Patients with advanced, unresectable, or metastatic solid tumors have a poor prognosis (patients suffer from end-stage diseases that are almost incurable and have a very low quality of life). Considering the potential impact of drug toxicity and existing comorbidities, treatment options for patients are very limited.Patients with advanced solid tumors who have exhausted standard therapies usually experience rapid tumor progression and have a very short survival period.
Recently, a subsidiary of The LancetThe Lancet OncologyPublished the results of an international, single-arm, Phase 2 study (RAGNAR study). The study confirmed,In patients who have exhausted other treatment options, erdafitinib (a fibroblast growth factor receptor [FGFR] inhibitor) can provideFGFRPatients with advanced solid tumors (unlimited cancer types) harboring genetic mutations bring clinical benefits.The analysis results support further trials to evaluate the application value of FGFR inhibitors in patients with advanced solid tumors.
Screenshot source:The Lancet Oncology
The current paper points out that,FGFR (including four receptor subtypes FGFR1~4) plays a crucial role in the proliferation, migration, differentiation, and survival of normal cells.FGFRGene mutations can cause constitutive activation of downstream cell signaling pathways and lead to tumorigenesis.
Erdafitinib is an oral, selective, potent FGFR tyrosine kinase inhibitor. Previously, erdafitinib has been approved by the FDA for the treatment of patients withFGFR2OrFGFR3Locally Advanced or Metastatic Urothelial Carcinoma with Gene Mutations. The current single-arm, phase 2 study, named RAGNAR, aims to evaluate the treatment of erdafitinib.FGFRAntitumor Activity and Safety in Patients with Mutation-Positive Advanced Solid Tumors.
The study was conducted at 156 medical centers across 15 countries and included a total of four cohorts. Patient inclusion criteria were: aged ≥12 years; accompanied byFGFR1~4Advanced or metastatic tumors of any histological type with genetic mutations (excluding urothelial carcinoma); disease progression after receiving at least one systemic treatment regimen; no alternative standard treatment available; ECOG performance status score of 0-1.
Patients enrolled in the study received oral erdafitinib once daily (in continuous 21-day cycles) until disease progression or the development of intolerable toxicity. The primary endpoint of the study was the objective response rate (ORR) assessed by an independent review committee. This paper reportsMain Cohort Study (All-Comer Cohort)The analysis results.
Between December 5, 2019, and February 15, 2022, a total of 217 patients (median age 57 years; 45% female) were assigned to the primary cohort and received erdafitinib treatment. Of these, 66% of patients carriedFGFRFusion mutation, carried by 35% of patientsFGFRGene Mutation;CarryFGFR1、FGFR2、FGFR3 andFGFR4The proportions of patients with variations were 10%, 47%, 44%, and 0, respectively.
The types of tumors suffered by the enrolled patients were: cholangiocarcinoma, high-grade glioma, pancreatic cancer, breast cancer, head and neck squamous cell carcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, cancer of unknown primary, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, ovarian cancer, low-grade glioma, cervical cancer, salivary gland cancer, soft tissue sarcoma, prostate cancer, and other types of tumors. As of August 15, 2022,The median follow-up time for patients was 17.9 months, and the median treatment duration was 4.3 months.
The analysis results show that, compared with the baseline,73% (159/217) of patients had a reduction in tumor burden, with an ORR of 30% (64/217).The study met its primary endpoint. Among patients who experienced an objective response,Of these, 3% were complete responses and 27% were partial responses.
Notably, the median duration of response in patients reached 6.9 months, and at the time of analysis,Still, 14 patients are still in continuous remission.Except for cervical cancer, soft tissue sarcoma, and prostate cancer, erdafitinib treatment has brought consistent benefits to patients with 16 different types of tumors.Overall, the disease control rate (DCR) was 74%, the clinical benefit rate (CBR) was 46%, the median progression-free survival (PFS) was 4.2 months, and the median overall survival (OS) was 10.7 months.
In terms of safety, the ≥3 grade treatment-emergent adverse events (TEAEs) related to erdafitinib in this study mainly manifested as stomatitis (12%), palmar-plantar erythrodysesthesia syndrome (6%), and hyperphosphatemia (5%). The most frequently occurring serious adverse events (≥3 grade) in the study were stomatitis (2%) and diarrhea (1%). No treatment-related deaths occurred in the study.
The paper emphasizes that the RAGNAR study"For the first time in different histological types andFGFRThe antitumor activity of erdafitinib was demonstrated in patients with advanced solid tumors harboring variant types.. Overall, the results of the current study suggest that, in conjunction withFGFRErdafitinib treatment shows a considerable ORR in patients with different types of advanced solid tumors harboring mutations. For patients experiencing disease progression during or after systemic therapy, and having no effective treatment options, erdafitinib can provide clinically meaningful sustained relief and survival benefits.
References
[1] Shubham Pant et al, Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study. The Lancet Oncology. Doi: 10.1016/S1470-2045(23)00275-9