Sintilimab Combined With Pemigatinib in Patients With PD-L1-positive and FGFR Mutated Advanced Non-small Cell Lung Cancer: an Open Label, Phase II Trial
Lung cancer is the leading cause of death from cancer in China. In recent years, immune checkpoint inhibitor has gradually become a research hotspot, and it has continuously achieved huge breakthroughs. The FDA and NMPA have approved multiple PD-1/PD-L1 inhibitors for first-line or second-line treatment of advanced or metastatic NSCLC. But In clinical practice, there is still some controversy about PD-1 inhibitor monotherapy, especially for patients with low PD-L1 expression, the efficacy of monotherapy needs to be further improved. Strong genetic and functional evidence indicates that FGFR dysregulation can lead to the development and progression of cancer. Genetic alterations of FGFR1, FGFR2 and FGFR3 have been found in a variety of tumors. Squamous non-small cell lung cancer has about 13% of FGFR variants, while there are only 4% of any FGFR variants in lung adenocarcinoma. Studies of FGFR inhibitors in NSCLC show that AZD4575 has shown partial efficacy in FGFR partially mutated and expanded lung squamous cell carcinoma. FGFR pathway is involved in the regulation of the tumor immune microenvironment. In the tumor suppressor model of rectal cancer, it has been observed that FGFR2 overexpression promotes the expression of PD-L1 by activating JAK/STAT3 pathway, leading to tumor growth. In a lung cancer suppressor mouse model, the combination of FGFR inhibitor and PD-1 inhibitor can improve tumor remission and prolong survival. Based on the preliminary clinical data, this study assumes that Sintilimab(anti-PD-1) combined with Pemigatinib(FGFR inhibitor) can further improve efficay of advanced NSCLC with PD-L1 positive and FGFR1-3 mutation) including but not limited to FGFR amplification, rearrangement/fusion, mutation, etc.).
• Age ≥18 years;
• Patients confirmed by histology or cytology non-small cell lung cancer with stage IIIB-IIIC and stage IV (UICC and AJCC, 8th edition TNM staging) which is unresectable or unsuitable for radical concurrent radiochemotherapy;
• Not applicable to EGFR/ALK/ROS1 targeted therapy;
• Histologically confirmed PD-L1 positive (TPS≥1%);
• Histology confirmed FGFR1-3 mutations, including but not limited to amplification, mutation, fusion/rearrangement, etc.;
• According to RECIST v1.1 version, there is at least one measurable lesion.
• Not received any systemic anti-tumor therapy for advanced/metastatic diseases. For participants who have received adjuvant/neoadjuvant therapy, or have received radical radiochemotherapy for locally advanced disease, if the interval between disease progression or recurrence and the end of the last treatment is more than 6 months, these participants are allowed to be included in this study;
• Not used small molecule multi-target inhibitors (including Anlotinib, Lenvatinib, Sorafenib, etc.) that target the FGFR pathway;
• Have not previously received the following immune checkpoint inhibitor therapy: anti-PD-1, anti-PD-L1 or anti-PD-L2 drugs or targeting another stimulating or synergistic inhibition of T cell receptors (including but not limited to CTLA-4 , OX-40, CD137, etc.);
⁃ ECOG physical status is 0-1;
⁃ Expected survival time\> 3 months;
⁃ The participants are allowed to receive palliative radiotherapy (including craniocerebral radiotherapy for symptomatic brain metastases), but the radiotherapy must be completed at least 2 weeks before the first study drug is administered (the end of palliative radiotherapy for the central nervous system should be 4 weeks before the first study drug administration), and the radiotherapy-related toxicity is restored to less than or equal to 1 degree (CTCAE 5.0, except for hair loss), no corticosteroid treatment is required, and radiation pneumonia is confirmed to be excluded;
⁃ Sufficient organ function, participants need to meet the following laboratory indicators:
∙ The absolute value of neutrophils (ANC) ≥1.5x10\^9/L when no granulocyte colony stimulating factor is used in the past 14 days;
‣ Platelets ≥100×10\^9/L in the case of no blood transfusion in the past 14 days, ;
‣ Hemoglobin\>9g/dL without blood transfusion or erythropoietin in the past 14 days ;
‣ Total bilirubin≤1.5 upper limit of normal (ULN); or total bilirubin\>1.5 ULN but direct bilirubin≤1.0 ULN;
‣ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are ≤2.5 ULN (patients with liver metastases are allowed to have ALT or AST ≤5 ULN);
‣ Serum creatinine ≤1.5 ULN and creatinine clearance rate (calculated by Cockcroft-Gault formula) ≥50 ml/min;
‣ Good coagulation function, defined as the international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 ULN; if the participant is undergoing anticoagulation therapy, as long as the PT is within the proposed range of anticoagulant drugs;
‣ Normal thyroid function is defined as thyroid stimulating hormone (TSH) within the normal range. If the baseline TSH is outside the normal range, participants whose total T3 (or FT3) and FT4 are within the normal range can also be included;
‣ Myocardial enzyme spectrum is within the normal range (for example, simple laboratory abnormalities that are judged by the investigator to be of no clinical significance are also allowed to be included in the group);
⁃ For female participants of childbearing age, a urine or serum pregnancy test should be performed within 3 days before receiving the first study drug administration (day 1 of cycle 1)and the result should be negative . If the urine pregnancy test result cannot be confirmed as negative, a blood pregnancy test is required. Women of non-bearing age are defined as at least 1 year after menopause, or have undergone surgical sterilization or hysterectomy;
⁃ If there is a risk of conception, all participants (whether male or female) need to use contraceptive measures with an annual failure rate of less than 1% during the entire treatment period until 120 days after the last study drug administration.