Agios presents final data from phase III ClarIDHy study of tibsovo in patients with previously treated IDH1-Mutant cholangiocarcinoma.

Agios Pharmaceuticals, Inc. reported a full analysis of the final data, including mature overall survival (OS) results, from its global Phase III ClarIDHy trial of Tibsova (ivosidenib tablets) in patients with previously treated isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma. Data from the study were featured in an oral presentation at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI), which is being held virtually January 15-17, 2021. The final analysis showed an improvement in the secondary endpoint of OS favoring patients randomized to Tibsova 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. claridhy phase iii trial : the claridhy trial is a global, randomized phase iii 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 tibsova 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: i. 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)." ii. 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). iii. 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. iv.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. v.treatment with tibsova 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)." vi.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. vii. 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 : i. 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). ii. teaes leading to discontinuation were more common with placebo compared with total tibsovo(8.5% vs. 6.6%). iii. 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. iv.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), 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. “the progression-free survival and overall survival data from the claridhy phase iii 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.”>