treated with TIBSOVO® compared to 1.4 months with placebo (HR=0.37; P<0.0001). More importantly, the median PFS at 6 and 12 months were 32% and 22% in the TIBSOVO® group, whereas no patients randomized to the placebo group were progression-free for 6 or more months, at the time of data cutoff.

The authors now reported the results of final analysis which 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 in the TIBSOVO® arm was 10.3 months compared to 7.5 months for patients in the placebo arm (HR=0.79; 1-sided P=0.093). A high proportion of patients in the placebo arm (70.5%) crossed over to TIBSOVO®. After adjusting for crossover from placebo to TIBSOVO®, the median OS for patients in the placebo arm was 5.1 months (HR=0.49; 1-sided P<0.0001).

The 6-month survival rate for patients in the TIBSOVO® arm was 69% compared to 57% of patients in the placebo arm, not adjusted for crossover. The 12-month survival rate for patients in the TIBSOVO® arm was 43% compared to 36% 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 starting cycle 2. The most common Adverse Events of any grade for TIBSOVO® were nausea (38%), diarrhea (33.1%) and fatigue (28.9%). Adverse Events leading to discontinuation were more common with placebo compared with total TIBSOVO® (8.5% versus 6.6%).

It was concluded that treatment with TIBSOVO® in patients with advanced Cholangiocarcinoma with an IDH1 mutation, resulted in significant improvement in Progression Free Survival as well as favorable Overall Survival trend, when compared to Placebo, despite a high rate of crossover. This is the first pivotal study demonstrating the clinical benefit of targeting IDH1 mutation in this patient group. This new oral, non-cytotoxic, targeted treatment option, with a tolerable safety profile, will be a welcome addition to treat this aggressive disease, for which there is an unmet need for new therapies.

Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. Zhu A, Macarulla T, Javle MM, et al. J Clin Oncol 39, 2021 (suppl 3; abstr 266)

FDA Approves PEMAZYRE®, First Targeted Therapy for Cholangiocarcinoma

SUMMARY: The FDA on April 17, 2020 granted accelerated approval to PEMAZYRE® (Pemigatinib), for the treatment of adults with previously treated, unresectable locally advanced or metastatic Cholangiocarcinoma with a Fibroblast Growth Factor Receptor 2 (FGFR2) fusion or other rearrangement, as detected by an FDA-approved test. The FDA also approved the FoundationOne® CDX (Foundation Medicine, Inc.), as a companion diagnostic for patient selection.

Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection, whereas a majority of patients at diagnosis have advanced disease. The 5-year survival is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.

FGFRs (Fibroblast Growth Factor Receptors) play an important role in tumor cell proliferation and survival, migration and angiogenesis. Activating fusions, rearrangements, translocations and gene amplifications in FGFRs result in dysregulation of FGFR signaling, and may contribute to the pathogenesis of various cancers, including Cholangiocarcinoma. FGFR2 fusions or rearrangements occur almost exclusively in intrahepatic Cholangiocarcinoma, where they are observed in 10-16% of patients. PEMAZYRE® is a potent, selective, oral kinase inhibitor of FGFR isoforms 1, 2 and 3, which in preclinical studies has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations.FGFR-Signaling-Pathway

The FIGHT-202 ((FIbroblast Growth factor receptor in oncology and Hematology Trials) is a Phase II, multi-center, open-label, single-arm study which evaluated the safety and efficacy of PEMAZYRE® (Pemigatinib) in adult patients with previously treated, locally advanced or metastatic Cholangiocarcinoma with documented FGFR2 fusion or rearrangement. Patients were enrolled into one of three cohorts: Cohort A with FGFR2 fusions or rearrangements (N=107), Cohort B with other FGF/FGFR genetic alterations (N=20) or Cohort C with no FGF/FGFR genetic alterations (N=18). All patients received PEMAZYRE® 13.5 mg orally once daily, two weeks on and one week off, on a 21-day cycle, until radiological disease progression or unacceptable toxicity. The median patient age of the entire enrolled patient group was 59 years and patients were scanned every eight weeks to assess response to PEMAZYRE®. The Primary endpoint of FIGHT-202 was Objective Response Rate (ORR) in Cohort A, assessed by Independent Review per RECIST criteria. Secondary endpoints included ORR in Cohorts B, A plus B, and C, Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS), Overall Survival (OS), and safety.

It was noted that PEMAZYRE® monotherapy resulted in an Objective Response Rate of 36%, with Complete Response Rate of 2.8% and a Partial Response Rate of 33%. Among those who had a response, 63% had a response lasting 6 months or longer and 18% had a response lasting 12 months or longer. The median Duration of Response was 7.5 months and the Disease Control Rate (DCR) was 82%. The median PFS and median OS were 6.9 months and 21.1 months, and the OS data was not mature at the time of data cutoff. In Cohorts B and C, none of the patients achieved a response. The most common Adverse Events were hyperphosphatemia, alopecia, diarrhea, fatigue, nail toxicities and dysgeusia. Hyperphosphatemia was managed with diet modifications, phosphate binders, diuretics or dose modifications. Fewer patients discontinued therapy in Cohort A compared to Cohort B and C.

It was concluded that based on Overall Response Rate and Duration of Response, PEMAZYRE® is the first and only FDA-approved treatment for previously treated patients with Cholangiocarcinoma, harboring FGFR2 gene rearrangements or fusions.

Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Lancet Oncol. 2020 Mar 20. pii: S1470-2045(20)30109-1. doi: 10.1016/S1470-2045(20)30109-1. [Epub ahead of print]

Late breaking Abstract – ESMO 2019 TIBSOVO® Improves Survival in IDH1 Mutated Advanced Cholangiocarcinoma

SUMMARY: Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.MOA-of-Ivosidenib

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia (AML) and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic CholangioCarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

TIBSOVO® (Ivosidenib) is an oral, targeted, small-molecule inhibitor of mutant IDH1. The FDA in July, 2018, approved TIBSOVO® for adult patients with relapsed or refractory AML with a susceptible IDH1 mutation. A previously published Phase I study demonstrated the safety and activity of TIBSOVO® in patients with IDH1 mutated advanced CholangioCarcinoma.

ClarIDHy is an international, randomized, double-blind, Phase III study, in which 185 patients with advanced CholangioCarcinoma with an IDH1 mutation were randomly assigned 2:1 to receive TIBSOVO® 500 mg orally once daily (N=124) or matched placebo (N=61). All patients had advanced unresectable CholangioCarcinoma. The median age was 62 years, 91% had intrahepatic CholangioCarcinoma, 92% of patients had metastatic disease and 43% had received two prior therapies. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Safety, Objective Response Rate (ORR) and Overall Survival (OS). Crossover from placebo to TIBSOVO® was permitted upon radiographic disease progression.

This study met its Primary endpoint and the median PFS was 2.7 months for patients treated with TIBSOVO® compared to 1.4 months with placebo (HR=0.37; P<0.001). More importantly, the median PFS at 6 and 12 months were 32% and 22% in the TIBSOVO® group, whereas no patients randomized to the placebo group were progression-free for 6 or more months, at the time of data cutoff. There was a favorable trend in Overall Survival with TIBSOVO® and the median OS was 10.8 months for TIBSOVO® and 9.7 months for placebo (HR=0.69, one-sided P=0.06). However, the adjusted OS among the placebo group patients was 6 months, after taking into account that 57% of these patients crossed over to TIBSOVO®, and this was significantly shorter, when compared to the TIBSOVO® group (HR=0.46; P=0.0008). Most common Adverse Events were nausea, diarrhea, fatigue, cough, abdominal discomfort, ascites, anemia and vomiting.

It was concluded that treatment with TIBSOVO® among patients with advanced CholangioCarcinoma with an IDH1 mutation, resulted in significant improvement in Progression Free Survival as well as favorable Overall Survival trend, when compared to Placebo. The authors added that this is the first pivotal study demonstrating the clinical benefit of targeting IDH1 mutation in this patient group. Studies are also underway targeting another molecular alteration, FGFR2, which is detected in approximately 15% of patients with CholangioCarcinoma. ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Abou-Alfa GK, Maraculla TM, Javle M, et al. Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA10_PR.

Adjuvant Therapy with XELODA® Improves Overall Survival in Biliary Tract Cancer

SUMMARY: Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. About 8,000 people in the US are diagnosed with bile duct cancer each year. The average age of an individual in the US diagnosed with bile duct cancer is 71 years and approximately 20% of the cases are suitable for surgical resection. The 5-year survival is less than 10%. There is no standard adjuvant therapy for patients with resectable bile duct cancer, although adjuvant intervention in a previously reported meta-analysis showed improved Overall Survival (Horgan AM, Amir E, Walter T, et al. JCO 2012;30:1934-1940).

The BILCAP trial is a phase III study conducted to determine whether XELODA® (Capecitabine) improved Overall Survival (OS) compared to Observation, following radical surgery. In this trial, 447 patients were randomized to receive XELODA® (N=223) or Observation (N=224). Eligible patients had completely resected, cholangiocarcinoma or gallbladder cancer (including liver and pancreatic resection, as appropriate), with a R0 resection (microscopically negative margin resection) for 62% and R1 resection (removal of all macroscopic disease, but microscopic margins are positive for tumor) for 38% and with negative lymph nodes in 46% of the patients. The primary disease sites were extrahepatic cholangiocarcinoma (35%), hilar (28%), intrahepatic (19%), and muscle-invasive gallbladder cancers (18%). Patients were randomized in a 1:1 ratio to receive XELODA® 1250 mg/m2, D1-14 every 21 days, for 8 cycles or Observation. The median age was 63 years and the follow up was at least 36 months in more than 80% of the surviving patients. The primary end point was Overall Survival in the Intent to Treat population and the primary analysis was performed with at least 24 months of follow up.

The median Overall Survival with XELODA® was 51 months compared with 36 months for Observation, and this was not statistically significant (P=0.097). In the sensitivity analyses however, with adjustment for nodal status, gender and grade of the disease, there was a 29% reduction in the risk of death with adjuvant XELODA®, when compared with Observation (HR=0.71; P < 0.01). In the per-protocol analysis which included 430 patients, the median Overall Survival was 53 months with adjuvant XELODA® versus 36 months with Observation, resulting in a 25% reduction in the risk of death with XELODA®, and these results were statistically significant (HR=0.75; P=0.028). The most common adverse events related to XELODA® as anticipated were, palmar plantar erythema, fatigue and diarrhea.

The authors concluded that single agent XELODA® improves Overall Survival in Biliary Tract Cancer, when used as adjuvant therapy, without a negative impact on Quality of Life. They added that this is the first phase III study to show a survival benefit in the adjuvant setting, and should become standard of care. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study. Primrose JN, Fox R, Palmer DH, et al. J Clin Oncol 35, 2017 (suppl; abstr 4006)

Adjuvant Therapy in the Treatment of Biliary Tract Cancer A Systematic Review and Meta-AnalysisAdjuvant Therapy in the Treatment of Biliary Tract Cancer A Systematic Review and Meta-Analysis

SUMMARY: The authors in this meta-analysis reviewed data on 6712 patients with biliary tract cancers, including gall bladder tumors. Ampullary tumors were excluded. These patients had resections done with a curative intent and this was defined as those with negative surgical margins (R0) or microscopic positive margins (R1). All these patients received adjuvant therapy, which included chemotherapy, radiation therapy or a combination of both, following surgery. There was an improvement in overall survival for those patients receiving adjuvant therapy. Patients who received chemotherapy or chemoradiation treatment derived greater benefit than those who received radiation therapy alone. The greatest statistically significant benefit was seen in those with lymph node positive disease and R1 disease. Based on this analysis, it may be reasonable to consider adjuvant therapy for patients with high risk biliary tract cancers. Horgan AM, Amir E, Walter T, et al. JCO  2012; 30:1934-1940