FDA Approval Summary: Fruquintinib for the Treatment of Refractory Metastatic Colorectal Cancer.

On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and if RAS wild-type and medically appropriate, an anti-EGFR therapy. Approval was based on Study FRESCO-2, a globally conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival. A total of 691 patients were randomly assigned (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 [95% confidence interval (CI), 0.55, 0.80; P < 0.001]. The median OS was 7.4 months (95% CI, 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI, 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with the inhibition of VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single-country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI, 0.51, 0.83; P < 0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, an anti-EGFR therapy.

FDA Approval Summary: Tucatinib with Trastuzumab for Advanced Unresectable or Metastatic, Chemotherapy Refractory, HER2-Positive RAS Wild-Type Colorectal Cancer.

On January 19, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Approval was based on the pooled analysis of patients receiving tucatinib in combination with trastuzumab in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. The primary endpoint was overall response rate (ORR) by RECIST 1.1 as per blinded central review committee (BIRC) assessment. The main secondary endpoint was duration of response (DOR) per BIRC assessment. Eighty-four eligible patients received the combination tucatinib and trastuzumab. With a median follow-up of 16 months, the ORR was 38% [95% confidence interval (CI): 28-49] and median DOR was 12.4 months (95% CI: 8.5-20.5); 81% of responders had a response lasting more than 6 months. The most common adverse reactions observed in at least 20% of patients receiving tucatinib in combination with trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and fever. FDA concluded that the magnitude of ORR and durable responses observed in patients treated with tucatinib in combination with trastuzumab in the MOUNTAINEER trial are clinically meaningful, particularly in the context of a disease with estimated survival of 6-7 months with available therapy. This is the first approval for the subset of patients with HER2-positive colorectal cancer. This article summarizes the FDA's thought process and review of the data supporting this accelerated approval.

Could Postnatal Age-Related Uridine Diphosphate Glucuronic Acid Be a Rate-Limiting Factor in the Metabolism of Morphine During the First Week of Life?

Neonates experience dramatic changes in the disposition of drugs after birth as a result of enzyme maturation and environmental adjustment, challenging therapeutic decision making. In this research, we establish postnatal age, postmenstrual age, and body weight as physiologically reasonable predictors of morphine's clearance in neonates. By integrating knowledge of bilirubin, morphine, and other drugs metabolized by glucuronidation pathways from previously published studies, we hypothesize that uridine diphosphate glucuronic acid, a postnatal age-dependent sugar, plays an important role in the metabolism of morphine during the first week of life. This finding can be extended to other drugs metabolized by uridine diphosphate glucuronosyltransferase pathways in neonates and thus has important clinical implications for the use of drugs in this population.

Subdermal Ultrasound Contrast Agent Injection for Sentinel Lymph Node Identification: An Analysis of Safety and Contrast Agent Dose in Healthy Volunteers.

OBJECTIVES: Mapping of the lymphatic chain for identification of the sentinel lymph node (SLN) is an important aspect of predicting outcomes for patients with breast cancer, and it is usually performed as an intraoperative procedure using blue dye and/or radiopharmaceutical agents. Recently, the use of contrast-enhanced ultrasound (CEUS) has been proposed as an alternative imaging technique for this mapping. The objective of this study was to evaluate the use of subdermal administration of the ultrasound (US) contrast agent Sonazoid (GE Healthcare, Oslo, Norway) in terms of patient safety and to select the dose to be used for lymphatic applications in humans. METHODS: This study was performed in 12 female volunteers who received bilateral subdermal injections of Sonazoid (1 or 2 mL dose) in the mid-upper outer quadrant of their breasts at 2 different time points. Contrast-enhanced US examinations were performed 0, 0.25, 0.5, 1, 2, 4, 6, and 24 hours after injection to identify SLNs. RESULTS: Sentinel lymph nodes were identified within the first hour after injection as enhanced structures, and there was no significant difference by dose in the number of SLNs identified (P = .74). The volunteers only had minor adverse experiences (AEs) that resolved completely without intervention by study completion. CONCLUSIONS: The subdermal use of Sonazoid in this study showed only minor local and nonsignificant AEs that were completely resolved without any intervention. Two different doses were compared with no significant differences observed between them. Hence, the lower dose studied (1 mL) was selected for use in future clinical studies.