Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase (DPYD) Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.

PURPOSE: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization. METHODS: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization. RESULTS: Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively (P = .085); 64%, 25%, and 13% were hospitalized (P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups (P < .001), with reactive carriers having the earliest onset and highest incidence. CONCLUSION: DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.

Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with lung cancer and ERBB2 mutation or amplification treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS: Eligible patients had advanced lung cancer of any histology, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2 mutation or amplification. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) per RECIST v. 1.1 or stable disease (SD) of at least 16 weeks duration (SD16+). Secondary end points included safety, duration of response, duration of SD, progression-free survival, and overall survival. RESULTS: Twenty-eight patients with lung cancer (27 non-small-cell, 1 small-cell) and ERBB2 mutation (n = 15), ERBB2 amplification (n = 12), or both (n = 1) were enrolled from November 2016 to July 2020. All patients were evaluable for efficacy and toxicity. Three patients with partial response (two ERBB2 mutation; one both mutation and amplification) and seven patients with SD16+ (five ERBB2 mutation; two amplification) were observed for a DC rate of 37% (95% CI, 21 to 50; P = .005) and OR rate of 11% (95% CI, 2 to 28). Five patients had one or more grade 3 or 4 adverse or serious adverse events at least possibly related to P + T. CONCLUSION: Combination P + T showed evidence of antitumor activity in heavily pretreated patients with non-small-cell lung cancer and ERBB2 mutation or amplification, particularly those with ERBB2 exon 20 insertion mutations.

Treatment of cerebral radiation necrosis with bevacizumab: the Cleveland clinic experience.

BACKGROUND: Cerebral radiation necrosis (RN) is a devastating complication of radiation therapy for brain tumors. Recent studies have explored the role of bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor in the treatment of RN of the brain. We report 24 patients with cerebral RN who were treated with bevacizumab. MATERIALS AND METHODS: Twenty-four patients diagnosed with cerebral RN and treated with different schedules of bevacizumab between July 2007 and June 2012, were identified from the Cleveland Clinic Brain Tumor and Neuro-Oncology Center's database. Pretreatment and posttreatment magnetic resonance imaging (MRI) studies were compared to evaluate bevacizumab efficacy. RESULTS: Posttreatment MRI demonstrated a radiographic improvement in 23 of 24 patients on the postcontrast T1-weighted MRI and fluid-attenuated inversion-recovery sequences. Using the McDonald criteria, the average change in the T1-weighted postcontrast MRI was a decrease of 48.1%, and the average change in the fluid-attenuated inversion-recovery images was a decrease of 53.7%. There was a mean daily dose reduction of 9.4 mg of dexamethasone after initiation of bevacizumab in patients who were on steroids at the start of bevaciuzmab therapy for RN. Treatment with bevacizumab was well tolerated with only 1 grade 3 adverse event. CONCLUSIONS: The current study demonstrates that bevacizumab treatment results in excellent clinical and radiologic response in patients with RN caused by common forms of radiation therapy. The safety profile of bevacizumab use in RN is acceptable. In the current study, we found no difference between different schedules of bevacizumab in treatment outcomes.