Citations

Objective In certain cases, clinicians may consider continued observation of a vestibular schwannoma after initial growth is detected. The aim of the current work was to determine if patients with growing sporadic vestibular schwannomas could be stratified by the likelihood of subsequent growth based on initial growth behavior. Study Design Slice-by-slice volumetric tumor measurements from 3,505 serial magnetic resonance imaging studies were analyzed from 952 consecutively treated patients. Setting Three tertiary-referral centers. Patients Adults with sporadic vestibular schwannoma. Interventions Wait-and-scan. Main Outcome Measures Composite end point of subsequent growth- or treatment-free survival rates, where growth is defined as an additional increase of at least 20% in tumor volume from the volume at the time of initial growth. Results Among 405 patients who elected continued observation despite documented growth, stratification, of volumetric growth rate into less than 25% (reference: n = 107), 25 to less than 50% (hazard ratio [HR], 1.39; p = 0.06; n = 96), 50 to less than 100% (HR, 1.71; p = 0.002; n = 112), and at least 100% (HR, 2.01; p < 0.001; n = 90) change per year predicted the likelihood of future growth or treatment. Subsequent growth- or treatment-free survival rates (95% confidence interval) at year 5 after detection of initial growth were 31% (21–44%) for those with less than 25% growth per year, 18% (10–32%) for those with 25 to less than 50%, 15% (9–26%) for those with 50 to less than 100%, and 6% (2–16%) for those with at least 100%. Neither patient age (p = 0.15) nor tumor volume at diagnosis (p = 0.95) significantly differed across stratification groups. Conclusions At the time of diagnosis, clinical features cannot consistently predict which tumors will ultimately display aggressive behavior. Stratification by volumetric growth rate at the time of initial growth results in a stepwise progression of increasing likelihood of subsequent growth. When considering continued observation after initial growth detection, almost 95% of patients who have tumors that double in volume between diagnosis and the first detection of growth demonstrate further tumor growth or undergo treatment if observed to 5 years.

Objectives The current study characterizes age and incidence of cochlear implantation among qualifying children with congenital bilateral profound hearing loss in the U.S. Study Design Deidentified cochlear implantation data were acquired from prospectively collected patient registries from two cochlear implant (CI) manufacturers (Cochlear Americas and Advanced Bionics). Children <36 months old were assumed to have congenital bilateral profound sensorineural hearing loss. Setting U.S. CI centers. Patients Children <36 months old who received CIs. Interventions Cochlear implantation. Main Outcome Measures Age at implantation and incidence. Results A total of 4,236 children <36 months old underwent cochlear implantation from 2015 to 2019. The median age at implantation was 16 months (interquartile range, 12–24 mo) and did not change significantly during the 5-year study period (p = 0.09). Patients residing closer to CI centers (p = 0.03) and treated at higher-volume centers (p = 0.008) underwent implantation at a younger age. Bilateral simultaneous implantation increased from 38% to 53% of CI surgeries in 2015 and 2019, respectively. Children who received bilateral simultaneous CIs were younger compared with those receiving unilateral or bilateral sequential CIs (median, 14 versus 18 mo; p < 0.001). The incidence of cochlear implantation increased from 7,648 per 100,000 person-years in 2015 to 9,344 in 2019 (p < 0.001). Conclusion Although the incidence of pediatric CI recipients and the frequency of bilateral simultaneous implantation increased over the study period, age at implantation did not change significantly and far exceeded current Food and Drug Administration (9 mo) and American Academy of Otolaryngology and Head and Neck Surgery position statement (6–12 mo) guidelines.

Background Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs. Methods We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment. Results We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04). Conclusion Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs ( NCT04940299 , NCT03999749 ).

Background: Multiple myeloma (MM) is the second most common hematologic malignancy, with 34,470 estimated new cases in 2022. High-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) remains a standard treatment for MM even in the era of novel therapies. This is usually performed in hospital-based settings, either in the inpatient or outpatient units. Advanced Care at Home (ACH) represents a virtual hybrid hospital-at-home program that combines a virtual provider-staffed command center with a vendor-mediated supply chain capable of delivering high-acuity care in the comfort of the patients’ own homes. In our program, we used the existing ACH platform to deliver post-HCT care for recipients of auto-HCT. Patients and methods: Four patients (female = 2, 50%) with MM, with a median age of 60 (range, 40–74) years, were admitted to the inpatient Blood and Marrow Transplant (BMT) unit. The conditioning regimen consisted of melphalan 200 mg/m 2 , administered on day –2. All patients received stem cell infusion (day 0) in the inpatient setting, with a median dose of 3.64 (range, 2.92–8.22) × 10 6 /kg CD34 cells. Results: Patients were discharged to their homes after completing the infusion on day 0 or day +1 at the latest. Postinfusion care was provided by the ACH team in coordination with the BMT team. The median time intervals to absolute neutrophil count and platelet engraftment were 12 (range, 11–13) and 11 (range, 9–16) days, respectively. All patients were successfully discharged from the ACH program at a median of day +14 (range, day +14 to day +15). Conclusions: Our results highlight the feasibility of delivering post-HCT care for auto-HCT recipients in the home setting and confirm the generalizability of this approach.

Abstract Immune related adverse events (irAEs) from immune checkpoint inhibitors (ICIs) are well documented for nearly every organ system, except for the reproductive system. Mouse models have demonstrated that ICIs can decrease ovarian follicular reserve and impair oocyte maturation, which may have implications for fertility (PMID: 36008687). There are no studies investigating the effect of ICIs on fertility in humans. We sought to evaluate ovarian function in women treated with ICIs compared to untreated women by evaluating non-invasive surrogate markers of ovarian reserve, anti-müllerian hormone (AMH) and antral follicle counts (AFC). We enrolled women 18 - 40 years old diagnosed with stage III or IV melanoma. Participants underwent phlebotomy for AMH levels and a pelvic ultrasound to assess AFC. The medical record was retrospectively reviewed to obtain data on patient characteristics, treatments, and outcomes. A total of 14 patients with stage IIIA - IV melanoma participated. Six patients received ICI treatment before AMH and AFC testing while 8 had no prior ICI exposure. The ICI group ages ranged from 22-40 years with a median age of 31 years. The untreated group ages ranged from 25-39 years with a median age of 32 years. The time between starting an ICI and enrolling in the study ranged from 28 - 351 days. ICI regimens included ipilimumab/nivolumab, nivolumab, pembrolizumab, and atezolizumab (on a clinical trial). Four of these six patients experienced an irAE during their course, including: dermatitis, hepatitis, colitis, thyroid dysfunction, and adrenal insufficiency. Median AMH levels were lower for patients treated with ICIs (2.9 vs 4.0 ng/mL), as was median AFC (22.5 vs 23.5 ng/mL). Only three patients’ clinicians discussed fertility preservation. None of the patients underwent fertility preservation. Our study found lower AMH and AFC in women with melanoma who were treated with an ICI compared to untreated women. Although AMH and AFC are surrogate markers for ovarian reserve and fertility, and our study is a small cohort, these early results suggest that ICIs may impact ovarian function. Age is less likely to be a confounding factor as the median age of the treated group was younger than the untreated group. While these results are preliminary, when considered in conjunction with recent pre-clinical data showing changes within the ovaries after ICI treatment, fertility consultation should be considered for young women prior to ICI initiation. We are investigating associations between AMH, AFC, age, ICI exposure, and future pregnancies in an ongoing prospective study. Citation Format: Ashley Hickman, Katherine Smith, Zaraq Khan, Elizabeth Ann Enninga, Yulian Zhao, Elizabeth Cathcart-Rake, Haidong Dong, Lisa Kottschade, Svetomir Markovic, Heather Montane, Anastasios Dimou, Yiyi Yan. Investigating the effect of immune checkpoint inhibitors (ICI) on ovarian function in young patients with melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6644.

Abstract Meningiomas are the most common primary intracranial tumor. They are slow growing and often incidentally found tumors that arise from the arachnoid villi. As they grow, they have a greater likelihood of becoming symptomatic with seizures being one of the most clinically significant symptoms. Seizures are more likely to present as a symptom of larger meningiomas and meningiomas that compress cortical areas particularly those in non-skull base locations. These seizures are often managed medically, utilizing the same anti-seizure medications that are used to treat other causes of epilepsy. We discuss common anti-seizure medications used including valproate, phenobarbital, carbamazepine, phenytoin, lacosamide, lamotrigine, levetiracetam and topiramate and their common adverse effects. The goal of pharmacotherapy for seizure control is to maximize seizure control while minimizing the adverse effects of the medication. The decision to provide medical management is dependent on individual seizure history and plans for surgical treatment. Patients who did not require seizure prophylaxis before surgery are commonly prescribed seizure prophylaxis postoperatively. Symptomatic meningiomas not controlled by medical management alone are commonly evaluated for surgical resection. The efficacy of surgical resection in providing seizure freedom is dependent on several features of the tumor including tumor size, the extent of the peritumoral edema, the number of tumors, sinus infiltration and the degree of resection.

3580 Background: TAS-102 (FTD/TPI) is a combination of a nucleoside analogue and a thymidine phosphorylase inhibitor, and has showed activity in 5FU-resistant CRC. Nal-IRI achieves higher intra-tumor concentrations than irinotecan (Iri; 142-fold) and its major metabolite, SN-38 (9-fold). This resulted in superior anti-tumor activity compared to free Iri in multiple tumor xenografts. Furthermore, multiple clinical trials have established the activity of nal-IRI in combination with 5FU in pancreaticobiliary cancers. The combination of nal-IRI with the more potent nucleoside analogue TAS-102 may thus result in a more effective systemic therapy. We conducted this study to define the safety and efficacy of the combination of TAS-102 and nal-IRI in advanced CRC. Methods: Eligible patients (pts) on this investigator-initiated phase II study had advanced CRC and must have had disease progression on at least one prior therapy. Additional inclusion criteria - measurable disease, ECOG PS 0-1 & adequate organ function. Based on previously published dose escalation phase I data, the pts were treated at the recommended phase II dose of TAS-102 (given orally at 35mg/m2 bid on days 1-5) and nal-IRI (60mg/m2 IV on day 1) in 14-day cycles. The primary endpoint was objective response rate (ORR) = complete (CR) + partial (PR) response per RECIST v1.1. Multiple secondary endpoints included safety/tolerability, progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DoR). Results: Twenty-two pts were enrolled, of whom 20 were evaluable for response. Male - 50%; ECOG PS 1 – 75%; African Americans – 38%; median age - 58yrs (interquartile range [IQR] 49-67). Median line of prior therapy was 1 (IQR 1-2) and 13.6% (3 pts enrolled during the dose escalation phase) had received prior Iri. 47.6% received concurrent Bevacizumab. ORR was 15% (3 PR, 0 CR). 60% had stable disease (SD) as best response; DCR of 75%. mPFS - 9.7 mos (95% CI: 5.6, 14.2); mOS - 10.1 mos (95% CI: 7.3, 15.9). 12-month PFS and OS rates were 34.6% and 39.5% respectively. At a median follow up of 11.9 mos, DoR was yet to be determined and 50% of the pts had maintained response for 12 mos. Median duration of progression free among pts with SD was 7.6 mos (95% CI: 4.6, 13.2), with a 12-month survival rate of 47.7% (95% CI: 15.5%, 74.5%). Median time to response (TTR) was 4.8mos. Most common treatment related toxicities included fatigue and neutropenia (G3; 27.3% each); anemia and leucopenia (G3; 18.2% each). Other G3 AEs included febrile neutropenia, diarrhea, hypokalemia, lymphopenia and nausea (4.5% each). Conclusions: We demonstrated that the combination of TAS-102 and nal-IRI had an acceptable safety profile, and showed antitumor activity in patients with advanced CRC. Additional biomarker analyses such as survival correlation with UGT1A1 phenotype and RAS mutational status are ongoing. (NCT03368963). Clinical trial information: NCT03368963 .

3579 Background: Panitumumab (Pmab) is a recombinant monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR) and it is indicated for the treatment of metastatic colorectal carcinoma (mCRC). However, the objective response rates (ORR) for the single agent are historically about 8-11%. EGFR inhibition induces synthetic lethality with poly ADP ribose polymerase inhibitors (PARPi) such as Niraparib, by attenuating DNA repair pathways. Combining PARP and EGFR inhibition has the potential to confer synergistic benefit, while also ameliorating resistance mechanism to EGFRi. We conducted this study to define the safety and efficacy of the combination of Niraparib and Pmab in RAS wildtype (WT) mCRC. Methods: Patients (pts) with RAS WT mCRC who have progressed on at least one line of systemic chemotherapy were eligible for the trial. Other selected inclusion criteria were ≥18 years of age, ECOG PS 0-1 and measurable disease per RECIST 1.1. Pmab was administered at 6 mg/kg IV on days 1 & 15 of each 28-day cycle, while Niraparib was taken orally at 200mg or 300mg (based on body weight and platelet count) daily throughout the cycle. The primary endpoint was clinical benefit rate (CBR) defined as complete (CR) + partial (PR) response + stable disease (SD) per RECIST v1.1. Multiple secondary endpoints included safety/tolerability, ORR, progression-free survival (PFS), overall survival (OS), and duration of response (DoR). Results: A safety run-in cohort of 6 pts was initially enrolled. Following a preplanned safety analysis showing an acceptable toxicity profile, an additional 19 pts were enrolled. Of the total 25 enrolled pts, 24 were evaluable for response. Male - 50%; Whites/African Americans/Asians – 65.2%/21.7%/13%; median age – 58.5yrs. The majority had left sided tumor (92%) and the median line of prior therapy was 2 (range 1-4). CBR was 83.3% (0 CR, 6 PR, 14 SD) and ORR was 25%. mPFS – 5.6mos (95% CI: 3.7, 6.9); mOS – 20.9mos (95% CI: 9.2, NR). Six-month PFS and OS rates were 48.4% and 100% respectively. At a median follow up time of 7.5mos (95% CI: 4.2, 10.4), 3 patients remained on treatment and DoR was yet to be determined. Muco-cutaneous adverse events (AEs) of any grade included rash (58.4%), oral mucositis (20.8%), dry skin (16.7%) and paronychia (4.2%). Most common (grade > 2) treatment related AEs (TRAEs) were anemia (G3; 12.5%), dermatitis, oral mucositis, hypertension and neutropenia (G3; 4.2% each). There were no grade 4-5 TRAEs. Conclusions: The combination of Pmab and Niraparib had an acceptable safety profile, and showed considerable antitumor activity in pts with advanced RAS WT mCRC compared to historical rates. Additional biomarker analyses such as survival correlation with immune cell infiltration in paired skin biopsies and HER2/BRAF mutational status are ongoing. Funding and product (Niraparib) for the study were provided by GSK (NCT03983993). Clinical trial information: NCT03983993 .

e14683 Background: Immune checkpoint inhibitors (ICIs) have altered the landscape of cancer treatment. ICIs are associated with immune mediated diarrhea and colitis (IMDC) which can be challenging to diagnose and differentiate from other etiologies of diarrhea. Clostridium difficile infection (CDI) is a common cause of diarrhea in patients with cancer and can have similar symptoms. In a similar study, CDI was found to be relatively common in ICI-treated cancer patients and especially those with IMDC requiring immunosuppressants. Our study evaluates the incidence of CDI and IMDC in patients with ICI exposure and compares clinical characteristics between the two to determine risk factors that may predispose patients to CDI or IMDC. Methods: This is a retrospective, single-center study of cancer patients on an ICI from 1/1/2011 to 4/7/2022 who were tested for Clostridium difficile with stool nucleic acid amplification tests during or after treatment with an ICI. Patients were determined to have CDI if clinically suspected and had to have a positive stool GDH Ag along with positive C. difficile toxins A & B or a positive stool C. difficile toxin B gene. Patients with positive GDH Ag in the stool but with negative toxins A&B were determined to be colonized. The diagnosis of IMDC was based on the clinical presentation and had to be made by the treating oncologist. Results: 375 patients met our study criteria and got CDI testing at any point during or after ICI exposure. 27 patients tested positive for CDI, whereas 24 were colonized. 105 patients were determined to have IMDC and 97/105 received treatment with steroids or immunosuppressants. Among patients determined to have IMDC, 6 were colonized for clostridium difficile. There were no patients with IMDC who were also positive for clostridium difficile. 71 patients were on a dual ICI regimen whereas 304 patients were on a single ICI. In patients on the dual ICI regimen, 67.6% were diagnosed with IMDC when compared to patients on a single ICI regimen where 18.8% of patients were diagnosed with IMDC (p<0.0001). The absolute lymphocyte count on the day of CDI testing was 1.185 ± 0.066 in the IMDC group when compared to 0.948 ± 0.044 in the non-IMDC group (p=0.003). The mean duration of diarrhea was longer in the IMDC group at 16.905 ± 1.211 days when compared to the CDI group at 9.852 ± 2.387 days (p= 0.0094). Smoking status, sex, history of autoimmunity, and history of prior immune related adverse events did not impact incidence of IMDC or CDI. Conclusions: IMDC was a common cause of diarrhea in patients with ICI exposure who were tested for CDI. We did not find IMDC to be a risk factor for CDI. IMDC has a longer duration of diarrhea and colitis symptoms when compared to CDI. The absolute lymphocyte count on symptom onset is higher in patients with IMDC when compared to patients with CDI and may be useful in identifying patients with IMDC earlier.

1552 Background: Immune checkpoint inhibitor therapy-related (ICI) pneumonitis poses a significant challenge in patients with cancer. There is a need for predictive modeling to identify those at high risk of developing serious adverse events of ICI pneumonitis. Methods: A newly created database of cancer patients diagnosed with ICI pneumonitis seen at Mayo Clinic from 2014-2022 was utilized for exploratory data analysis. Modeling was used to determine if three clinical outcomes could be predicted, namely risk of death from: pneumonitis prior to starting immunotherapy, pneumonitis at time of diagnosis of ICI pneumonitis, and any cause at time of ICI pneumonitis diagnosis. The data consisted of 170 patients with annotation for 71 clinical features. Data was divided into features available at time of cancer diagnosis and at time of ICI pneumonitis diagnosis. Exploratory modeling was performed using the gradient boosting technique Xgboost (Chen, 2015) and conducted using k-fold balanced cross validation best practices as well as a train/test/validate schema with 70%/20%/10% data proportions, respectively. Model reverse engineering was done with Shapley statistics (Lundberg, 2017) to determine which features had the largest contribution per model. Once identified, only those highly weighted features were used for logistic regression analysis providing more reproducible predictions by decreasing model variance. Results: Risk of death from pneumonitis prior to starting immunotherapy was modeled with an area under the curve of the receiver operator characteristic (AUC-ROC) of 0.79 with the most contributory features including lymphocyte count, oxygen dependence, PFT values, and PD-L1 expression. Logistic regression produced an AUC-ROC of 0.87 (95% CI 0.72-1.0, p < 0.0013). Risk of death from pneumonitis at the time of ICI pneumonitis diagnosis was modeled with an AUC-ROC of 0.85 and the most contributory features were similar to the list described in the previous endpoint. Logistic regression produced an AUC-ROC of 0.89 (95% CI 0.81-0.96, p < 0.0001). Risk of death from any cause at the time of ICI pneumonitis diagnosis until follow up concluded by 12/2022 produced a model with an AUC-ROC of 0.75 with the most contributory features including supplemental oxygen, PFT values, basic laboratory values, and PD-L1 expression, among others. Logistic regression produced an AUC-ROC of 0.85 (95% CI 0.76-0.93, p < 0.0001). Conclusions: We demonstrate that commonly available clinical data can be used to identify patients at high risk of death from ICI pneumonitis. This study identified clinical features that were predictive in each scenario from which further concerted effort could produce a new clinical model to provide clinician decision support when considering immunotherapy. Further studies should be done to further elucidate feature interdependence and generalizability.