Accelerated Approval to Futibatinib for Cholangiocarcinoma
The FDA granted accelerated approval to futibatinib for adult patients with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements. Efficacy was evaluated in TAS-120-101, a multicenter, open-label, single-arm trial that enrolled 103 patients with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring a FGFR2 gene fusion or other rearrangement. The presence of FGFR2 fusions or other rearrangements was determined using next-generation sequencing testing. Patients received 20 mg of futibatinib orally once daily until disease progression or unacceptable toxicity.
The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee according to RECIST v1.1. ORR was 42 percent (95% CI: 32, 52); all 43 responders achieved partial responses. The median DoR was 9.7 months (95% CI: 7.6, 17.1).
The most common adverse reactions occurring in 20 percent or more of patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye, nausea, decreased appetite, urinary tract infection, palmar-plantar erythrodysesthesia syndrome, and vomiting. The recommended futibatinib dose is 20 mg orally once daily until disease progression or unacceptable toxicity occurs.
Sodium Thiosulfate to Reduce Risk of Ototoxicity in Pediatric Patients
The FDA approved sodium thiosulfate to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month and older with localized, non-metastatic solid tumors. Efficacy was evaluated in two multicenter, open-label, randomized, controlled trials in pediatric patients undergoing treatment with cisplatin-based chemotherapy for cancer: SIOPEL 6 and COG ACCL0431.
SIOPEL 6 enrolled 114 patients with standard-risk hepatoblastoma undergoing 6 cycles of perioperative cisplatin-based chemotherapy. Patients were randomized (1:1) to receive cisplatin-based chemotherapy with or without sodium thiosulfate administered at various doses of 10 g/m2, 15 g/m2, or 20 g/m2 based on actual body weight. The primary outcome was the percentage of patients with Brock Grade >=1 hearing loss, assessed using pure tone audiometry after treatment or at an age of at least 3.5 years, whichever was later. The incidence of hearing loss was lower in the sodium thiosulfate and cisplatin arm (39%) compared with the cisplatin alone arm (68%); unadjusted relative risk 0.58 (95% CI: 0.40, 0.83).
COG ACCL0431 enrolled 125 pediatric patients with solid tumors undergoing a chemotherapy regimen, including cumulative cisplatin doses of 200 mg/m2 or higher, with individual cisplatin doses to be infused over 6 hours or less. Patients were randomized (1:1) to receive cisplatin-based chemotherapy with or without sodium thiosulfate. Efficacy was evaluated in a subset of 77 patients with localized, non-metastatic solid tumors. The primary outcome was hearing loss according to American Speech-Language-Hearing Association (ASHA) criteria, assessed at baseline and 4 weeks after the final course of cisplatin. The incidence of hearing loss was lower in the sodium thiosulfate and cisplatin arm (44%) compared with the cisplatin alone arm (58%); unadjusted relative risk 0.75 (95% CI: 0.48, 1.18).
The most common adverse reactions in the two trials were vomiting, nausea, decreased hemoglobin, hypernatremia, and hypokalemia. The recommended sodium thiosulfate dose is based on surface area according to actual body weight. Sodium thiosulfate is administered as an intravenous infusion over 15 minutes following cisplatin infusions that are 1-6 hours in duration.
Selpercatinib for Locally Advanced or Metastatic RET Fusion-Positive Solid Tumors
The FDA granted accelerated approval to selpercatinib for adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.
Efficacy was demonstrated in LIBRETTO-001, a multicenter, open-label, multi-cohort trial that evaluated 41 patients with RET fusion-positive tumors (other than non-small cell lung cancer [NSCLC] and thyroid cancer) with disease progression on or following prior systemic treatment or who had no satisfactory alternative treatment options. The efficacy evaluation was supported by data in 343 patients with RET fusion-positive NSCLC and thyroid cancer enrolled in the same trial already described in product labeling. Patients received selpercatinib until disease progression or unacceptable toxicity.
The primary efficacy measures were overall response rate (ORR) and duration of response (DOR) as determined by a blinded independent review committee. Among 41 evaluable patients, ORR was 44 percent (95% CI: 28, 60) with a DOR of 24.5 months (95% CI: 9.2, not estimable). Tumor types with responses included pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma.
The median age of patients was 50 years (range 21-85). Selected demographics were as follows: 54 percent female, 68 percent White, 24 percent Asian, 4.9 percent Black, 7 percent Hispanic/Latino, 95 percent had ECOG performance status of 0 or 1, 95 percent had metastatic disease. Thirty-seven patients (90%) received prior systemic therapy (median 2 [range 0-9]; 32% received three or more). The most common cancers were pancreatic (27%), colorectal (24%), salivary (10%), and unknown primary (7%). RET fusion-positive status was detected in 97.6 percent of patients using NGS and 2.4 percent using FISH.
The most common adverse reactions (>=25%) in patients were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The recommended selpercatinib dose based on body weight is as follows: 1) Less than 50 kg: 120 mg orally twice daily and 2) 50 kg or greater: 160 mg orally twice daily.
Selpercatinib for Locally Advanced or Metastatic RET Fusion-Positive NSCLC
The FDA granted regular approval to selpercatinib for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test. The FDA also approved the Oncomine Dx Target Test as a companion diagnostic for selpercatinib.
Selpercatinib was previously granted accelerated approval for the NSCLC indication on May 8, 2020, based on initial overall response rate (ORR) and duration of response (DOR) in 144 patients enrolled in the LIBRETTO-001 trial, a multicenter, open-label, multi-cohort trial. The conversion to regular approval was based on data from an additional 172 patients and 18 months of additional follow-up to assess durability of response.
Efficacy was demonstrated in total of 316 patients with locally advanced or metastatic RET fusion-positive NSCLC. Patients received selpercatinib until disease progression or unacceptable toxicity.
The primary efficacy measures were ORR and DOR as determined by a Blinded Independent Review Committee. Among 69 treatment-naive patients, ORR was 84 percent (95% CI: 73, 92) with a DOR of 20.2 months (95% CI: 13, not estimable). Among 247 patients previously treated with platinum-based chemotherapy, ORR was 61 percent (95% CI: 55, 67) with a DOR of 28.6 months (95% CI: 20, not estimable).
The median age of patients was 61 years (range 23-92). Selected demographics were as follows: 58 percent female; 49 percent White, 41 percent Asian, and 5 percent Black; 97 percent had ECOG performance status 0 or 1; 97 percent had metastatic disease.