Profile of Capmatinib for the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC): Patient Selection and Perspectives.

Aberrant c-MET (Mesenchymal-Epithelial Transition) signaling contributes to cancer cell development, proliferation, and metastases of non-small cell lung cancer (NSCLC). MET exon 14 (METex14) skipping mutation is noted in approximately 4% of NSCLC cases and is targetable with the recently approved tyrosine kinase inhibitors capmatinib and tepotinib. Capmatinib, the focus of this review article, is a highly selective MET inhibitor approved for use in patients with METex14 mutated NSCLC. In this review, we discuss cMET as a target, the pharmacology of capmatinib, key trials of capmatinib in MET-altered lung cancer, and toxicity profile. We highlight some ongoing capmatinib clinical trials that expand their role to other subsets of patients, especially those with EGFR mutations, who develop MET alterations as a resistance pathway. We further provide our perspective on the management of METex14 NSCLC, strategies for sequencing agents, and toxicity management.

Safety and Efficacy of Immune Checkpoint Inhibitors in Cancer Patients and Preexisting Autoimmune Disease: A Systematic Review and Meta-Analysis in Non-Small-Cell Lung Cancer.

BACKGROUND: Cancer patients with preexisting autoimmune diseases (AID) have been traditionally excluded from clinical trials of immune checkpoint inhibitors (ICI) due to concerns for toxicity. As indications for ICI expand, more data are needed on the safety and efficacy of ICI treatment in cancer patients with AID. METHODS: We systematically searched for studies consisting of NSCLC, AID, ICI, treatment response, and adverse events. Outcomes of interest include incidence of autoimmune flare, irAE, response rate, and ICI discontinuation. Study data were pooled using random-effects meta-analysis. RESULTS: Data were extracted from 24 cohort studies, consisting of 11,567 cancer patients (3774 NSCLC patients and 1157 with AID). Pooled analysis revealed an AID flare incidence of 36% (95% CI, 27%-46%) in all cancers and 23% (95% CI, 9%-40%) in NSCLC. Preexisting AID was associated with an increased risk of de novo irAE in all cancer patients (RR 1.38, 95% CI, 1.16-1.65) and NSCLC patients (RR 1.51, 95% CI, 1.12-2.03). There was no difference in de novo grade 3 to 4 irAE and tumor response between cancer patients with and without AID. However, in NSCLC patients, preexisting AID was associated with a 2-fold increased risk of de novo grade 3 to 4 irAE (RR 1.95, 95% CI, 1.01-3.75) but also better tumor response in achieving a complete or partial response (RR 1.56, 95% CI, 1.19-2.04). CONCLUSIONS: NSCLC patients with AID are at a higher risk of grade 3 to 4 irAE but are more likely to achieve treatment response. Prospective studies focused on optimizing immunotherapeutic strategies are needed to improve outcomes for NSCLC patients with AID.

Characteristics of Patients With Second Primary Lung Cancer Following Breast Cancer: A Retrospective Descriptive Study.

BACKGROUND: Breast cancer (BC) is the most common noncutaneous malignancy in women and survivors are at an increased risk for secondary malignancy with lung cancer (LC) being the most common. There are few studies that have explored the clinicopathological specifics of LC in BC survivors. METHODS: In this single-institution, retrospective study, we identified BC survivors who subsequently developed LC, examined their breast and LC clinical and pathological characteristics and compared them to the general BC and LC population as published in the literature. RESULTS: In our study, we found the following associations that could be meaningful: an association between receiving radiation (RT) and LC (including a statistically significant P = .03 chance of ipsilateral LC after BC treatment with RT), a higher incidence and amount of smoking and LC, high BRCA positivity (78.9%) in the few patients who had germline testing, and a higher incidence of EGFR mutations in NSCLC after BC (60.9%) as well as an earlier stage of NSCLC disease. CONCLUSION: Treatments such as RT, genetic factors such as BRCA mutations, and tobacco use may increase the risk of developing LC amongst BC survivors. Exploring this further can potentially lead to better risk stratification through modified low-dose CT chest screening protocols to catch LCs earlier and ultimately improve outcomes. Past studies have shown that BC survivors who are subsequently diagnosed with NSCLC may have improved OS compared with primary NSCLC and our study showed a high incidence of EGFR mutated NSCLC, which also suggest both improved prognosis and a different molecular profile of NSCLC, which warrants further investigation. Lastly, BC survivors who subsequently are diagnosed with NSCLC had earlier stage disease in our study, perhaps a result of surveillance, highlighting the importance of close monitoring of BC survivors.

A Retrospective Study of the Effect of Metformin on Patients with Metastatic Prostate Cancer.

Introduction: Previous studies demonstrated that metformin could lead to an inhibition of proliferation of cancer cells through a shift from anabolic to catabolic metabolism. In this study, we seek to investigate the effect of metformin in metastatic prostate cancer. Methods: Patients followed at Northwell Health Zuckerberg Cancer Center during 2014-2018 were included if they were diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC), with ⩾6 months follow-up with and without metformin treatment. The primary outcomes, 6-month prostate-specific antigen (PSA) response, overall survival (OS), and radiographic progression free survival (rPFS), were evaluated. Results: There were 267 patients included in the final analysis; 196 patients had mHSPC (73.2%) and 71 had mCRPC (26.8%). Within the mHSPC subjects, there was a significant difference in OS between metformin vs nonmetformin groups (148.5 vs 85.6 months; P < .046) in a univariate analysis; patients who took metformin had a significantly longer OS than subjects who did not (median OS: 148.5 vs 86 months; P < .046). There was no significant difference between the 2 groups with respect to either PSA response rate at 6 months or rPFS or OS in patients with mHSPC in both univariate and multivariate analysis. Within the mCRPC subjects, there was no significant difference between metformin and nonmetformin groups with respect to OS (43.3 vs 51.5 months; P < 0.160) or PSA response at 6 months (38.5% vs 57.1%; p < 0.24); however, patients on metformin had a significantly shorter rPFS in both the univariate analysis (7.3 vs 17.4; P < .0002) and in the multivariate analysis (HR = 2.52; 95% CI: 1.24m 5.11; P < .0109). Conclusions: Among patients with mHSPC, use of metformin was not significantly associated with improved OS in the multivariate analysis.

Alectinib-induced hemolytic anemia.

INTRODUCTION: Alectinib is an oral anaplastic lymphoma kinase tyrosine kinase inhibitor with central nervous system activity. It is currently approved and a preferred first-line option for those with anaplastic lymphoma kinase-positive non-small cell lung cancer. Alectinib has been shown to cause anemia, usually mild. CASE REPORT: We report a case of alectinib-induced hemolytic anemia in a patient receiving alectinib as first-line treatment for anaplastic lymphoma kinase-positive non-small cell lung cancer. MANAGEMENT AND OUTCOME: The patient's dose was reduced from 600 mg twice daily to 450 mg twice daily and further down to 300 mg twice daily and eventually discontinued. At that point, the hemoglobin normalized. DISCUSSION: Our case demonstrates objective evidence for hemolytic anemia induced by alectinib.

A deep dive into CDK4/6 inhibitors: Evaluating real world toxicities and treatment paradigms in the elderly population.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors have become part of the standard of care in the treatment of hormone receptor positive, Her2Neu negative metastatic breast cancer. There is concern regarding the efficacy and potential increased cyclin-dependent kinase 4/6 inhibitors toxicity in the geriatric population in the community compared to the clinical trial population. METHODS: We evaluated patients treated with cyclin-dependent kinase 4/6 inhibitors from 2015 to 2019 and stratified according to age ≥70 and <70 years. Complete blood count from the first two cycles was recorded. Rates of hematologic toxicities, dose interruptions and reductions, progression-free survival, and overall survival were compared between both groups. We sought to assess the hematologic toxicities between the age groups and the relationship between previous chemotherapy exposure, bone metastasis and starting cyclin-dependent kinase 4/6 inhibitors dose with progression-free survival and overall survival. RESULTS: A total of 202 patients were included, 73 were ≥70 years and 129 were <70 years of age. There was no association between age group and grade of neutropenia or thrombocytopenia. There was a profound association between progression-free survival and overall survival and starting dose, where patients with recommended starting dose had higher progression-free survival and overall survival than those with a reduced dose (p = 0.0003 and p = 0.04). CONCLUSIONS: Our study showed similar progression-free survival and overall survival between age groups without significant differences in neutropenia or thrombocytopenia toxicity. Nevertheless, we found an association between starting dose and progression-free survival and overall survival that has not been previously reported. Given the good tolerability across age groups and the improvement in progression-free survival and overall survival, patients should be treated at the cyclin-dependent kinase 4/6 inhibitors recommended dose and monitored appropriately.

A Real World Perspective of PARP Inhibitor Use in Gynecological Cancer Patients.

Introduction: Over the last few years, targeted therapy has become the mainstay maintenance treatment of patients with ovarian cancer including patients with BRCA1/BRCA2 mutations. Poly ADP ribose polymerase inhibitors (PARPi) are effective in the treatment of patients who are in complete or partial remission. PARPi are known to cause hematological adverse events (AEs), but have not been compared directly to each other. Objective: Primary objective was to compare the incidence of hematological and non-hematological AEs associated with the use of PARPi. Methods: This was a single institution, retrospective study evaluating patients who were treated with PARPi for ovarian cancer from January 2017 to October 2020. Patients were stratified according to which PARP inhibitor they received. Results: Ninety-two patients were included in final analysis. Thirty-one (33.7%) patients received niraparib and 61 (66.3%) patients received olaparib. Median age of patients were 64.3 (range, 33.8 to 92.3) years, 66 (71.7%) were white, and 84 (91.3%) had an ECOG PS of 0/1. Patients in the niraparib group experienced a higher rate of hematologic AEs, with 11 (35.5%), 20 (64.5%), and 18 (58.1%) experiencing neutropenia, anemia, and thrombocytopenia, respectively. Eight (13.1%), 24 (39.3%), and 16 (26.2%) patients in the olaparib group experienced neutropenia, anemia, and thrombocytopenia, respectively. Conclusion: This single institution retrospective study outlines the hematological toxicities observed between two PARPi. Our results suggested that niraparib tended to be associated with a higher risk for hematologic toxicities than olaparib. Anemia was the most common hematologic toxicity which was consistent with what has been widely documented in the literature.

Inpatient utilization of immune checkpoint inhibitors and clinical outcomes.

INTRODUCTION: Retrospective studies have suggested that patients with poor performance status treated with immune checkpoint inhibitors have shorter overall survival and poorer response rates. This study was undertaken to investigate the possible relationships between inpatient immune checkpoint inhibitor use and clinical outcomes. METHODS: This was a retrospective chart review of cancer patients who received an immune checkpoint inhibitor while hospitalized from 1 January 2016 to 30 December 2020. The primary outcome was 90-day mortality or admission to hospice rate. Secondary outcomes included overall survival, time to death or discharge to hospice, and descriptive summarization of patient characteristics. RESULTS: A total of 52 patients were analyzed. At 90 days, 68.2% of subjects were expired or admitted to hospice (95% CI: 54.7-81%). 90-day overall survival was 47.1%; median survival time was 81 days (95% CI: 28-242 days). The median time to death or hospice was 35 days (95% CI: 24-72 days). The time to death or hospice was shorter for immune checkpoint inhibitor-naive patients compared to those who received immune checkpoint inhibitors prior to admission (29 days, 95% CI: 12-43 days vs. 242 days, 95% CI: 36-1288 days, respectively; HR: 2.74, 95% CI: 1.2-6.25; p = 0.0121). No differences were found when comparing other baseline characteristics. CONCLUSION: A majority of patients who received an immune checkpoint inhibitor while hospitalized were either discharged to hospice or expired by 90 days. An increased rate of death or discharge to hospice was observed for patients who were immune checkpoint inhibitor-naive prior to their admission.

A contemporary review of rearranged during transfection-selective inhibitors.

OBJECTIVE: Rearranged during transfection genes are present in 1-2% of patients who have non-small cell lung cancer and 10-30% of patients with papillary thyroid cancer. The objective of this article is to review the current rearranged during transfection inhibitors indicated for patients with rearranged during transfection-mutated cancers and their future directions.Data sources: The pivotal phase I/II studies for selpercatinib and pralsetinib were evaluated. Current studies on rearranged during transfection inhibitors were searched on ClinicalTrials.gov using the key word "RET."Data summary: Selpercatinib and pralsetinib were the first two U.S. Food and Drug Administration-approved rearranged during transfection-selective inhibitors for advanced or metastatic rearranged during transfection fusion-positive non-small cell lung cancer, rearranged during transfection-mutant medullary thyroid cancer, and rearranged during transfection fusion-positive thyroid cancer. Both agents showed promising efficacy with objective response rate ranging from 60% to 73% in all aforementioned rearranged during transfection-mutated cancers. Additionally, benefits were seen even in patients with intracranial metastasis at baseline. Both showed favorable safety profiles. Some common class adverse events included elevated liver function tests and hypertension. Hematologic side effects such as anemia and neutropenia were more common with pralsetinib. Selpercatinib had interactions with acid suppressive therapy and specific instructions when used concomitantly. CONCLUSIONS: While the rearranged during transfection inhibitors are generally well-tolerated, each agent possesses slightly different efficacy, side-effect profile, and drug-drug interactions.

A real world analysis of first line treatment of advanced EGFR mutated non-small cell lung cancer: A multi-center, retrospective study.

INTRODUCTION: The recently published FLAURA trial demonstrated that osimertinib has remarkable efficacy in front-line setting for non-small cell lung cancer (NSCLC). While this has transformed current practice, there are no effective treatments following progression on osimertinib. The aim of our study was to compare progression-free survival (PFS) and overall survival (OS) between patients initiated on osimertinib to those started on other EGFR TKIs. METHODS: This was a multicenter, retrospective study conducted at two large academic centers. Adult patients with EGFR-mutated non-small cell lung cancer (NSCLC) who received EGFR therapy between 2014 and 2019 were included. Patients were dichotomized based on front-line TKI (osimertinib vs. other). PFS, OS, and time-to-discontinuation were evaluated. RESULTS: One-hundred seventy-two patients were included in the final analysis. Fifty-two (30.2%) patients received osimertinib and 120 (69.8%) patients received another EGFR TKI. The PFS rates at 6, 12, and 18 months were 86.3%, 79.5%, 69.8% in the osimertinib group and 86.6%, 64.2%, 39.3% in the other EGFR TKI group, respectively (p < 0.0036).Estimated OS at 6, 12, and 18 months was similar for both groups: 94.2%, 94.2%, 80.2% and 95.7%, 93.9%, 84.1%, respectively [Adjusted HR = 0.95 (95% CI, 0.37-2.44; p < 0.9128]. CONCLUSION: Osimertinib demonstrated greater 12 and 18 month PFS compared to other EGFR TKIs. This finding is consistent with results of the FLAURA trial. However, unlike FLAURA, there were no differences in estimated OS between the two groups in our study. Further research to evaluate optimal sequencing strategies in the real world of first, second and third generation TKIs is needed.

Osimertinib in EGFR-Mutated Lung Cancer: A Review of the Existing and Emerging Clinical Data.

The use of epidermal growth factor receptor (EGFR) inhibitors such as osimertinib has improved outcomes and quality of life for patients with EGFR-mutated non-small cell lung cancer (NSCLC). Osimertinib has become the preferred EGFR tyrosine kinase inhibitor (TKIs) for patients with these mutations after demonstrating superior efficacy compared to first generation EGFR TKIs, such as erlotinib and gefitinib. More recently osimertinib has also shown to be beneficial in patients with resectable NSCLC harboring EGFR mutations irrespective of whether they received adjuvant chemotherapy or not. The drug is now FDA approved in this setting. With osimertinib being used more commonly in earlier stage and front-line settings, we are more likely to see patients who develop resistance to this drug. The aim of this review is to provide a comprehensive review of the data with osimertinib in EGFR mutation positive NSCLC, potential resistance mechanisms and an overview of key ongoing clinical trials.

Clinical efficacy with dabrafenib and trametinib in a T599_V600insT poorly differentiated metastatic thyroid carcinoma.

BRAF (v-raf murine sarcoma viral oncogene homolog B1) and MEK (mitogen-activated protein kinase kinase) inhibitors have been shown to improve clinical outcomes in tumours presenting with mutations in the BRAF gene. The most common form of BRAF mutation is V600E/K and has been shown to occur in thyroid cancers. Treatment data for patients harbouring less frequent BRAF mutations are limited. In vitro studies have shown that mutations in codons 599-601 increase kinase activity similar to that in V600E mutations, which suggests that BRAF and MEK inhibitors could be an effective treatment option. Here, we report a case of a patient with thyroid carcinoma harbouring a rare amino acid insertion in codon 599 of the BRAF gene (T599_V600insT) treated with a BRAF and MEK inhibitor.

Epidemiology and clinicopathological features of lung cancer in patients with prior history of breast cancer.

Breast cancer is the most common malignancy in women, and lung cancer, the leading cause of cancer-related mortality in the United States, is the most common subsequent primary cancer among breast cancer survivors. In this review, we examine the risk factors that cause subsequent primary lung cancer after breast cancer (referred to herein as BCLC patients) as well as the prognostic factors that may affect survival. Notable clinicopathological features include patient characteristics such as age, smoking history, and the presence of EGFR or BRCA mutations, as well as factors related to the treatment of breast cancer such as radiation, surgery, chemotherapy, stage, anti-estrogen therapy, and ER/PR/HER2 status.

Impact of Tyrosine Kinase Inhibitor Starting Dose on Outcomes in Patients With Non-Small Cell Lung Cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can cause intolerable adverse events in patients with non-small cell lung cancer (NSCLC) and may be prescribed at a lower dose. OBJECTIVE: Our objective was to analyze the starting doses of oral EGFR and ALK TKIs in patients diagnosed with NSCLC at our institution. METHODS: We conducted a retrospective chart review with patients on EGFR and ALK TKIs for NSCLC. Patients were categorized into 2 groups: patients initiated on Food and Drug Administration (FDA) standard dose (SD) and patients initiated on a reduced dose (RD). Progression-free survival (PFS), overall survival (OS) and other treatment outcomes were compared between both groups. RESULTS: Ninety patients were included for analysis. The median time-to-progression for the SD group (n = 67) and RD group (n = 23) were 13.4 months (95% confidence interval [CI]:8.9-15.6) and 15.1 months (95%CI: 5.6-21.5), respectively. Median time-to-death was not estimable for OS. The predicted OS probability at approximately 15 months post treatment initiation for the SD group and RD group was 81.8% and 80.5%, respectively. CONCLUSION: Patients who initiated TKI therapy at a RD did not have different PFS and 15-month survival outcomes than patients who initiated TKI therapy at the FDA SD.

Lorlatinib induced proteinuria: A case report.

INTRODUCTION: Lorlatinib is an oral anaplastic lymphoma kinase (ALK) and C-ros oncogene (ROS1) tyrosine kinase inhibitor with excellent central nervous system (CNS) penetrability. It is currently approved for use as second line therapy for those with ALK positive non-small cell lung cancer (NSCLC). Given its CNS penetrating effects, lorlatinib has shown to cause CNS adverse events such as seizures, hallucinations, and changes in cognitive function. To our knowledge proteinuria has not been previously described with this medication. CASE REPORT: We report a case lorlatinib induced proteinuria in a patient receiving lorlatinib as second line treatment for ROS1 rearranged NSCLC.Management & Outcome: The patient's dose was reduced from 100 mg to 75 mg and further down to to 50 mg daily. At that point the proteinuria improved. Other adverse events attributable to the medication, specifically hallucinations and peripheral neuropathy also improved. DISCUSSION: Our case demonstrates objective evidence for proteinuria induced by lorlatinib, which may also be dose dependent.

A Comprehensive Review of Contemporary Literature for Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer and Their Toxicity.

Mutations in the epidermal growth factor receptor (EGFR) are common amongst those with non-small cell lung cancer and represent a major factor in treatment decisions, most notably in the advanced stages. Small molecule tyrosine kinase inhibitors (TKIs) that target the EGFR, such as erlotinib, gefitinib, icotinib, afatinib, dacomitinib and osimertinib, have all shown to be effective in this setting. Osimertinib, a third-generation EGFR TKI, is a favorable option, but almost all patients develop resistance at some time point. There are no effective treatment options for patients who progress on osimertinib, but ongoing trials will hopefully address this unmet need. The aim of this review is to provide a comprehensive review of the data with EGFR TKIs, management of the toxicities and the ongoing trials with this class of agents.

Pretreatment nutritional status and response to checkpoint inhibitors in lung cancer.

BACKGROUND: Checkpoint inhibitors are integral to non-small-cell lung cancer treatment. Existing data suggests that nutritional status may play a role in antitumor immunity. MATERIALS & METHODS: This retrospective study of 106 non-small-cell lung cancer patients who started checkpoint inhibitors between 2014 and 2017 at our institution assessed relationship of nutritional parameters to overall survival (OS) and progression-free survival. RESULTS: Mean age was 68.7 ± 9.2 years and 59.4% patients were male. On multivariate analysis for OS, hypoalbuminemia and significant weight loss were prognostic at p-values of 0.0005 and 0.0052, respectively. We noted a parabolic association between age and OS (p = 0.026, 0.0025). CONCLUSION: In our study, some malnutrition parameters were associated with decreased OS. U-shape relationship between age and OS noted here warrants further evaluation.

A retrospective analysis of tumor lysis syndrome management in a quaternary care hospital.

PURPOSE: Due to an increased use of rasburicase, the study's purpose was to evaluate both the management of tumor lysis syndrome and the utilization of rasburicase in the hospital system. Additionally, the efficacy of flat dose rasburicase in lowering uric acid levels was evaluated. Based on the study's findings, the investigators will evaluate the usefulness of implementing a tumor lysis syndrome order set. METHODS: This study evaluated patients from January 2013 through December 2016 for the rasburicase dose and the tumor lysis syndrome therapy administered. RESULTS: Overall, 251 patients were included: prophylactic rasburicase group (n = 125) vs. treatment rasburicase group (n = 126) and of rasburicase 3 mg (R3) group (n = 168) vs. 6 mg (R6) group (n = 83). The prophylactic rasburicase vs. treatment rasburicase group had a significantly lower rate of receiving a xanthine oxidase inhibitor (48.0% vs. 64.3%, p = 0.009), a phosphate binder (6.4% vs. 17.5%, p = 0.007) and an additional dose of rasburicase (20.8% vs. 41.3%, p = 0.001). Intravenous hydration was neither significantly different between the rasburicase groups (p = 0.399) nor between the two rasburicase dosing groups (p = 0.874). Between the rasburicase dosing groups, there was no significant difference in the rate of receiving a xanthine oxidase inhibitor (p = 0.521) or a phosphate binder (p = 0.390). R6 patients had a significantly greater reduction in uric acid change compared to R3 patients (median = -7.9 (-10.1, -5.5) vs. -4.3 (-6.0, -2.7), p < 0.0001). There was no significant difference in uric acid change between the prophylactic rasburicase and treatment rasburicase groups (p = 0.875). CONCLUSION: The study's findings justified the need to implement a tumor lysis syndrome order set. In the study population, utilizing a flat dosing method was effective for hyperuricemia.

Bevacizumab-induced dysphonia: A case report with brief review of literature.

INTRODUCTION: Anti-angiogenic treatment in adjunct with chemotherapy is widely used for the treatment of various cancers. These agents inhibit vascular endothelial growth factor (VEGF) signaling thereby inhibiting tumor proliferation and invasion. Dysphonia, or voice changes, has been documented, but is an underreported side effect of anti-angiogenic agents. We report a case of intermittent dysphonia in a patient with metastatic, platinum-refractory ovarian cancer treated with bevacizumab. CASE REPORT: A 48-year-old female with high grade mixed type ovarian adenocarcinoma and concurrent left sided breast cancer was transitioned to palliative therapy with gemcitabine-bevacizumab for her ovarian cancer. At a follow-up visit after three cycles of the new therapy, the patient complained of intermittent changes in her voice, describing periods of hoarseness or softness in her voice after the chemotherapy-sometimes to the point that her voice was inaudible. Management and outcome: A new pelvic thrombus was discovered upon assessment of the patient's disease. Bevacizumab was held and she was referred to ear, nose, and throat evaluation for dysphonia. Laryngoscopic examination showed normal vocal cord, with normal movements and no lesion or necrosis. During subsequent follow-up, the patient reported improvement in her voice with no additional dysphonia. DISCUSSION: Vocal adverse effects of anti-VEGF agents have been documented in landmark trials and case reports; however, clinicians are often unaware of this rare side effect. Although VEGF-induced dysphonia may be rare and may not impede the patient's quality of life in some cases, it is critical to acknowledge and not underestimate this adverse effect.