FDA Approval Summary: Ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an IDH1 mutation

Abstract

On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular isocitrate-dehydrogenase-1 (IDH1) mutated cholangiocarcinoma (CCA) as detected by an FDA-approved test with disease progression after 1–2 prior lines of systemic therapy for advanced disease. The approval was based on data from Study AG120-C-005 (ClarIDHy), a double-blind placebo-controlled trial which randomly allocated (2:1) patients to receive either ivosidenib or placebo. Independently-assessed progression free survival (PFS) was the primary endpoint. With a median follow up of 6.9 months, the hazard ratio for PFS was 0.37 (95% confidence interval 0.25, 0.54, p< 0.0001). Overall survival (OS) was the key secondary endpoint. At the final analysis of OS, with 70.5% patients in the placebo arm receiving ivosidenib post disease progression, a non-statistically significant improvement in the ivosidenib arm with a HR = 0.79 (95% CI: 0.56, 1.12) and median OS of 10.3 months (95% CI 7.8, 12.4) and 7.5 months (95% CI 4.8, 11.1) in the ivosidenib and placebo arms respectively were reported. Adverse reactions occurring in >20% of patients receiving ivosidenib were fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, and decreased appetite. Adverse reactions occurring in >20% of patients receiving placebo were fatigue/asthenia, nausea, abdominal pain, and vomiting. This is the first approval for the subset of patients with CCA harboring an IDH1 mutation.

Introduction

In 2018, an estimated 8000 adults in the US were diagnosed with cholangiocarcinoma (CCA) (1). Risk factors vary by geographic region, including liver flukes, chronic liver diseases and cirrhosis, biliary stones, metabolic conditions including obesity, diabetes, and nonalcoholic fatty liver disease, and hepatitis B and C viruses (2,3). CCA is often advanced and incurable at the time of diagnosis, with a 5-year survival of less than 10%. In patients with advanced disease with prior treatment, median overall survival (OS) is approximately 6 months (4,5).

Isocitrate dehydrogenase (IDH) enzymes catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate during cellular metabolism. In a recently published review of 5,393 patients with CCA, 10.4% had mutations in the IDH1 isoform (IDH1m); most of these patients had intrahepatic CCA (incidence 13.1% vs. 0.8% in patients with extrahepatic CCA). The frequency of IDH1m in patients with intrahepatic CCA has been reported to range from 4.5–55.6%, with an estimated prevalence of 18.0% in US centers (6). The prognostic effect of IDH1m appears uncertain (6).

Ivosidenib is a small-molecule inhibitor of IDH1m that was approved on July 20, 2018, for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with susceptible IDH1 mutations (R132C, R132G, R132H, R132S, and R132L) (7). Preliminary activity assessment in an early dose-finding study of ivosidenib led to the conduct of a randomized trial (AG120-C-005) intended to support expansion of the indication to include the treatment of previously treated, locally advanced or metastatic CCA with an IDH1 mutation (8).

The authors summarize the FDA’s review of data supporting the approval of ivosidenib for the treatment of patients of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an FDA-approved test. The Investigators’ analyses and interpretation of the data have been previously published (9, 10).

Clinical Trial Design

ClarIDHy (AG120-C-005, NCT02989857) was an international, double-blind, placebo-controlled, randomized (2:1) two-arm trial in patients with previously treated, locally advanced or metastatic CCA with an IDH1 R132 (C/G/H/L/S) mutation based on central lab testing using a Next Generation Sequencing (NGS) assay. The primary objective was to evaluate the progression-free survival (PFS) of patients randomized to ivosidenib vs placebo. Eligible patients had measurable disease, documented disease progression following at least 1 and no more than 2 prior systemic chemotherapies for advanced disease (containing gemcitabine or 5-fluorouracil), and Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Randomization was stratified by number of prior therapies (1 vs. 2). Patients received either ivosidenib 500 mg orally daily or placebo. Treatment was administered until intolerable toxicity or disease progression. Patients randomized to the placebo arm who continued to meet eligibility criteria at the end of treatment were given the opportunity to cross over to the investigational arm and receive ivosidenib.

Disease response and progression were measured at baseline and every 6 weeks until Week 54, and every 9 weeks thereafter. The primary endpoint was progression-free survival (PFS) using RECIST 1.1 (11) as assessed by an Independent Review Committee (IRC). Key secondary endpoints were OS, IRC- and investigator-assessed overall response rate (ORR), and duration of response.

With a planned sample size of 186 patients randomized 2:1 to the ivosidenib and placebo arms, and with 131 PFS events, the study had 96% power to detect a hazard ratio (HR) of 0.5 for PFS using a log-rank test at a one-sided significance level of 0.025 (median improvement vs. control of 4.9 months). Two OS analyses were planned only if PFS was statistically significant: an interim analysis at the time of PFS analysis when 131 PFS events occurred and a final analysis at the occurrence of 150 deaths. The Type I error rate for OS analyses was controlled using the gamma spending function (gamma=−8). Assuming an HR of 0.67 for OS (median OS of 8 months in the placebo arm vs. 12 months in the ivosidenib arm), a total of 150 OS events would have provided 64% power at a 1-sided alpha of 0.025.

The efficacy analyses were conducted in the intention-to-treat population (ITT), defined as all patients who were randomly assigned to treatment. The stratified log-rank test was used to compare OS and PFS between arms and the Cox proportional hazard model was used to estimate the hazard ratios. Kaplan–Meier (KM) methodology was applied to summarize PFS and OS. Safety was analyzed in patients who received at least one dose of study treatment.

Results

Efficacy

As of the data cutoff date of January 31, 2019, the PFS and interim OS analyses were based on the ITT population of 185 patients (124 patients in ivosidenib and 61 patients in placebo) enrolled in six countries (France, Italy, South Korea, Spain, UK and U.S). Baseline demographics and disease characteristics were balanced (Table 1). A mere 2 patients (1.1%) across both arms reported Black or African American race and 9 patients (4.9%) reported Hispanic or Latino ethnicity. As of the data cutoff date of May 31, 2020, the final OS analysis was based on the ITT population of 187 patients (126 patients in ivosidenib and 61 patients in placebo); this analysis included two patients randomized after the data cutoff date for the PFS analysis.

Table 1 –

ClarIDHy Trial : Baseline demographics and disease characteristics

	Ivosidenib (n= 124)	Placebo (n= 61)
Median age, years (range)	61 (33–80)	63 (40–83)
Sex
Female, n (%)	80 (65%)	37 (61%)
Male, n (%)	44 (35%)	24 (39%)
Race
White	71 (56%)	35 (57%)
Asian	15 (12%)	8 (13%)
Black	1 (1%)	1 (2%)
Other	3 (2%)	0
Missing/not reported	36 (29%)	17 (28%)
Ethnicity
Hispanic or Latino	7 (6%)	2 (3%)
Not Hispanic or Latino	84 (67%)	40 (66%)
Missing/not reported	35 (28%)	19 (31%)
ECOG
PS 0, n (%)	49 (40%)	19 (31%)
PS 1, n (%)	74 (60%)	41 (67%)
Prior lines of therapy
One prior line, n (%)	66 (53%)	33 (54%)
Two prior lines, n (%)	58 (47%)	28 (46%)
Primary tumor location
Intrahepatic, n (%)	111 (90%)	58 (95%)
Extrahepatic, n (%)	1 (<1%)	1 (2%)
Perihilar, n (%)	4 (3%)	0
Unknown, n (%)	8 (5%)	2 (3%)
Extent of disease
Metastatic1, n (%)	115 (93%)	56 (92%)
Locoregional, n (%)	9 (7%)	5 (8%)
IDH1 mutation
R132C, n (%)	84 (68%)	45 (74%)
R132G, n (%)	17 (14%)	6 (10%)
R132H, n (%)	0	2 (3%)
R132L, n (%)	21 (17%)	7 (11%)
R132S, n (%)	2 (2%)	1 (2%)

ECOG PS: Eastern Cooperative Group Performance Status; IDH: isocitrate dehydrogenase

¹Patients with both locoregional and metastatic disease are considered metastatic

Source: FDA analysis, unpublished data

At the time of the analysis of PFS, 126 PFS events were observed. With a median follow up of 6.9 months, the AG120-C-005 trial demonstrated a statistically significant improvement in PFS, with a HR of 0.37 (95% confidence interval [CI]: 0.25, 0.54, p <0.0001); the estimated median PFS was 2.7 months (95% CI: 1.6, 4.2) in the ivosidenib arm vs. 1.4 months (95% CI: 1.4, 1.6) in the placebo arm (Figure 1). The prespecified interim OS analysis conducted with 78 deaths (42% of the population) did not cross the alpha boundary for statistical significance. The median OS was 10.8 months (95% CI: 7.7, 17.6) in the ivosidenib arm compared to 9.7 months (95% CI: 4.8, 12.1) in the placebo arm (HR 0.69 [95% CI: 0.44, 1.10]; p=0.06). For the final OS analysis, 43 patients (70.5%) originally assigned to placebo received ivosidenib post-progression. The estimate for OS was longer in the ivosidenib arm with a HR of 0.79 (95% CI: 0.56, 1.12) with a median OS of 10.3 months (95% CI 7.8, 12.4) in the ivosidenib arm compared to 7.5 months (95% CI 4.8, 11.1) in the placebo arm (Figure 2); however, this effect was not statistically significant. The overall treatment effect was generally consistent across subgroups. Efficacy analyses are summarized in Table 2.

Figure 1-. ClarIDHy: K-M Curves of PFS.

K-M: Kaplan-Meier; PFS: progression free survival. Table at the bottom represents the number of patients at risk by treatment arm. Data from TIBSOVO Prescribing Information (15)

Figure 2 -. ClarIDHy: K-M Curves of OS.

K-M: Kaplan-Meier; OS: overall survival. Table at the bottom represents the number of patients at risk by treatment arm. Source: FDA analysis, unpublished data

Table 2 –

ClarIDHyTrial: Efficacy results

	Ivosidenib (n= 124)	Placebo (n= 61)
Progression-Free Survival by Independent Review Committee
Events, n (%)	76 (61)	50 (82)
Progressive disease, n (%)	64 (52)	44 (72)
Deaths, n (%)	12 (10)	6 (10)
Hazard ratio (95% CI)1	0.37 (0.25, 0.54)
p-value2	<0.0001
Objective Response Rate, n (%)	3 (2%)	0
Overall Survival 3	N= 126	N=61
Deaths, n (%)	100 (79)	50 (82)
Hazard ratio (95% CI)1	0.79 (0.56, 1.12)
p-value2	0.093

CI: confidence interval

¹Hazard ratio is calculated from stratified Cox regression model. Stratified by number of prior lines of therapy.

²P-value is calculated from the one-sided stratified log-rank test. Stratified by number of prior lines of therapy.

³OS results are based on the final analysis of OS (based on 150 deaths) which occurred 16 months after the final analysis of PFS without adjusting for crossover. In the analysis of OS, 70% of the patients randomized to placebo had crossed over to receive ivosidenib after radiographic disease progression.

Data from TIBSOVO Prescribing Information (15)

A prespecified sensitivity analysis using a rank preserving structural failure time (RPSFT) method (12, 13) was conducted by the Applicant to further explore the effect of crossover from the placebo arm to the ivosidenib arm, on OS. In this exploratory analysis, the HR for OS for ivosidenib compared to placebo was 0.49 (95% CI: 0.34, 0.70). These results supported the primary findings of the PFS endpoint after taking treatment cross over into consideration. However, because the assessment of OS using the RPSFT method depends upon unverifiable assumptions, this method may overestimate the treatment effect. Therefore, this analysis should be interpreted with caution.

Safety

The safety analysis was based on 182 patients who received at least one dose of ivosidenib (n: 123) or placebo (n: 59). Comparative safety data in patients randomized to the placebo arm are only included from the placebo portion of the trial (the analysis excludes data from these patients at the time of cross-over to ivosidenib). The most common treatment emergent adverse events (TEAEs) observed with at least 10% increased incidence in patients receiving ivosidenib when compared with patients receiving placebo were fatigue/asthenia, nausea, diarrhea, abdominal pain, cough, anemia, and peripheral neuropathy. The most common treatment emergent laboratory abnormalities observed with at least 10% increased incidence in patients receiving ivosidenib when compared with patients receiving placebo were increased aspartate aminotransferase, increased bilirubin, and decreased hemoglobin. Table 3 lists the most common (incidence ≥10%) TEAEs.

Table 3 -.

ClarIDHy: Safety summary

	Ivosidenib (n= 124)		Placebo (n= 59)
Adverse reaction	All Grades; n (%)	Grade ≥ 3; n (%)	All Grades; n (%)	Grade ≥ 3; n (%)
General disorders and administration site conditions
Fatigue/asthenia	53 (43)	4 (3)	18 (31)	3 (5)
Gastrointestinal disorders
Nausea	51 (41)	3 (2)	17 (29)	1 (2)
Diarrhea	43 (35)	0	10 (17)	0
Abdominal pain1	43 (35)	3 (2)	13 (22)	2 (3)
Ascites	28 (23)	11 (9)	9 (15)	4 (7)
Vomiting2	28 (23)	3 (2)	12 (20)	0
Respiratory, thoracic, and mediastinal disorders
Cough3	33 (27)	0	5 (9)	0
Metabolism and nutrition disorders
Decreased appetite	30 (24)	2 (2)	11 (19)	0
Blood and lymphatic system disorders
Anemia	22 (18)	8 (7)	3 (5)	0
Skin and subcutaneous tissue disorders
Rash4	19 (15)	1 (1)	4 (7)	0
Nervous system disorders
Headache	16 (13)	0	4 (7)	0
Peripheral neuropathy5	13 (11)	0	0	0
Investigations
ECG QT prolonged	12 (10)	2 (2)	2 (3)	0

ECG: electrocardiogram

¹Grouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, epigastric discomfort, abdominal tenderness, and gastrointestinal pain.

²Grouped term includes vomiting and retching.

³Grouped term includes cough and productive cough.

⁴Grouped term includes rash, rash maculo-papular, erythema, rash macular, dermatitis exfoliative generalized, drug eruption, and drug hypersensitivity.

⁵Grouped term includes neuropathy peripheral, peripheral sensory neuropathy, and paresthesia.

Data from TIBSOVO Prescribing Information (15)

The incidence of AEs leading to on-treatment death was 4.9% in the ivosidenib arm and 0% in the placebo arm. Most deaths in the ivosidenib arm were attributable to progressive disease. In 6 patients in the ivosidenib arm who died for reasons other than disease progression, the listed causes were pneumonia, intestinal obstruction, pulmonary embolism, hepatic encephalopathy (one patient each), and sepsis (2 patients).

The median duration of exposure to ivosidenib was 2.8 months (range: 0.1–34.4 months) and to placebo was 1.6 months (range: 0–6.9 months). TEAEs leading to study discontinuation were reported in 9 (7.3%) patients in the ivosidenib arm and 5 (8.5%) patients in the placebo arm. TEAEs leading to discontinuation of ivosidenib were intestinal obstruction, generalized edema, hyperbilirubinemia, abdominal infection, sepsis, ascites, hepatic encephalopathy (one patient each), and acute kidney injury (2 patients). The TEAEs leading to placebo discontinuation were cirrhosis, liver failure, pneumonia, wound infection, hyperkalemia, and hyponatremia. Treatment doses were reduced or held in 39% and 27% of patients in the ivosidenib and placebo arms, respectively. TEAEs of patients who crossed over and received ivosidenib were consistent with the toxicity reported in patients in the ivosidenib arm.

Regulatory considerations

This is the first FDA approval for the treatment of patients with unresectable or metastatic CCA harboring an IDH1 mutation after 1 to 2 prior lines of systemic therapy for advanced disease.

The control arm of ClarIDHy was placebo, which is an increasingly rare comparator given a growing number of available therapies in many indications. Given the efficacy of active chemotherapy is modest in second and later lines of CCA treatment, it was considered acceptable for a consented patient to forgo chemotherapy to enroll in the trial. Specifically, in Study ABC-06 for the second-line treatment of patients with CCA, patients receiving FOLFOX chemotherapy had a median OS of 6.2 months compared to 5.3 months with best supportive care alone (hazard ratio [HR] 0.69; 95% CI: 0.50–0.97; p = 0.031) (4). This OS effect observed in Study ABC-06 was modest and associated with toxicities including neutropenia and neuropathy. Even though the median PFS improvement in the ClarIDHy trial was modest, the Kaplan Meier PFS curves showed a clear separation of the arms, with further separation after the medians were reached. These results show that it can be challenging to summarize benefit in some trials when the proportional hazard assumption may not hold. Although the hazard ratio showed a large relative effect (HR 0.37), the modest median PFS difference highlights that it may not be an optimal summary measure of treatment effect in all cases. Nevertheless, sensitivity analyses of PFS using alternative methods were supportive and the benefit on PFS was consistent across most subgroups analyzed supporting the conclusion of clinically meaningful PFS improvement.

The ORR in the ivosidenib arm was low (2.4%), which in the context of the PFS results suggests that the PFS effect may be driven mostly by disease control or stable disease, consistent with ivosidenib’s postulated mechanism of action. Mutated IDH1 produces the oncometabolite 2-hydroxyglutarate (2-HG), which alters normal DNA methylation and impairs differentiation (7); ivosidenib inhibits 2-HG formation and is postulated to promote cellular differentiation rather than induce a direct cytotoxic effect.

The OS analysis was not statistically significant, but it nevertheless trended in favor of ivosidenib (HR 0.79 [95% CI: 0.56, 1.12]) with a median OS of 10.3 months (95% CI: 7.8, 12.4) with ivosidenib compared to 7.5 months (95% CI: 4.8, 11.1) with placebo. The FDA considered the results of the OS analysis in the context of 70.5% of patients in the placebo arm crossing over to receive ivosidenib upon disease progression. The exploratory but prespecified sensitivity analysis using the RPSFT method provides supportive evidence by taking treatment cross-over into consideration.

The observed safety profile of ivosidenib in patients with metastatic or unresectable relapsed or refractory IDH1 mutated CCA was generally consistent with the disease and the clinical experience with ivosidenib in patients with acute myeloblastic leukemia. Other than anemia, the incidence rates of most adverse events occurring at Grade 3 or greater severity were similar to placebo; indicating most of these appeared related to underlying disease. These risks are largely manageable with patient surveillance, treatment delays, and supportive care in most patients.

The review team concluded that the overall risk:benefit assessment favored approval of ivosidenib for the treatment of patients with relapsed/refractory advanced or metastatic cholangiocarcinoma IDH1 mutation (a mutation reported to occur in approximately 20% of patients with intrahepatic cholangiocarcinomas). The observed improvement in PFS with a HR of 0.37, supported by K-M curves and exploratory results from sensitivity analyses, is considered statistically robust and clinically meaningful. Given crossover and the uncommon frequency of the mutation, a much larger number of patients would have had to been screened to identify a sufficient number of patients to demonstrate a statistical effect on OS.

Results of the ClarIDHy trial will likely lead to a change in the paradigm for the treatment of patients with IDH1-mutated, relapsed/refractory locally unresectable or metastatic CCA, with ivosidenib likely being selected as the preferred standard of care for patients who are eligible. Prior to the approval of ivosidenib, patients were treated with chemotherapy or supportive care. As the treatment landscape of patients with CCA is now incorporating targeted drugs for patients with tumors harboring IDH1 mutations, fibroblast-growth factor receptor-2 (FGFR2) fusions or rearrangements, neurotrophic tyrosine receptor kinase (NTRK) gene fusions, microsatellite-instability high (MSI-H), and tumor mutational burden-high (TMB-H), tumor mutation profiling is warranted. Additionally, only 2 patients (1.12%) in the ClarIDHy trial were Black or African-American and 9 patients (4.8%) were Hispanic or Latino, a finding that is consistent with trials supporting other approvals for CCA. Increased efforts are needed to enroll a more representative patient population in future clinical trials (14).

Conclusions

In summary, ivosidenib for the treatment of patients with relapsed/refractory advanced or metastatic CCA with an IDH1 mutation has a favorable risk:benefit profile. The observed improvement in PFS with a HR of 0.37, supported by favorable OS trend and exploratory results from sensitivity analyses, is considered statistically robust and clinically meaningful.

Overall, the safety profile of ivosidenib is acceptable given the demonstrated benefits in patients with advanced relapsed or refractory IDH1 mutated CCA.

Ivosidenib for the treatment of patients with locally advanced or metastatic IDH1 mutated CCA with disease progression was approved on August 25, 2021. Concurrently with the approval of ivosidenib, the FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to aid in selecting patients for ivosidenib treatment. This approval adds to the increasing number of options to treat biomarker selected patients with CCA.