Sintilimab With Pemigatinib in Patients With PD-L1-positive and FGFR Mutated Advanced Non-small Cell Lung Cancer

Advanced Non Small Cell Lung Cancer

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.).

This study is a prospective, Phase II clinical study. 20 Histologically confirmed NSCLCs with unresectable or locally advanced, recurrent or metastatic disease not suitable for radical concurrent chemo-radiotherapy, treatment naive, and confirmed PD-L1 positive with FGFR 1-3 mutations are enrolled. The participants will receive Sintilimab combined with Pemigatinib every 3 weeks (Q3W): Sintilimab is administered every 3 weeks (200mg, IV), Pemigatinib 13.5 mg once daily (QD) orally, continuous administration. The subject will continue treatment until disease progression, intolerable toxicity, withdrawal of informed consent, start of other anti-tumor treatments, death or other conditions that should be stopped as prescribed by the protocol. The longest administration time of Sintilimab is 2 years (35 cycles). In consideration of the safety of the combination therapy, this study will conduct safety monitoring on the 6 subjects initially enrolled in the safety observation period (defined as 21 days after the subjects received the study drug treatment for the first time) . After the study enrollment reaches 6 subjects, enrollment will be suspended until the safety observation period of the 6th patient is over and the conditions for continuing the study are met. If ≥2 dose-limiting toxicity (DLT) are observed in these 6 patients, the investigators will review the data and discuss, and decide to revise the dosing regimen of the follow-up study to reduce the incidence of adverse events, or terminate it completely. If DLT is less than or equal to 1 of the 6 participants, the study will continue to follow the original protocol. The primary endpoint is objective response rate, the secondary endpoints are progression free survival, duration of response, time to response, disease control rate, overall survival, safety and tolerance.

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