Treatment with erdafitinib resulted in clinical benefit for patients with advanced solid tumors harboring susceptible FGFR alterations who had exhausted all other treatment options, meeting the primary end point of overall response rate of the phase 2 RAGNAR trial.
Treatment with erdafitinib (Balversa) resulted in clinical benefit for patients with advanced solid tumors harboring susceptible FGFR alterations who had exhausted all other treatment options, meeting the primary end point of overall response rate (ORR) of the phase 2 RAGNAR trial (NCT04083976), according to findings published in the Lancet Oncology.1
At a median follow-up of 17.9 months (interquartile range [IQR], 13.6-23.9), the ORR was 30% (95% CI, 24%-36%) with a 3% complete response (CR) rate per independent review among 217 patients with 16 different tumor types from the primary cohort who were treated with the pan-FGFR TKI. The median time to response was 1.4 months (IQR, 1.4-2.7) with erdafitinib, and 73% of patients experienced a reduction in tumor burden compared with baseline. The median duration of response (DOR) was 6.9 months (95% CI, 4.4-7.1), the median progression-free survival (PFS) was 4.2 months (95% CI, 4.1-5.5), and the median overall survival was 10.7 months (95% CI, 8.7-12.1).
In April 2019, the FDA granted accelerated approval to erdafitinib for the treatment of patients with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 or FGFR2 genetic alterations who experienced disease progression during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The regulatory decision was supported by findings from a cohort of the phase 2 Study BLC2001 trial (NCT02365597), which demonstrated that patients (n = 87) who receivederdafitinib achieved an ORR of 32.2% (95% CI, 22.4%-42.0%), including 2.3% with a CR, and a median DOR of 5.4 months (95% CI, 4.2-6.9).2
RAGNAR was a single-arm, open-label, international trial conducted at 156 centers across 15 countries. The study enrolled 4 cohorts of patients based on age and tumor histology; the primary cohort was tumor agnostic. Eligible patients were at least 12 years old with an unresectable, locally advanced, or metastatic solid tumor malignancy and a predefined FGFR1/2/3/4 mutation or fusion with an intact kinase domain. Measurable disease per RECIST v1.1 criteria or RANO criteria for primary brain tumors was required, and patients needed to have disease progression on at least 1 prior line of systemic therapy with no alternative standard therapy available. Those who received previous treatment with an FGFR inhibitor were excluded from the study. 1
Adults had an ECOG performance status of 0 or 1; pediatric patients aged 12 to 15 years had a Lansky score of at least 80, and adolescents aged 16 to 17 years had a Karnofsky score of at least 80.
Oral erdafitinib was administered once daily on a 21-day cycle until disease progression, intolerable toxicity, withdrawal, or discontinuation by investigator’s decision. Patients who were aged 15 years or older received the agent at a starting dose of 8 mg with the possibility for up-titration to 9 mg based on serum phosphate concentrations on day 14 of cycle 1. Patients aged 12 to 14 years received erdafitinib at a starting dose of 5 mg with possible up-titration to 6 mg or further to 8 mg based on serum phosphate concentrations on day 14 of cycle 1 and day 7 of cycle 2.
The primary end point was ORR by RECIST 1.1, or RANO for central nervous system tumors, assessed by independent review committee. Secondary end points included ORR, DOR, disease control rate (DCR), PFS, overall survival, clinical benefit rate (CBR), safety, health-related quality of life, and pharmacokinetics.
At baseline, the median patient age was 57 years (range, 48-64) and the median time from progression or relapse on the last line of treatment to first dose of erdafitinib was 1.25 months (range, 0.82-2.14). Most patients were male (55%), White (52%) or Asian (26%), had an ECOG performance status of 1 (69%), present metastases (82%), and received prior chemotherapy (99%). Patients with metastases (n = 179) had a median of 2 sites of metastatic disease (IQR, 2-3), and the most frequent sites included the lymph node (55%), liver (46%), lung (43%), and bone (23%).
The median number of prior lines of anticancer therapies was 2 (IQR, 2-4), with patients receiving 1 (23%), 2 (31%), or 3 or more (46%) prior lines. The study included patients with cholangiocarcinoma (14%), high-grade glioma (14%), pancreatic cancer (8%), breast cancer (7%), squamous-cell head and neck cancers (7%), squamous non–small cell lung cancer (NSCLC; 6%), non-squamous NSCLC (4%), carcinoma of unknown primary (4%), colorectal cancer (4%), endometrial cancer (4%), esophageal cancer (4%), gastric cancer (4%), ovarian cancer (4%), low-grade glioma (3%), salivary gland cancer (2%), soft-tissue sarcoma (1%), prostate cancer (1%), or other solid tumors (6%).
Additional findings from RAGNAR showed that the CBR was 46% (95% CI, 39%-53%), and the DCR was 74% (95% CI, 67%-80%). The investigator-assessed ORR and DOR were 25% (95% CI, 20%-32%) and 7.0 months (95% CI, 5.5-8.5), respectively, which investigators noted was consistent with results determined by independent review.
Subgroup analyses showed that antitumor activity was observed across FGFR1-3 mutations and fusions. Responses and disease control were observed in patients with salivary gland cancer (ORR, 100%; DCR, 100%), pancreatic cancer (56%; 94%), cholangiocarcinoma (52%; 97%), endometrial cancer (50%; 75%), non-squamous NSCLC (33%; 56%), squamous-cell head and neck cancers (33%; 87%), breast cancer (31%; 69%), low-grade glioma (29%; 71%), carcinoma of unknown primary (25%; 88%), ovarian cancer (25%; 63%), squamous NSCLC (21%; 86%), gastric cancer (13%; 63%), esophageal cancer (13%; 38%), high-grade glioma (10%; 57%), and other cancers (15%; 77%).
Safety findings showed that at a median treatment exposure of 4.3 months (IQR, 2.1-9.2), nearly all patients (n = 216/217) experienced at least 1 treatment-emergent adverse effect (TEAE), including grade 1 to 2 (29%), grade 3 (57%), grade 4 (9%), and grade 5 (4%). Sixty-three percent, 75%, and 10% of patients experienced TEAEs leading to dose reduction, interruption, or discontinuation, respectively. Serious TEAEs occurred in 39% of patients and included grade 3 or higher stomatitis (2%) and diarrhea (1%).
The most common grade 1 to 2 TEAEs were hyperphosphatemia (66%), diarrhea (55%), dry mouth (48%), and stomatitis (44%). A TEAE of special interest was central serous retinopathy, which was reported at any grade in 14% of patients. Dose reduction and interruption due to central serous retinopathy occurred in 19 and 17 patients, respectively. Central serous retinopathy led to treatment discontinuation in 1 patient.