Pemigatinib Plus PD-1 Inhibitor With or Without Chemotherapy in FGFR2 Fusion/Rearrangement-Positive Cholangiocarcinoma

An Open-Label, Phase II Clinical Study Evaluating the Efficacy and Safety of Pemigatinib in Combination With a PD-1 Inhibitor, With or Without Chemotherapy, in Patients With Unresectable or Metastatic Cholangiocarcinoma Harboring FGFR2 Fusions or Rearrangements

This is a prospective, single-arm, phase II clinical study. Patients with advanced cholangiocarcinoma harboring FGFR2 fusions or rearrangements who have either not previously received standard therapy or have experienced treatment failure following standard therapy will be screened for eligibility and enrolled in the study after providing written informed consent.

Inclusion Criteria:

1. Male or female patients aged 18 to 80 years. 2. Histologically or cytologically confirmed unresectable locally advanced or metastatic biliary tract cancer (Stage III or IV according to the AJCC Cancer Staging Manual, 2010).

3. At least one measurable lesion according to RECIST version 1.1. 4. Histologically confirmed FGFR2 fusion or rearrangement. 5. No prior treatment with a selective FGFR inhibitor, including pemigatinib, futibatinib, or other selective FGFR inhibitors.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 7. Estimated life expectancy of at least 6 months. 8. Adequate organ function, defined by the following laboratory criteria:

1. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, without granulocyte colony-stimulating factor support within 14 days before assessment.
2. Platelet count ≥ 90 × 10⁹/L, without transfusion within 14 days before assessment.
3. Hemoglobin > 9 g/dL, without transfusion or erythropoiesis-stimulating agent use within 14 days before assessment.
4. Total bilirubin ≤ 2.5 × the upper limit of normal (ULN).
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN; for patients with liver metastases, AST or ALT ≤ 5.0 × ULN is permitted.
6. Serum creatinine ≤ 1.5 × ULN and creatinine clearance, calculated using the Cockcroft-Gault formula, ≥ 50 mL/min.
7. Adequate coagulation function, defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN. Patients receiving anticoagulant therapy are eligible if their PT is within the intended therapeutic range of the anticoagulant.

9.Women of childbearing potential must have a negative urine or serum pregnancy test within 3 days before the first administration of study treatment (Cycle 1, Day 1). A serum pregnancy test is required if a negative urine pregnancy test cannot be confirmed. Women not of childbearing potential are defined as those who have been postmenopausal for at least 1 year or have undergone surgical sterilization or hysterectomy.

10.All participants with reproductive potential, regardless of sex, must agree to use highly effective contraception, with a failure rate of less than 1% per year, throughout the treatment period and for 120 days after the last dose of study treatment (or 180 days after the last dose of chemotherapy, if applicable).

Exclusion Criteria:

1. Diagnosis of another malignancy within 5 years before the first dose of study treatment, except for definitively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or carcinoma in situ that has been curatively resected.
2. Prior treatment with a selective FGFR inhibitor.
3. Failure to adequately recover from toxicities and/or complications resulting from any prior intervention before treatment initiation (i.e., recovery to Grade ≤ 1 or baseline), except for fatigue or alopecia.
4. Known symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may be eligible if they are clinically stable, have no radiographic evidence of progression for at least 4 weeks before the first dose of study treatment, have no evidence of new or enlarging brain metastases on repeat imaging, and have not required steroid treatment for at least 14 days before the first dose of study treatment. Patients with carcinomatous meningitis are excluded regardless of clinical stability.
5. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
6. Any of the following laboratory abnormalities:

1)Serum phosphate level > ULN. 2)Serum calcium outside the normal range, or albumin-corrected serum calcium outside the normal range if serum albumin is outside the normal range.

3)Potassium level below the lower limit of normal. Potassium supplementation is permitted to correct the potassium level during screening.

7. Known history of human immunodeficiency virus (HIV) infection or a confirmed positive HIV test result.

8. Active or clinically uncontrolled serious infection. 9. Clinically significant pleural effusion, ascites, or pericardial effusion requiring drainage.

10. Acute or chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, defined as HBV DNA > 2,000 IU/mL or > 10⁴ copies/mL, HCV RNA > 10³ copies/mL, or concurrent positivity for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies. Patients whose viral load decreases below these thresholds after nucleos(t)ide analogue antiviral therapy may be eligible.

11. Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months before the first dose of study treatment, New York Heart Association (NYHA) Class III or IV congestive heart failure, or uncontrolled arrhythmia. Patients with a pacemaker or atrial fibrillation with well-controlled heart rate may be eligible. Patients with clinically significant electrocardiogram (ECG) abnormalities or relevant cardiac history, as determined by the investigator, are also excluded.

12. Uncontrolled hypertension despite optimal medical treatment, defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg, or a history of hypertensive crisis or hypertensive encephalopathy.

13. Hepatic encephalopathy, hepatorenal syndrome, Child-Pugh liver function score > 7, or more severe cirrhosis.

14. Major surgery, including craniotomy, thoracotomy, or laparotomy, within 4 weeks before the first dose of study treatment, or anticipated need for major surgery during the study treatment period.

15. Pregnant or breastfeeding women, or participants who expect to conceive or father a child during the period from the screening visit through completion of the safety follow-up visit (for male participants, through 90 days after the last dose).

16. Radiotherapy within 4 weeks before the first dose of study treatment. All radiotherapy-related toxicities must have resolved, corticosteroid treatment must not be required, and radiation pneumonitis must be excluded. A 2-week washout period is permitted for palliative radiotherapy to non-CNS lesions.

17. History of disorders of calcium-phosphate metabolism or systemic electrolyte metabolic imbalance associated with ectopic soft-tissue calcification. This excludes calcification of soft tissues, such as the skin, kidneys, tendons, or blood vessels, caused by injury, disease, or advanced age without systemic electrolyte metabolic imbalance.

18. Clinically significant corneal or retinal disease confirmed by ophthalmologic examination.

19. Use of any strong CYP3A4 inhibitor or inducer within 14 days or 5 half-lives before the first dose of study treatment, whichever is shorter. Topical ketoconazole is permitted.

20. Known hypersensitivity to pemigatinib or any excipient in the pemigatinib study drug product.

21. Inability or unwillingness to swallow pemigatinib, or clinically significant gastrointestinal disease that may interfere with the absorption, metabolism, or excretion of pemigatinib.

22. History of vitamin D deficiency requiring vitamin D supplementation at supraphysiologic doses, excluding routine dietary vitamin D supplementation.

23. Prior immune checkpoint inhibitor treatment associated with Grade ≥ 3 immune-related adverse events (irAEs).

24. Any other acute or chronic medical condition, psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or administration of study treatment, interfere with interpretation of study results, or render the participant unsuitable for study participation in the investigator's judgment.