Overview
Primary objective:
● To evaluate the efficacy of pemigatinib in advanced non-small cell lung cancer patients with fibroblast growth factor receptor 1-3 (FGFR 1-3) alterations (including but not limited to FGFR amplification, rearrangement/fusion, mutation, etc.) who have failed standard therapy.
Secondary objective:
● To evaluate the safety and tolerability of pemigatinib in advanced non-small cell lung cancer patients with known FGFR 1-3 alterations (including but not limited to FGFR amplification, rearrangement/fusion, mutation, etc.) who have failed standard therapy, including the incidence of adverse events (AEs) and serious adverse events (SAEs), as well as the incidence of AEs/SAEs resulting in treatment discontinuation.
Description
This study is a prospective single-arm clinical study. Advanced non-small cell lung cancer patients with known FGFR 1-3 alterations (including but not limited to FGFR amplification, rearrangement/fusion, mutation, etc.) who have failed standard therapy will be enrolled in this study once they have signed the informed consent form (ICF) and been identified as eligible in screening. The patients will receive 13.5 mg of pemigatinib once a day (QD) orally following a 2-week administration/
1-week interruption regimen. They will be dosed until disease progression or intolerable toxicity. During treatment, clinical tumor imaging evaluation will be performed according to RECIST v1.1 every 6 weeks (± 7 days) and then every 9 weeks (± 7 days) after week 48. Safety will be assessed according to NCI-CTCAE 5.0.
Eligibility
Inclusion Criteria:
Subjects must sign a written ICF prior to the implementation of any procedures related to
the study;
1. Aged ≥ 18 years old;
2. Patients with histologically or cytologically confirmed unresectable stage IIIB-IIIC
or stage IV NSCLC (staged according to the 8th Edition of the TNM Classification for
Lung Cancer published by the International Association for the Study of Lung Cancer
and American Joint Committee on Cancer);
3. Have at least one measurable lesion according to RECIST v1.1;
4. With histologically confirmed FGFR 1-3 alterations, including but not limited to
amplification, mutation, fusion/rearrangement, etc.;
5. Have failed second-line and above standard therapies. Patients who have EGFR-sensitive
mutations or are positive for ALK/ROS1 rearrangements shall receive at least one line
of EGFR/ALK/ROS1 inhibitor treatment (Patients with EGFR-sensitive mutations who have
received a first- or second-generation TKI should fail the treatment with a
third-generation TKI (e.g., osimertinib) if they are positive for T790M mutations);
Note: Patients who have a relapse within 6 months after a radical surgery or radical
concurrent chemoradiotherapy can be enrolled if they have failed at least one line of
systematic therapy after the relapse.
6. No previous use of small molecule multi-target drugs targeting the FGFR pathway
(including anlotinib, lenvatinib, sorafenib, apatinib, bevacizumab, Endostar, etc.);
7. ECOG physical performance status score of 0-1;
8. Expected survival time > 3 months;
9. Patients with brain metastases who are asymptomatic or have stable symptoms after
locoregional treatment can be enrolled as long as they:
1) Have measurable lesions outside the central nervous system; 2) Have no central nervous
system symptoms or no aggravation of symptoms for at least 2 weeks; 3) Do not need
glucocorticoid treatment or stop glucocorticoid treatment within 7 days before the first
dose of the investigational drug.
10. Patients who have completed palliative radiotherapy one week prior to study enrollment
with their radiotherapy-related toxicity reduced to grade 1 or lower (CTCAE5.0) can be
enrolled.
11. For evidence of sufficient organ functions, the subjects shall meet the following
laboratory parameters:
1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L without use of granulocyte colony
stimulating factor in recent 14 days;
2. Platelet count ≥ 100 × 109/L without blood transfusion in recent 14 days;
3. Hemoglobin > 9 g/dL without blood transfusion or erythropoietin use in recent 14 days;
4. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); or total bilirubin
> ULN, direct bilirubin ≤ ULN;
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
≤ 2.5 × ULN (ALT or AST ≤ 5 × ULN for patients with liver metastasis);
6. Blood creatinine ≤ 1.5 × ULN and creatinine clearance (calculated by Cockcroft-Gault
formula) ≥ 50 mL/min;
7. Good coagulation function: international normalized ratio (INR) or prothrombin time
(PT) ≤ 1.5 × ULN. (For subjects receiving an anticoagulant therapy, PT within the
range proposed for the anticoagulant drug is acceptable).
12. Women of childbearing potential shall obtain a negative result in the urine or serum
pregnancy test performed within 3 days before the first dose of the investigational drug
(cycle 1, day 1). If the urine pregnancy test result cannot be identified as negative, a
blood pregnancy test is needed. Women of non-childbearing potential are defined as those
who have not had menses for at least 1 year or who have undergone surgical sterilization or
hysterectomy; 13. All subjects at risk of conception (including their partners) shall use
contraceptives with an annual failure rate of less than 1% throughout the entire treatment
period up to 120 days after the last dose of the investigational drug (or 180 days after
the last dose of the chemotherapy drug).
Exclusion Criteria:
- 1. Diagnosed with malignant tumors other than non-small cell lung cancer within 5
years before the first dose, excluding radically cured cutaneous basal cell carcinoma,
cutaneous squamous cell carcinoma, and/or radically resected carcinoma in situ; 2.
Previously treated with selective FGFR inhibitors; 3. Have received any other
investigational drug treatment or participated in another interventional clinical
trial within 28 days before the first dose of the investigational drug, or have
received anti-tumor drug treatment within 28 days before the first dose of the
investigational drug (including Chinese herbal medicine with anti-tumor indications);
4. Have not recovered (i.e., reaching ≤ grade 1 or the baseline status, excluding
asthenia and alopecia) from toxicity and/or complications caused by any intervention
before the start of treatment; 5. With known symptomatic central nervous system
metastasis and/or carcinomatous meningitis. Subjects with previously treated brain
metastases are eligible if the disease is stable (no imaging evidence of progression
in at least 4 weeks prior to the first dose of study treatment), there is no evidence
of new or enlarging brain metastases on repeated imaging, and corticosteroids are not
required in at least 14 days prior to the first dose of study treatment. Patients with
carcinomatous meningitis should be excluded regardless of their clinically stability;
6. During pregnancy or lactation; 7. Known history of allotransplantation or
allogeneic hematopoietic stem cell transplantation; 8. Subjects with abnormal
laboratory parameters listed below:
1. Serum phosphate > ULN;
2. Serum calcium exceeds the normal range, or the calcium concentration corrected
for serum albumin exceeds the normal range when serum albumin exceeds the normal
range;
3. Potassium level < lower limit of normal (LLN); potassium levels can be corrected
by supplements at screening.
9. With known history of human immunodeficiency virus (HIV) infection or
confirmed with positive immune test results; 10. Presence of severe infection in
the active phase or with poor clinical control; 11. Pleural effusion, ascites, or
pericardial effusion with obvious clinical symptoms that require drainage; 12.
Acute or chronic active hepatitis B or C infection; hepatitis B virus (HBV) DNA >
2000 IU/mL or 104 copies/mL; hepatitis C virus (HCV) RNA > 103 copies/mL;
hepatitis B surface antigen (HbsAg) and anti-HCV antibody positive concurrently.
Those who with relevant parameters lower than the above criteria after nucleotide
antiviral treatment can be enrolled; 13. With clinically significant or
uncontrolled heart diseases, including unstable angina, acute myocardial
infarction within 6 months before the first dose, grade III/IV congestive heart
failure (New York Heart Association), and uncontrolled arrhythmia (subjects with
pacemakers or with atrial fibrillation but well controlled heart rate are
allowed); 14. With ECG changes or medical history considered clinically
significant by the investigator; QTcF interval > 480 ms at screening; for
subjects with intraventricular conduction block (QRS interval > 120 ms), JTc
interval can be used instead of QTc interval upon approval of the sponsor (in
such cases, JTc must be ≤ 340 ms); 15. With uncontrolled hypertension (systolic
pressure > 160 mmHg or diastolic pressure > 100 mmHg after the optimal medical
treatment), or a history of hypertensive crisis or hypertensive encephalopathy;
16. With hepatic encephalopathy, hepatorenal syndrome, or liver cirrhosis with
Child-Pugh grade B or C.
17. Have received a major surgery (craniotomy, thoracotomy, or laparotomy) within
4 weeks prior to the first dose of study treatment, or will receive a major
surgery during the study treatment period; 18. Pregnant or lactating women, or
subjects expected to conceive or give birth during the study period from the
screening visit to the completion of the safety follow-up visit (90 days after
the last dose for male subjects); 19. Have received radiotherapy within 4 weeks
before the first dose of the investigational drug. The subjects must be
completely recovered from radiotherapy-related toxicity, with no need for
corticosteroid treatment, and radiation pneumonitis must be excluded. For
palliative radiotherapy for non-CNS diseases, a 2-week washout period is allowed;
20. Have a history of disorders of calcium and phosphorus metabolism or systemic
electrolyte metabolism imbalance with ectopic calcification of soft tissues
(excluding calcification of soft tissues such as skin, kidneys, tendon, or blood
vessels without systemic electrolyte metabolism imbalance caused by injury,
disease, and old age); 21. Clinically significant corneal or retinal diseases
confirmed by ophthalmological examination; 22. Have used any potent CYP3A4
inhibitor (see Appendix A for details) or inducer within 14 days or 5 half lives
(whichever is shorter) before the first dose of the investigational drug.
Ketoconazole is allowed for external use; 23. With known allergic reactions to
pemigatinib or excipients of pemigatinib; 24. Unable or unwilling to swallow
pemigatinib or are suffering from significant digestive system diseases that may
interfere with absorption, metabolism, or excretion; 25. Subjects with a history
of vitamin D deficiency who require supraphysiological dose of vitamin D (except
dietary vitamin D supplements); 26. Other acute or chronic diseases, psychiatric
disorders, or laboratory abnormalities that may result in an increased risk
associated with study participation or investigational drug administration or
interfere with the interpretation of study results, and disqualify patients from
the study in the investigator's judgment.