High-grade Adverse Events Research Articles

Adverse events (AEs) –derived biomarker in predicting clinical outcomes in patients with colorectal cancer (CRC) treated with immunotherapy (IC).

132 Background: There are insufficient studies evaluating the role of AEs in CRC patients treated with IC. This study aims to transform AEs from traditional toxicity evaluation tools to informative biomarkers for assessing treatment efficacy by utilizing modern analytical strategies. Methods: We analyzed a single arm study of 51 mismatch repair proficient, refractory CRC patients (NCT03712943) treated with regorafenib and nivolumab. Data for analysis included CTCAE version 5 AE data, RECIST treatment response, progression-free survival (PFS), and overall survival (OS). Analytic approach leveraged multiple AE parameters to develop a set of innovative AE biomarkers. One AE biomarker of interest was treatment related low-grade early AEs (TR-LG-AE) which was defined as frequency of all TR-LG-AEs occurring between the 1st day and day 30 after the 1st treatment. Results: TR-LG-AE was associated with treatment response (p<0.001 by ANOVA trend test). Patients with higher AE events tended to be a responder, compared to PD patients with a lower frequency of AE events. The TR-LG-AE also correlated with improved PFS and OS with hazard ratio of 0.83 (p=0.01) and 0.89 (p=0.03), respectively. Accordingly, patients were grouped into high versus low TR-LG-AE based on optimal cutoff of 6 events for further analysis. The dichotomized TR-LG-AE (high vs low) showed significant association with survival outcomes (median PFS: 15.3 vs 3.7 months; p<0.001; median OS: 21.9 vs 9 months; p=0.02). Further interaction analysis showed patients with high TR-LG-AE had improved PFS regardless of occurrence of high-grade AE (HG-AE) (p=0.01), suggesting its independence of HG-AE. Individual AE analysis identified patients experienced with early low-grade rash maculo-papular, lipase increased, or hypertension had improved PFS (p<0.001). In biomarker analysis, one key mutation biomarker, RAS, did not show significant association with survival outcomes (PFS: p=0.66; OS: p=0.81). In contrast, integration with TR-LG-AE led to remarkable improvement. Specifically, the TR-LG-AE was able to help improve RAS classification by identifying patients with better treatment benefit. Specifically, patients with RAS mutation and high TR-LG-AE experiences had a median PFS of 15.3 months compared to others (median PFS of 3.7 months; p=0.007), and a median OS of 21.9 months compared to others (median OS of 9.4 months; p=0.04). Conclusions: The study demonstrated utility of AE in predicting clinical outcomes in CRC, similar to our previous findings in lung cancer. Moreover, it discovered that integration of AE-derived biomarkers with molecular biomarkers could produce a more robust classifier than when considered individually. This analysis is the first of its kind to identify subgroups of CRC patients that benefit from IC treatment.

Evaluation of fruquintinib's efficacy and safety in refractory metastatic colorectal cancer: a systematic review and meta-analysis of phase II and III randomized controlled trials.

Metastatic colorectal cancer (mCRC) remains a significant cause of mortality despite advancements in treatments. Fruquintinib, a potent VEGFR inhibitor, has shown promise as an advanced therapy for mCRC. This review evaluates the efficacy and safety of fruquintinib compared to placebo in patients with refractory mCRC, focusing on Phase II and III trials. This study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A literature search was performed using PubMed, EBSCOHost, ProQuest, and Google Scholar. The analysis of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety was pooled using hazard ratios (HR) and risk ratios (RR) in RevMan 5.4 software. Three RCTs comprising 1,178 patients were included. Fruquintinib significantly improved OS (HR: 0.66; 95% CI 0.57-0.76) and PFS (HR: 0.30; 95% CI 0.26-0.35) compared to placebo. ORR (RR: 5.91; 95% CI 1.09-32.16) and DCR (RR: 3.83; 95% CI 3.00-4.90) were also higher with fruquintinib. Grade 3 or higher adverse events were more frequent with fruquintinib (RR: 1.31; 95% CI 1.02-1.70). No significant difference was observed in serious adverse events or treatment-related deaths. Fruquintinib significantly improves survival and tumor response in patients with refractory mCRC. While associated with an increased risk of high-grade adverse events, fruquintinib remains a viable and relatively safe treatment option for mCRC patients. Further studies are needed to confirm its efficacy and safety across diverse populations.

CT-guided Left Stellate Ganglion Cryoneurolysis for Refractory Ventricular Arrhythmias.

Background Ventricular arrhythmias (VAs), including ventricular tachycardia and ventricular fibrillation, present substantial therapeutic challenges due to their high morbidity, mortality, and increasing prevalence. Current treatments often prove infeasible or inadequate in patients with refractory VAs. Purpose To evaluate the safety and effectiveness of CT-guided left stellate ganglion cryoneurolysis (SGC) in the treatment of refractory VAs. Materials and Methods This retrospective study reviewed all consecutive patients with refractory VAs who underwent SGC between June 2020 and December 2023 at two tertiary care centers. Patients with refractory VAs who underwent CT-guided left SGC were included. No patients were excluded. Data on preprocedural clinical status, procedural approach, procedural outcomes, and adverse events were analyzed. The pre- and postprocedural number of defibrillations were compared using the Wilcoxon matched-pairs signed rank test. Results A total of 17 patients (mean age, 60.4 years ± 2.7 [standard error of the mean]; 14 male) were included; seven patients (41%) were receiving β-adrenergic blocking agents. The mean number of antiarrhythmic medications per patient was 2.2 ± 0.2. CT-guided left SGC led to a significant reduction in defibrillations, from a median of 3 (IQR, 3-15) to 0 (IRQ, 0-0) in the 24 hours before and after the procedure, respectively (P < .001). Clinical success, defined as freedom from defibrillation within the preceding 24-hour period, was achieved in 14 of 17 patients (82%) 24 hours after and 15 of 17 patients (88%) 72 hours after the procedure. Of 17 patients, 12 (71%) proceeded to additional procedural management after SGC. At a mean follow-up of 469.2 days ± 90.8, 14 of 17 patients (82%) were alive. No moderate or high-grade adverse events were observed; mild adverse events included left upper extremity neurapraxia (n = 1) and transient Horner syndrome (n = 3). Conclusion CT-guided left SGC demonstrated promising effectiveness and safety in treating patients with refractory VAs. Thus, SGC warrants consideration for inclusion in a multidisciplinary treatment algorithm for VAs. © RSNA, 2024 See also the editorial by Cadour and Scemama in this issue.

Stereotactic arrhythmia radioablation - A systematic review and meta-analysis of the prospective clinical studies

Abstract Background Stereotactic arrhythmia radioablation (STAR) is increasingly being evaluated in prospective studies as a new promising treatment option for patients with therapy-refractory ventricular tachycardia (VT). In STAR, the VT substrate is noninvasively treated with a high dose of radiotherapy. Recently, several single-arm prospective studies evaluating the clinical outcomes of STAR were published. Considering that the evidence base consists mainly of retrospective case series, we conducted a systematic review and meta-analysis to synthesize the prospective data on outcomes of STAR. Purpose To perform a systematic review and meta-analysis of prospective studies evaluating clinical outcomes of STAR for VT. Methods This study was registered in PROSPERO and adhered to the PRISMA reporting guidelines. Full-text studies describing prospective studies evaluating the safety and efficacy of STAR for VT were included in this study. Records published until August 2023 were retrieved from OVID MEDLINE, OVID Embase, Web of Science Core Collection, the Cochrane Central Register of Controlled Trials, and Google Scholar search engine (top 200 hits), deduplicated, and screened for eligibility. Abstract screening, full-text screening, data extraction and quality assessment were performed by two reviewers independently. Endpoints were defined as treatment related CTCAE grade ≥3 adverse events within 90 days after treatment, overall survival (OS), time to VT recurrence, and recurrence-free survival. Rates of patients achieving pre-defined 50%, 75% and 95% VT burden reduction thresholds were summarised. Random-effects generalized linear mixed-effects models and inverse variance models were used for the meta-analysis. Results 1861 records were identified, 987 were screened, and 10 full-text manuscripts published between 2019 and 2023 describing the results of STAR in 82 patients were included in this study. The majority were male (n=72; 88%), between 45 and 85 years old, and suffered from ischaemic cardiomyopathy (n=51; 62%). Median left ventricular ejection fraction ranged from 21 to 38% between studies. 20 patients did not undergo a prior catheter ablation for VT. All patients were treated with a single dose of 25 Gy and median planned target volume ranged from 45 to 198 cc between studies. Pooled 12-month OS rate was 0.73, and the proportion of patients experiencing grade ≥3 adverse events within 90 days after STAR was 0.11 (Figure 1). Reduction in VT burden is shown in Table 1. Although these were not pooled because of large heterogeneity in VT reduction time frame definitions, it can be appreciated that most of the patients experienced a reduction in VT burden. Conclusion The increasing evidence from prospective studies on STAR shows acceptable 12-month OS in a population of patients with advanced heart failure and refractory VT. Moreover, there is a modest rate of high-grade adverse events and most patients experience a reduction in VT burden.

Comparative Meta-Analysis of Triplet vs. Quadruplet Induction Regimens in Newly Diagnosed, Treatment Naïve, Multiple Myeloma.

The use of 4-drug induction regimens for treatment naïve newly diagnosed multiple myeloma (NDMM) is associated with improved depth of response and progression-free survival (PFS). However, head-to-head trials of 4-drug combinations are lacking, and instead, these regimens are typically compared to 3-drug backbones; limiting the ability to discern whether any additional benefit (or toxicity) is simply additive or represents a synergy (or interaction). We conducted a meta-analysis of phase 2 and phase 3 clinical trials that randomized treatment naïve NDMM patients to either a 4-drug or 3-drug induction regimen. We included 11 trials which represented 6509 unique patients. PFS for all trials in the meta-analysis was 54 months with a 4-drug induction and 8.9 months with a 3-drug induction (HR: 0.49; 95% CI: 0.45; 0.54), but there was no benefit to using a 4-drug induction that did not include an anti-CD38 antibody (PFS 4-drug 8.1 months, PFS 3-drug 8.0 months; HR 0.95; 95% CI 0.86; 1.06). Adverse events were more frequent with the quadruplet regimens but were predominately mild. High-grade (≥3) adverse events (AEs) that were more common with 4-drug regimens were infections (RR: 1.34; 95% CI 1.17; 1.54) and thrombocytopenia (RR: 1.39; 95% CI 1.12; 1.74). This study suggests that 4-drug induction regimens which include an anti-CD38 antibody improve efficacy although with additional toxicity in NDMM patients.

Evaluation of drug tolerability as a function of toxicity and quality of life in patients enrolled on I-SPY2.

11113 Background: Patient-reported outcomes (PROs) are valuable for understanding treatment tolerability and toxicity. I-SPY2 is a phase-II neoadjuvant clinical trial for breast cancer with electronic PROs and quality of life (QOL) assessments. We sought to understand how well the GP5 self-reported tolerability item reflected toxicity burden and QOL during treatment and follow-up in I-SPY 2 participants. Methods: Our study included 306 patients who completed the FACIT Item GP5 and answered PROMIS surveys at two or more timepoints. Analysis timepoints included screening (SC), inter-regimen (IR), pre-surgery (PS), 1-month post-surgery (FU1), and 6-months post-surgery (FU2). Symptoms were assessed weekly using PRO-CTCAE and CTCAEv4.0. QOL was evaluated using PROMIS. The GP5: “I am bothered by side effects of treatment,” was used to estimate tolerability, where worse tolerability is a higher score. Odds ratios, Spearman correlation, and regularized multi-variate regression were used to evaluate the associations between individual symptoms and adverse events with GP5 scores. Results: Demographic information was available for 243 of the 306 (70.2%) participants (median age=47,73.7% white). In the 306, tolerability scores worsened over study treatment, with a maximum mean score of 1.71 at Cycle 11. Tolerability improved after treatment cessation at FU1(1.09). Mean tolerability at week 6 was 1.53. The only clinical factor that was associated with early change in tolerability (week 6 to PS) was age &gt;50 (mean score ranged from 1.55-1.70 vs 1.29-1.45 (age&lt;50), p&lt;0.05). PRO-CTCAE and GP5 correlative analysis suggested that higher grade abdominal pain, decreased appetite, dizziness and blurry vision significantly associated with higher GP5 scores at multiple timepoints (p&lt;0.05). Symptoms not associated with tolerability were nail loss, acne, hair loss, and rash (p&gt;0.05). Additionally, the total number of low-grade (mild to moderate) symptoms a patient experienced during study treatment was significantly correlated to poor tolerability (p&lt;0.00001). Among patients with CTCAE data, 9% had adrenal insufficiency, and higher GP5 was found across all study timepoints in those with (compared to without) adrenal insufficiency (mean GP5 = [1.7-1.9] vs [1.3-1.5] respectively). Similarly, among patients with neuropathy (14%), higher GP5 scores were reported across all study timepoints (mean GP5 = [1.8-2.3] vs [1.3-1.5] respectively). Higher GP5 scores during treatment were correlated with higher fatigue scores at PS and FU1 (p&lt;0.02 and p&lt;0.001) and lower physical functioning at PS (p&lt;0.01). Conclusions: TheGP5 measure is associated with self-reported symptoms, higher grade adverse events and quality of life scores. Furthermore, greater accumulation of lower grade symptoms can lead to poor tolerability. The single measure GP5 composite score reflects multiple components of treatment toxicity.

Adverse Event Profile of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer: An Updated Meta-analysis.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer. An updated toxicity profile of EGFR-TKIs proves valuable in guiding clinical decision making. This study comprehensively assessed the risk of EGFR-TKI-related adverse events (AEs) involving different systems/organs. We systematically searched PubMed, Embase, Web of Science, and Cochrane library for phase III randomized controlled trials comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with non-small cell lung cancer. The odds ratio (OR) of all-grade and high-grade adverse events (AEs) including dermatologic, gastrointestinal, hematologic, hepatic, and respiratory events was pooled for a meta-analysis. Subgroup analyses based on the control arm (placebo or chemotherapy) and individual EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) were conducted. Thirty-four randomized controlled trials comprising 15,887 patients were included. The pooled OR showed EGFR-TKIs were associated with a significantly increased risk of all-grade dermatologic AEs including paronychia, pruritus, rash, skin exfoliation, and skin fissures, gastrointestinal AEs including abdominal pain, diarrhea, dyspepsia, mouth ulceration, and stomatitis, hepatic AEs including elevated alanine aminotransferase and aspartate aminotransferase, and respiratory AEs including epistaxis, interstitial lung disease and rhinorrhea. Furthermore, a significantly increased risk of high-grade rash (OR 7.83, 95% confidence interval [CI] 5.11, 12.00), diarrhea (OR 2.10, 95% CI 1.44, 3.05), elevated alanine aminotransferase (OR 3.93, 95% CI 1.71, 9.03), elevated aspartate aminotransferase (OR 3.22, 95% CI 1.05, 9.92) and interstitial lung disease (OR 2.35, 95% CI 1.38, 4.01) was observed in patients receiving EGFR-TKIs. When stratified by individual EGFR-TKIs, gefitinib showed a significant association with all-grade and high-grade hepatotoxicity and interstitial lung disease. Epidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.

225 Ac-PSMA-617 Augmentation in High-Risk mCRPC Undergoing 177 Lu-PSMA-617 Radioligand Therapy : Pilot Experience From a Prospective Registry.

This pilot study investigates the efficacy and safety profile as well as predictive biomarkers of 225 Ac-PSMA-617-augmented 177 Lu-PSMA-617 radioligand therapy (RLT) in a cohort of high-risk patients with metastatic castration-resistant prostate cancer (mCRPC), enrolled in a prospective registry (NCT04833517). A group of n = 33 high-risk mCRPC patients received 177 Lu-PSMA-617 RLT, augmented by 1 or more cycles of 225 Ac-PSMA-617. Response was assessed by prostate-specific antigen (PSA) serum value after 2 cycles of treatment. Overall survival (OS) and PSA-based progression-free survival were evaluated using Kaplan-Meier analysis. To assess the side effect profile, Common Terminology Criteria for Adverse Events were applied. In total, 12 potential pretherapeutic biomarkers were tested for association with OS. The median decrease in serum PSA value was -49.1%, and 16/33 (48.5%) patients experienced a partial response after 2 cycles RLT. The median PSA-based progression-free survival and median OS was 7.2 and 14.8 months, respectively. Alkaline phosphatase ( P < 0.001), lactate dehydrogenase ( P = 0.035), Eastern European Oncology Group Performance Score ( P = 0.037), and the presence of visceral metastases ( P = 0.029) revealed significant association with OS in Kaplan-Meier analysis (log-rank test). Most of the recorded adverse events were rated as mild or moderate. Higher-grade adverse events were very limited with only 1 case (3.0%) of grade 3 anemia. Treatment-related mild xerostomia was recorded in 6/33 (18.2%) patients. 225 Ac-PSMA-617 augmentation in high-risk mCRPC undergoing 177 Lu-PSMA-617 RLT appears to be an effective treatment option with a favorable safety profile. The pretherapeutic values of alkaline phosphatase, lactate dehydrogenase, the Eastern European Oncology Group Performance Score, and the presence of visceral metastases may be appropriate biomarkers predicting survival outcome of this treatment regimen.

Low-dose lenvatinib and anti-programmed cell death protein-1 combination therapy in patients with heavily pre-treated recurrent ovarian and endometrial cancer: a pilot study

ObjectiveTreatment options for heavily pre-treated recurrent ovarian and endometrial cancer are limited. Lenvatinib plus anti-programmed cell death protein-1 (PD-1) combination therapy has been efficacious in advanced endometrial cancer, but at...

Clinical Manifestation, Risk Factors, and Immune Checkpoint Inhibitor Rechallenge of Checkpoint Inhibitor-Associated Pneumonitis in Patients With Lung Cancer.

Immune-related adverse effects can lead to damage to various systems of the body, checkpoint inhibitor-associated pneumonitis (CIP) is one of the potentially lethal immune-related adverse effects. However, evidence regarding the risk factors associated with CIP is limited. To timely and accurate identification and prompt treatment of CIP, understanding the risk factors for multimorbidity among diverse study populations becomes crucial. We retrospectively analyzed the clinical data of 1131 patients with lung cancer receiving immunotherapy to identify 110 patients with CIP, the clinical characteristics and radiographic features of patients with CIP were analyzed. A case-control study was subsequently performed to identify the risk factors of CIP. The median treatment cycle was 5 cycles and the median time to onset of CIP was 4.2 months. CIP was mainly grade I or II. Most cases improved after discontinuation of immune checkpoint inhibitors (ICIs) or hormone therapy. Severe CIP tended to occur earlier in comparison to mild to moderate cases. The recurrence rate was 20.6% in ICI-rechallenged patients, and patients with relapsed CIP were usually accompanied by higher-grade adverse events than at first onset. Among the 7 patients with relapse, ICI-associated deaths occurred in 2 patients (28.6%). For rechallenging with ICIs after recovery from CIP, caution should be practiced. Male [odds ratio (OR): 2.067; 95% CI: 1.194-3.579; P = 0.009], history of chest radiation (OR: 1.642; 95% CI: 1.002-2.689; P = 0.049) and underlying lung disease (OR: 2.347; 95% CI: 1.008-5.464; P =0.048) was associated with a higher risk of CIP.

High grade adverse event reporting and enrolment in gynecologic oncology clinical trials

ObjectiveThe primary objective is to assess factors associated with treatment related high grade (CTCAE grade ≥ 3) adverse event (AE) reporting among participants in gynecologic oncology clinical trials. MethodsAll AEs recorded in the Princess Margaret Clinical Trial adverse event database between 01/2016 and 12/2018 were evaluated. Gynecologic oncology clinical trials assessing systemic therapy were included. Inferential statistics on risk factors of related grade ≥ 3 adverse event reporting and GEE logistic models with Odds Ratios (OR) were performed. Multivariable analysis adjusting for age, clinical trial phase, sponsor, and therapy type. ResultsThe gynecology cancer clinical trials accrued 317 unique patients (359 nested on trials) in 42 systemic therapy trials. In the period, 17,175 related AEs were reported in the gynecological cancer trials, 7.4% were grade ≥ 3. On multivariable analysis, no odds differences of grade ≥ 3 related AEs were detected according to study phase. Patients in immunotherapy clinical trials had lower odds of related grade ≥ 3 AEs than patients on targeted or other therapy (adjusted OR [aOR] 0.43; 95% CI 0.24–0.75). There was greater odds of related grade ≥ 3 AEs in clinical trials assessing combination vs single therapeutics (aOR 2.26, 95% CI 1.34–3.80). Patients aged ≥65 (aOR 1.77; 95% CI 1.08–2.89) had greater odds of related grade ≥ 3 AEs than patients aged 50 to 65 years. When compared to other disease sites, the odds of having a grade ≥ 3 related AE reported in gynecology clinical trials was no different. ConclusionsIn this cohort, factors influencing the odds of related grade ≥ 3 AE reporting in gynecologic trials included type of therapy and age. The study phase did not correlate with odds of high-grade AE reporting.

Real-World Outcomes of Inoperable and Metastatic Cutaneous Head and Neck Melanoma Patients.

This study aims to describe the overall survival (OS) and to identify associated prognostic factors in patients with inoperable and metastatic cutaneous melanoma of the head and neck (H&N) region, undergoing modern systemic treatments. This is a retrospective single institutional study. Data on all consecutive H&N melanoma patients treated with systemic oncologic treatments between 2015 and 2022 were collected from electronic medical files. Kaplan-Meier curves were used to describe survival and Cox regression analysis was used to identify patient and tumor factors associated with prognosis. A total of 144 patients were included. Median OS was 45 months (95% confidence interval [CI] 28-65 m). On univariable analysis for OS, the primary disease site, specifically the nape and neck (hazard ratio [HR] 3.3, 95% CI 1.4-7.7, p = 0.007), high Eastern Cooperative Oncology Group Performance Status ([ECOG-PS], HR 2.5, 95% CI = 1.9-3.3, p < 0.001), high lactate dehydrogenase (LDH) levels (HR 2.8, 95% CI = 1.7-4.6, p < 0.001), and treatment with targeted therapy (TT) as compared with immunotherapy (HR 2.6, 95% CI = 1.06-6.3, p = 0.03) were all associated with shorter OS. High-grade adverse events (AEs) were associated with a longer OS (HR 0.41, 95% CI = 0.25-0.68, p = 0.001). On multivariable analysis for OS, the ECOG-PS, LDH levels, site of disease, and the development of moderate-severe AEs remained significant. In the era of modern oncologic treatments, the prognosis of inoperable and metastatic cutaneous H&N melanoma aligns with other cutaneous melanomas. Primary tumor site of the nape and neck region emerges as a significant prognostic factor. 3 Laryngoscope, 134:2762-2770, 2024.

Association between genetic variants of membrane transporters and the risk of high-grade hematologic adverse events in a cohort of Mexican children with B-cell acute lymphoblastic leukemia.

Advances in the understanding of the pathobiology of childhood B-cell acute lymphoblastic leukemia (B-ALL) have led towards risk-oriented treatment regimens and markedly improved survival rates. However, treatment-related toxicities remain a major cause of mortality in developing countries. One of the most common adverse effects of chemotherapy in B-ALL is the hematologic toxicity, which may be related to genetic variants in membrane transporters that are critical for drug absorption, distribution, and elimination. In this study we detected genetic variants present in a selected group genes of the ABC and SLC families that are associated with the risk of high-grade hematologic adverse events due to chemotherapy treatment in a group of Mexican children with B-ALL. Next generation sequencing (NGS) was used to screen six genes of the ABC and seven genes of the SLC transporter families, in a cohort of 96 children with B-ALL. The grade of hematologic toxicity was classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, Subsequently, two groups of patients were formed: the null/low-grade (grades 1 and 2) and the high-grade (grades 3 to 5) adverse events groups. To determine whether there is an association between the genetic variants and high-grade hematologic adverse events, logistic regression analyses were performed using co-dominant, dominant, recessive, overdominant and log-additive inheritance models. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated. We found two types of associations among the genetic variants identified as possible predictor factors of hematologic toxicity. One group of variants associated with high-grade toxicity risk: ABCC1 rs129081; ABCC4 rs227409; ABCC5 rs939338, rs1132776, rs3749442, rs4148575, rs4148579 and rs4148580; and another group of protective variants that includes ABCC1 rs212087 and rs212090; SLC22A6 rs4149170, rs4149171 and rs955434. There are genetic variants in the SLC and ABC transporter families present in Mexican children with B-ALL that can be considered as potential risk markers for hematologic toxicity secondary to chemotherapeutic treatment, as well as other protective variants that may be useful in addition to conventional risk stratification for therapeutic decision making in these highly vulnerable patients.

The Efficacy and Safety of Neoadjuvant Immunotherapy in Patients with Non-Small Cell Lung Cancer.

After the success of immunotherapy in the treatment of advanced non-small cell lung cancer (NSCLC), the benefit of neoadjuvant chemoimmunotherapy was compared with chemotherapy for localized NSCLC in several trials. However, the available studies had variable study designs, and study cohorts had limited follow-up times. Therefore, we conducted a systematic review and meta-analysis to evaluate the benefit of adding immunotherapy to neoadjuvant chemotherapy in patients with localized NSCLC. We conducted a systematic review using Pubmed, Web of Science, and Scopus databases for studies published until 5 December 2023. This protocol was registered in the PROSPERO database (Registration Number: CRD42023466337). We performed the meta-analyses with the generic inverse-variance method with a fixed effects model. Overall, 7 studies encompassing 2993 patients were included in the analyses. The use of neoadjuvant chemoimmunotherapy was associated with a 41% reduction in the risk of progression or death compared to neoadjuvant chemotherapy (HR: 0.59, 95% CI: 0.52-0.66, p < 0.0001) and a lower risk of death (HR: 0.67, 95% CI: 0.55-0.82, p < 0.0001). The neoadjuvant chemoimmunotherapy improved pCR rates compared to chemotherapy (21.8% vs. 3.8%, OR: 7.04, 95% CI: 5.23-9.47, p < 0.0001), while high-grade adverse events were higher with neoadjuvant chemoimmunotherapy (OR: 1.18, 95% CI: 1.02-1.36, p = 0.0300). The available evidence demonstrates a statistically significant and clinically meaningful event-free survival benefit and possibly an overall survival benefit with neoadjuvant chemoimmunotherapy with a slight increase in high-grade toxicities.

Abstract 16450: Increased Monocyte Count and Neutrophil-to-Lymphocyte Ratio With ICI Myocarditis

Introduction: Diagnosing immune checkpoint inhibitor (ICI) myocarditis remains complex in practice, often requiring advanced imaging or invasive endomyocardial biopsy. We constructed an institutional cohort of patients who received at least 1 dose of ICI and developed probable or definite ICI myocarditis. Hypothesis: We hypothesized that routine serum biomarkers, including troponin I, neutrophil-to-lymphocyte ratio (NLR), monocytes, and AST/ALT, would be elevated and peak at diagnosis. Methods: This retrospective cohort study used EHR data from patients on ICI at a single academic institution who developed probable or definite myocarditis from 7/2015 - 1/2023. Inclusion criteria and diagnosis date were defined using Bonaca criteria and/or documented clinical consensus, e.g. initiation of steroids for presumed myocarditis. Primary outcomes were levels of troponin I/high sensitivity troponin I, monocytes, NLR, and AST/ALT. LOESS regression with default smoothing parameter α = 0.75 was used to evaluate biomarker patterns 7 days pre- and post- diagnosis. Results: We included 16 cases of myocarditis. At diagnosis, most patients had at least 1 significant elevation in troponin I (100%), AST (81%), ALT (63%), or monocytes (69%) while on ICI (Figure 1). After diagnosis, absolute monocyte and lymphocyte count initially decreased before rebounding. Serum NLR rose prior to and briefly after diagnosis (Figure 2). Conclusions: Peripheral cardiac and non-cardiac biomarkers change with ICI myocarditis. Further research on routine non-cardiac biomarkers associated with myocarditis and other ICI toxicities may help prevent high-grade adverse events.

Evaluation of symptom severity, tolerability, and physical function in the I-SPY2 trial.

369 Background: Patient-reported outcomes (PROs) are a valuable component to understand treatment tolerability and toxicity. We have implemented an electronic system for monitoring PROs and quality of life (QOL) for patients enrolled in the I-SPY2 trial, a phase II trial evaluating the effect of novel neoadjuvant therapies for breast cancer. We associated patient demographic factors with symptoms, decline in physical function (PF), and tolerability to treatment. Methods: Study population for this analysis includes 259 enrolled patients receiving combinations of experimental immunotherapy and chemotherapy. Patients completed PRO-CTCAE/PROMIS/FACT surveys reflecting symptom severity, symptom frequency, tolerability of drug, and physical function at baseline through follow up (12 months). CTCAE 5.0 was collected weekly at these timepoints to assess adverse events (AE). Odds ratio and regularized multi-variate regression was used to evaluate early symptoms predictive of a clinically significant decline in PF from baseline to post-treatment follow-up. Results: Of 259 patients, 160 (58%) were White, 13 (5%) were Asian, 26 (10%) were African American (AA), and 25 (9.3%) were Hispanic. 25% of all patients had a clinically significant decline in PF between baseline and pre-surgery/follow-up. Symptom predictors of decline included high frequency of diarrhea and severity of joint pain. African American (AA) patients had higher severity of joint pain than White patients (OR = 14.9, P &lt; 0.05). Within the first 12 weeks of treatment, AA patients and non-white (NW) patients were more likely to report severe vomiting than White patients (OR =13.22 and 12.72, P&lt; 0.05 and P&lt; 0.03 respectively). Overall, patients that reported lower tolerance to therapy had higher grade of AE. While patients with low-grade adverse events were less bothered by their side effects at follow-up, higher grade adverse events such as hypothyroidism impacted distress levels by more than double. Conclusions: Among I-SPY2 participants, when higher grade of symptoms is persistent through follow up, it impacts physical function and tolerability even after end of therapy. Our study can allow physicians to be more diligent in active and post treatment monitoring. Clinical trial information: NCT01042379 .

Safety and Efficacy of Combination Therapy of Remdesivir, Baricitinib, and High-dose Steroids in Patients Hospitalized with Moderate to Severe COVID-19

Objective Dexamethasone, remdesivir (REM), and baricitinib (BAR) are commonly used to treat coronavirus disease 2019 (COVID-19). High-dose steroids have also been reported to be well tolerated, even when used in combination with multiple drugs. In this retrospective study, we assessed the safety and therapeutic efficacy of a three-drug combination of high-dose steroids, REM, and BAR in hospitalized COVID-19 patients. Methods We retrospectively evaluated the safety and efficacy of three-drug combination therapy. Patients We evaluated 107 patients hospitalized with moderate or severe COVID-19 who underwent 3-drug combination therapy with high-dose steroids (80 mg of methylprednisolone or more, REM, and BAR) in our institution from December 2020 to June 2021. The mean age was 62.1±13.7 years old, and 71.2% were men. The severity of the study patients was as follows: 18 (16.8%) with an 8-category ordinal score of 4, 84 (78.5%) with a score of 5, and 5 (4.7%) with a score of 6. Results The frequency of high-grade adverse events was low, except for hyperglycemia (n=59, 45.8%). The median duration from symptom onset to the start of three-drug combination therapy was eight days. All but one of the patients treated with the combination therapy improved. The median time to improvement by 1 category of the eight-category ordinal score was 6 days, and the 28-day mortality was 0.9%. Conclusion This study showed the safety profile of three-drug combination therapy of high-dose steroids, REM, and BAR in moderate to severe COVID-19 patients. The three-drug combination therapy is well tolerated and has the potential to prevent exacerbation of severity.

The Effects of Drug Exposure and Single Nucleotide Polymorphisms on Aaptinib-Induced Severe Toxicities in Solid Tumors.

In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed. Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01). Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG. Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.

P11.66.A COMBINATION OF TROFOSFAMIDE AND ETOPOSIDE IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Standard of care treatment options at glioblastoma relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide plus etoposide treatment at disease recurrence of adult glioblastoma patients. MATERIAL AND METHODS We collected clinicopathological data from adult recurrent glioblastoma patients treated with the combination of trofosfamide and etoposide for more than four weeks (one course). A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors served as control. RESULTS A total of n=22 recurrent glioblastoma patients were eligible for this analysis. Median progression-free survival (3.1 versus 2.3 months, HR: 1.961, 95% CI: 0.9724-3.9560, p=0.0274) and median overall survival (9.0 versus 5.7 months, HR: 4.687, 95% CI: 2.034-10.800, p=0.0003) were significantly prolonged compared to the control cohort (n=17). In a multivariable Cox regression analysis, treatment with trofosfamide plus etoposide emerged as a significant prognostic marker regarding progression-free and overall survival. We observed high-grade adverse events in n=16/22 (73%) patients with hematotoxicity comprising the majority of adverse events (n=15/16, 94%). Lymphopenia was by far the most commonly observed hematotoxic adverse event (n=11/15, 73%). CONCLUSION This study provides first indication that the combination of trofosfamide plus etoposide is safe in adult glioblastoma patients and may be associated with prolonged survival in recurrent glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.

Quality of Life, Clinical, and Patient-Reported Outcomes after Pencil Beam Scanning Proton Therapy Delivered for Intracranial Grade WHO 1-2 Meningioma in Children and Adolescents.

The purpose of this study was to report the clinical and patient-reported outcomes of children and adolescents with intracranial meningioma treated with pencil beam scanning proton therapy (PBS-PT). Out of a total cohort of 207 intracranial meningioma patients treated with PBS-PT between 1999 and 2022, 10 (4.8%) were children or adolescents aged < 18 years. Median age was 13.9 years (range, 3.2-17.2). Six (60%) children were treated as primary treatment (postoperative PT, n = 4; exclusive PT, n = 2) and four (40%) at the time of tumor recurrence. Acute and late toxicities were registered according to Common Terminology Criteria of Adverse Events (CTCAE). Quality of life (QoL) before PBS-PT was assessed using PEDQOL questionnaires. Educational, functional, and social aspects after PT were assessed through our in-house developed follow-up surveys. Median follow-up time was 71.1 months (range, 2.5-249.7), and median time to last questionnaire available was 37.6 months (range, 5.75-112.6). Five (50%) children developed local failure (LF) at a median time of 32.4 months (range, 17.7-55.4) after PBS-PT and four (80%) were considered in-field. One patient died of T-cell lymphoma 127.1 months after PBS-PT. Estimated 5-year local control (LC) and overall survival (OS) rates were 19.4% and 100.0%, respectively. Except for one patient who developed a cataract requiring surgery, no grade ≥3 late toxicities were reported. Before PT, patients rated their QoL lower than their parents in most domains. During the first year after PT, one child required educational support, one needed to attend to a special school, one had social problems and another three children required assistance for daily basic activities (DBA). Three years after PT, only one child required assistance for DBA. The outcome of children with intracranial meningioma treated with PBS-PT is in line with other centers who have reported results of radiation therapy delivered to this particular patient group. This therapy provides acceptable functional status profiles with no high-grade adverse radiation-induced events.