Pemigatinib and Immune Checkpoint Inhibitor Treated FGFR1/2/3 Alteration Advanced Solid Tumor

This prospective phase Il study is aim to evaluate the efficacy and safety of FGFR inhibitor combined with immune checkpoint inhibitors in FGFR1/2/3 variant advanced solid tumors.


Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 18 years;
* Histologically or cytologically confirmed unresectable advanced solid tumors with failure or intolerance to standard treatments;
* At least one measurable lesion per RECIST v1.1 criteria;
* Gene testing confirms FGFR1/2/3 variants, including but not limited to mutations, fusions/rearrangements in solid tumors;
* Patients have not previously used specific small molecule multi-target inhibitors of the FGFR pathway, as assessed by investigators, and have been treated with immune checkpoint inhibitors;
* ECOG performance status of 0-1;
* Expected survival time \> 3 months;
* Laboratory criteria:

  1. Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L in the past 14 days without granulocyte colony-stimulating factor;
  2. Platelets ≥ 100 x 10⁹/L without transfusion in the past 14 days;
  3. Hemoglobin \> 9 g/dL in the last 14 days without transfusion or erythropoietin;
  4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN), or total bilirubin \> ULN but direct bilirubin ≤ ULN;
  5. AST, ALT ≤ 2.5 x ULN (≤ 5 x ULN in patients with liver metastasis);
  6. Serum creatinine ≤ 1.5 x ULN and creatinine clearance (Cockcroft-Gault) ≥ 50 ml/min;
  7. Good coagulation function, defined as INR or PT ≤ 1.5 x ULN. If on anticoagulant therapy, PT should be within the therapeutic range of anticoagulants;
* Female subjects of reproductive age must have a negative urine or serum pregnancy test within 3 days prior to the first dose (Cycle 1, Day 1). If the urine test is inconclusive, a blood test is required. Non-reproductive females are defined as post-menopausal for at least one year or surgically sterile;
* Subjects with reproductive potential must use contraception with an annual failure rate of less than 1% during treatment and for 120 days after the last study drug dose (or 180 days after the last chemotherapy dose).

Exclusion Criteria:

* Diagnosis of other malignancies within 3 years before the first dose, except for certain treated skin carcinomas and in-situ carcinomas;
* Previous treatment with selective FGFR inhibitors;
* Receipt of other investigational drugs within 21 days or antitumor drugs within 14 days before the first dose;
* Unresolved toxicity from prior treatments unless ≤ Grade 1 or related to alopecia or fatigue;
* Known symptomatic CNS metastasis or carcinomatous meningitis. Stable patients post-treatment with no evidence of progression may be eligible if steroid-free for at least 14 days;
* History of allogeneic organ or hematopoietic stem cell transplantation;
* Abnormal laboratory parameters:

  1. Serum phosphate \> 1.5 x ULN;
  2. Elevated serum calcium or albumin-adjusted calcium outside the reference range;
* Known HIV infection or positive HIV test;
* Active or poorly controlled serious infection;
* Need for drainage treatment for pleural effusion, ascites, or pericardial effusion;
* Active hepatitis B or C infection with high viral load, or positive HBsAg or anti-HCV antibodies. Patients on antiviral therapy must meet lower thresholds;
* Significant uncontrolled heart disease, including recent MI, severe heart failure, or uncontrolled arrhythmias;
* Clinically significant ECG changes or history of significant cardiac issues; Screening QTcF interval \> 480 ms, or JTc interval if applicable, must be ≤ 340 ms;
* Uncontrolled hypertension despite treatment;
* Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh grade B or higher cirrhosis;
* Major surgery within 4 weeks before the first dose or planned major surgery during the study;
* Unresolved complications from prior surgery;
* Pregnant or breastfeeding women, or those planning to become pregnant during the study period and for safety follow-up;
* Radiotherapy within 4 weeks before the first dose, except for non-CNS palliative radiotherapy with a 2-week washout period;
* History of systemic electrolyte imbalance or ectopic soft tissue calcification;
* Clinically significant corneal or retinal disease;
* Use of potent CYP3A4 inhibitors or inducers within 14 days or 5 half-lives before the first dose;