Oral IDH1 Inhibitor Ivosidenib Holds Rare Liver Cancer at Bay for 35 Months in Case Report

A rare and stubborn form of liver cancer that carries mutations in the metabolic enzyme isocitrate dehydrogenase-1 has been held in check for nearly three years with a once-daily oral tablet, according to a case report published in the journal Drugs & Therapy Perspectives. The report describes a 55-year-old man with combined hepatocellular–cholangiocarcinoma, an uncommon primary liver tumor that contains both hepatocellular carcinoma and cholangiocarcinoma components, whose disease had already failed standard first-line chemotherapy. After switching to ivosidenib, a targeted inhibitor of mutated IDH1, his main liver tumor shrank from 11.5 centimeters to 7.5 centimeters and then remained stable for the rest of the observation period. By the time of the report, he had been receiving the drug for 35 months, continued to take it without any documented adverse events, and remained alive and well.

The case matters because combined hepatocellular–cholangiocarcinoma, abbreviated cHCC-CCA, sits awkwardly between the two better-known liver cancers. It features malignant cells of bile duct origin alongside hepatocyte-like tumor cells, is thought to arise from the malignant transformation of hepatic progenitor cells, and displays substantial intratumoral heterogeneity. Diagnosis does not depend on the relative proportions of the two components, which makes the tumor difficult to classify and, consequently, difficult to treat. The disease accounts for between 0.4 and 14.2 percent of primary liver cancers, and its outlook is grim: published figures include a median disease-free survival of 13.7 months and a median overall survival of 9 to 17.2 months. Larger tumors of 5 centimeters or more, higher TNM stage, and elevated serum alpha-fetoprotein at 200 nanograms per milliliter or above, or raised carcinoembryonic antigen, have all been associated with poorer overall survival.

Because the tumor combines features of two distinct cancer types, treatment cannot simply follow the playbook for either one. There is currently no standardized treatment protocol for cHCC-CCA. Surgical resection is the only curative option, but tumors are often unresectable and recurrence after surgery is high. Other approaches include liver transplantation and locoregional liver-directed therapies such as transarterial chemoembolization and radiofrequency ablation. For unresectable disease, systemic options borrow from both parent cancers: the cisplatin plus gemcitabine combination, commonly used with immunotherapy in cholangiocarcinoma, or sorafenib, commonly used in hepatocellular carcinoma. In later lines of therapy, clinicians can potentially personalize treatment using the tumor’s gene profile, targeting alterations frequently seen in cholangiocarcinoma, including HER2, FGFR2 and IDH1.

The most commonly mutated genes in cHCC-CCA are TP53, TERT and PTEN, but IDH1 mutations have also been identified as a common aberration, correlated with the cholangiocellular subtype of the tumor. The IDH1 protein is a key metabolic enzyme in the cytoplasm that normally catalyzes the conversion of isocitrate to alpha-ketoglutarate, generating NADPH in the process. When the gene is mutated, the resulting protein instead catalyzes the reduction of alpha-ketoglutarate to 2-hydroxyglutarate, a reaction that consumes NADPH. This metabolic switch makes cells vulnerable to oxidative stress, induces epigenetic dysregulation and impairs cellular differentiation, driving tumorigenesis. Mutated IDH1 also promotes tumor maintenance through immune-evasive activity, giving the mutation a double role in cancer biology.

Ivosidenib was designed to exploit precisely this vulnerability. It is a first-in-class, small-molecule, oral, highly selective IDH1 inhibitor that potently blocks several isoforms of the mutated enzyme. The drug is approved in the United States and Europe for patients with previously treated locally advanced or metastatic cholangiocarcinoma carrying a susceptible IDH1 R132 mutation. That approval rested on the randomized, double-blind, phase III ClarIDHy study, which enrolled 185 patients with previously treated advanced cholangiocarcinoma and an IDH1 mutation. In the primary analysis, median progression-free survival was significantly longer with ivosidenib than with placebo, at 2.7 versus 1.4 months, with a hazard ratio of 0.37 and a 95 percent confidence interval of 0.25 to 0.54, at p less than 0.0001. Only 3 of 124 patients treated with ivosidenib, about 2 percent, had a partial response, while 63 of 124, or 51 percent, had stable disease.

Overall survival results were more modest. At the final analysis of ClarIDHy, median overall survival was 10.3 months with ivosidenib versus 7.5 months with placebo, a hazard ratio of 0.79 with a 95 percent confidence interval of 0.56 to 1.12 and a p value of 0.09, which did not reach conventional statistical significance. The drug was nevertheless well tolerated. The most common grade three or worse adverse event was ascites, reported in 7 percent of patients in both treatment groups, and serious adverse events occurred in 30 percent of ivosidenib recipients and 22 percent of placebo recipients. Most treatment-emergent adverse events in the trial were grade one to two in severity. Treatment durations in the study reached up to 34.4 months, a detail that lends context to the longevity of the response now described in the new case report.

The patient at the center of the report first presented to hospital in August 2021 with epigastric pain in the upper right quadrant and vomiting that had spontaneously resolved after three days. His medical history included hypertension and prior surgery for an umbilical hernia, but no hepatitis infection, no alcohol consumption and no family history of cancer. Laboratory testing showed mildly elevated alanine aminotransferase at 68 units per liter against an upper limit of normal of 50, and gamma-glutamyl transferase at 71 units per liter against an upper limit of 55. Imaging revealed a mass spanning the third and fourth segments of the liver. Computed tomography confirmed a liver tumor measuring 10 centimeters in diameter in segment three, a second smaller tumor of 2.8 centimeters in the same segment, and enlarged lymph nodes in the hilus and in the peripancreatic and infradiaphragmatic regions.

A biopsy taken in September 2021 from the segment four portion of the tumor settled the diagnosis. Histologic examination showed cytomorphology of a hepatic tumor, and immunohistochemical staining revealed that the cancer cells were of cholangiocellular origin, confirming cHCC-CCA. The tumor cells formed structures with irregular lumens, while separate tissue fragments held larger fields of tumor cells with broader cytoplasm resembling hepatocytes. Staining showed strong expression of C-reactive protein and cytokeratin 7, with arginase 1 positivity confined to the hepatocyte-like tumor cells. Further laboratory work in October 2021 showed normal levels of alpha-fetoprotein, carbohydrate antigen 19-9 and carcinoembryonic antigen, a pattern supportive of a predominant cholangiocarcinoma component. Because surgical resection was unfeasible, the oncology team recommended cisplatin plus gemcitabine as first-line therapy, delivered at 25 and 1000 milligrams per square meter respectively on days 1 and 8 of every 21-day cycle.

Genetic testing told a story of its own. Two months into chemotherapy, the tumor showed wild-type K-ras, N-ras and BRAF, no microsatellite instability, no NTRK or FGFR2 translocations by fluorescence in situ hybridization, and no HER2 amplification. Pan-cancer sequencing with the TruSight Oncology 500 panel in June 2022 confirmed an IDH1 pathogenic mutation, p.R132C, along with presumed pathogenic mutations in ARID1A and LATS1, and a low degree of HER2 copy number alteration at 4.8 copies. After ten months of cisplatin plus gemcitabine, a CT scan showed no significant change in tumor size, and a drug holiday was taken at the patient’s request. By December 2022, however, the liver lesion had grown to 11.5 centimeters, prompting further treatment. Given the IDH1 mutation, ivosidenib at 500 milligrams once daily was started on January 23, 2023. Three months later the target lesion had regressed to 10 centimeters, and six further CT scans between July 2023 and November 2024 showed the lesion stable at 7.5 to 10 centimeters. A retrospective review confirmed that the best overall response met RECIST version 1.1 criteria for partial remission, with the target lesion down more than 30 percent from baseline. Carbohydrate antigen 19-9 levels, normal during chemotherapy, rose slightly at various timepoints on ivosidenib, ranging from 40 to 62 units per milliliter against a normal range of 0 to 37.

The authors are candid about the limits of a single case. They note that the information is anecdotal in nature, carries a high risk of selection and publication bias, and that retrospective analysis of the patient’s records may have missed key data. The proportion of patients with durable responses in ClarIDHy was small, and one exceptional course cannot predict outcomes for others. Still, the report suggests that durable tumor response is possible in IDH1-mutant cholangiocarcinoma, and it illustrates a practical point emphasized in current European guidance, which recommends molecular profiling to identify targetable aberrations in advanced-stage cHCC-CCA and lists ivosidenib as a second-line option for patients with an IDH1 mutation after cisplatin plus gemcitabine failure. From the patient’s perspective, the oral route meant fewer hospital visits and a more flexible lifestyle than intravenous chemotherapy, and with no adverse events, no dose modifications and no adherence issues, he remained fully active and continued working. Prescribing information directs that ivosidenib be continued until disease progression or intolerance, and this patient, at 35 months of therapy, exemplifies that recommendation.

Subject of Research: Long-term ivosidenib treatment of IDH1-mutant combined hepatocellular–cholangiocarcinoma in a single patient

Article Title: Long‑term treatment with ivosidenib in IDH1‑mutant combined hepatocellular–cholangiocarcinoma: a case report

Article References: Tegze, B., & Ambrus, V. (2026). Long‑term treatment with ivosidenib in IDH1‑mutant combined hepatocellular–cholangiocarcinoma: a case report. Drugs & Therapy Perspectives. https://doi.org/10.1007/s40267-026-01255-8

Image Credits: AI Generated

DOI: 10.1007/s40267-026-01255-8

Keywords: ivosidenib, IDH1 mutation, combined hepatocellular-cholangiocarcinoma, liver cancer, case report, targeted therapy, ClarIDHy trial, cholangiocarcinoma, precision oncology, drug tolerance, RECIST partial remission, molecular profiling