Dermatologic Toxicity Research Articles

Oral Immune-Related Adverse Events Associated with PD-1 Inhibitor Treatment: A Case Series

Introduction: Immune Checkpoint Inhibitor (ICI) drugs have led to a revolution in the treatment of different forms of cancer, shifting the target of action from cancer cells to the patient’s immune system, enhancing their responses against the tumor itself. On the other hand, this mechanism can lead to responses against oneself, with the appearance of immune-related adverse events. The aim of the present study was to examine the immune-related adverse events (irAEs) affecting the mucous membranes of the oral cavity and the possible correlation between these and skin toxicities, which are reported in the literature as the most common adverse events. Materials and methods: Thirteen patients treated with anti-Programmed Death (PD-1) drugs (pembrolizumab, nivolumab, and cemiplimab) were selected. The data collected include the general history of the patient and the type of anticancer treatment. The sample was then analyzed by recording the alterations found on the mucous membranes of the oral cavity and on the skin. Finally, the average time that elapsed between the start of immunotherapy and the onset of lesions was analyzed. Results: Patients often had multiple lesions at the same time. Hyperkeratosis was found in three patients, candidiasis (pseudomembranous and median rhomboid glossitis) in two patients, epithelial atrophy in four patients, and ulcerative areas in two patients. One patient reported xerostomia with dysphagia. The anatomical areas most involved were the dorsal tongue and palate. Skin irAEs included skin rash erythema (n = 7) with diffuse redness, the presence of small bubbles with a crusty outcome, and dryness of the skin in the affected areas. Discussion: In the literature, there are few studies that analyze how irAEs affect the mucous membranes of the oral cavity in patients treated with ICI drugs. The most frequently described lesions are lichenoid reactions and xerostomia. Moreover, the development of mucositis, generally of low grade, has been reported. The present study has confirmed the data from the literature and, in addition, reports two cases of candidiasis, an adverse event that has never been shown in the literature. Conclusions: irAEs have the potential to affect any organ. The only way to avoid the occurrence of serious events that is currently available is early interception, which is only possible through the knowledge of these manifestations. It is therefore considered necessary to deepen our knowledge of oral irAEs and their correlation with dermatological toxicities, allowing for a multidisciplinary classification of the patient and a timely diagnosis of any adverse event and avoiding progression to more advanced stages, which could lead to the temporary or permanent suspension of anticancer drugs.

Bortezomib-Melphalan-Prednisone (VMP) Vs. Lenalidomide-Dexamethasone (Rd) in Transplant-Ineligible Real-Life Multiple Myeloma Patients: Updated Results of the Randomized Phase IV Real MM Trial

BACKGROUND. Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) have represented standards of care for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts) until the recent introduction of daratumumab (Dara) in the frontline setting. However, no prospective randomized trial has directly compared VMP with Rd. Moreover, real-life older NTE pts are underrepresented in clinical trials, and only few data on safety and efficacy in this population are available. AIMS. We conducted a randomized multicenter phase IV trial (NCT03829371; funded by the Italian Medicine Agency AIFA - Independent Research) to compare safety and efficacy of the two standard regimens, VMP vs Rd, in an unselected real-life population of NTE NDMM pts. METHODS. NDMM pts ineligible for transplant due to age ≥65 years or comorbidities were randomized 1:1 to: 9 VMP cycles (42-day cycles, V: 1.3 mg/m2, days (dd) 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1-4 and dd 1, 8, 22, and 29, cycles 5-9; M: 9 mg/m2, dd 1-4; P: 60 mg/m2, dd 1-4) vs continuous Rd (28-day cycles, R: 25 mg, dd 1-21; d: 40 mg, dd 1, 8, 15, and 22) according to standard practice. Pts gave written informed consent and were enrolled regardless of performance status, comorbidities, renal function, or baseline laboratory values. Pts were stratified according to the International Myeloma Working Group (IMWG) frailty score and cytogenetic risk by fluorescence in situ hybridization [high risk if positive for del(17p), t(14;16), or t(4;14)]. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population. Key secondary endpoints included response rates, overall survival (OS), and safety. RESULTS. At the data cut-off (July 4, 2022), 231 pts were randomly allocated to receive VMP (n=114) or Rd (n=117). Baseline characteristics were evenly balanced between the two arms: median age was 77 (IQR 73-80) and 76 years (IQR 73-79); 49% vs 50% of pts were frail; 17% vs 19% pts had high-risk cytogenetics, respectively. After a median follow-up of 19 months, the median PFS in the ITT population was 29.6 vs 26.2 months with VMP vs Rd (hazard ratio [HR] 0.82, 95% CI 0.51-1.31, P=0.41; Figure - panel A). However, the HR was not constant over time: from 0.65 (95% CI 0.36-1.19, P=0.16) during the first year of treatment (suggesting a slight benefit of VMP vs Rd) to 1.37 (95% CI 0.65-2.86, P=0.40) after the first year of treatment (suggesting a slight benefit of continuous Rd therapy). The subgroup analysis according to cytogenetic risk showed a significant effect modification of the comparison VMP vs Rd in terms of PFS, with an HR=0.21 (95% CI 0.04-0.99) in the high-risk group vs an HR=1.24 (95% CI 0.70-2.18) in the standard-risk group (interaction P=0.036). No significant effect modification was observed in terms of age or frailty status. In the ITT population, the 2-year OS was 89% with VMP vs 75% with Rd (HR 0.53, 95% CI 0.26-1.07, P=0.08; Figure - panel B). No safety concerns were reported. The most frequent grade (G)3-4 adverse events (AEs) with VMP were thrombocytopenia (15%) and neuropathy (7%), while neutropenia (23%), infections (12%), and dermatologic toxicities (9%) were the most frequent G3-4 AEs observed in the Rd arm. Sixty-six percent of pts in the VMP and 59% in the Rd arms had ≥1 dose reductions of any drug, including 35% of pts in the VMP arm switching to once-weekly V before cycle 5. CONCLUSION. We confirmed the efficacy of VMP and Rd in an older real-life population of NTE NDMM pts including ~50% of frail pts. VMP and Rd were equally effective in standard-risk pts and in all frailty subgroups in terms of PFS. However, high-risk pts benefited more from VMP (HR 0.21), suggesting that the doublet Rd is suboptimal in this subgroup. Safety data were consistent with those previously reported. Of note, only one third of real-life pts were able to receive full-dose VMP or Rd therapy according to their schedule. Despite the limited follow-up, the difference in terms of OS between the two arms may be explained by the poor outcomes of patients failing lenalidomide-based treatments. Importantly, following a recent amendment, as of July 2022, enrolled pts will be randomized to Dara-VMP vs Dara-Rd. Decision-making and treatment selection will be further supported by a future analysis of this addition of Dara, based on patient and disease characteristics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Leukoreductive response to the combination of sorafenib and chemotherapy in hyperleukocytosis of FLT3-ITD mutated pediatric AML.

Twelve to 22% of pediatric acute myeloid leukemia (AML) patients present with hyperleukocytosis, which is one of the main risk factors of early death due to its clinical complications: leukostasis, causing pulmonary or central nervous system injuries, tumor lysis syndrome, and disseminated intravascular coagulation. Sorafenib is a multi-kinase inhibitor that blocks the Fms-Related Tyrosine Kinase 3 receptor (FLT3) in AML patients with a FLT3-internal tandem duplication (FLT3-ITD), leading to a reduction of proliferation. Here we report four de novo diagnosed or relapsed pediatric FLT3-ITD-positive AML patients with hyperleukocytosis, which were treated with sorafenib in combination with cytoreductive chemotherapy prior to the start of the induction phase. We observed a fast reduction of white blood cells in peripheral blood and bone marrow. This resulted in a rapid clinical stabilization of the patients. Adverse side effects-such as dermatologic toxicity, elevation of transaminases and hypertension-occurred but were mild and inductive chemotherapy could be started in parallel or subsequently. This implies sorafenib as a safe and effective treatment option in combination with chemotherapy during cytoreductive prephase for children with this life-threatening condition.

Mechanisms of dermatological toxicities to immune checkpoint inhibitor cancer therapies.

The discovery of immune checkpoint inhibition (ICI) sparked a revolution in the era of targeted anticancer therapy. However, although monoclonal antibodies targeting the cytotoxic T-lymphocyte antigen-4 and programmed death-1 axes have improved survival in patients with advanced cancers, these immunotherapies are associated with a wide spectrum of dermatological immune-related adverse events (irAEs), ranging from mild to life-threatening. Several publications have addressed the clinical and histopathological classification of these skin-directed irAEs, their impact on anti-tumour immunity and survival, and the critical role of supportive oncological dermatology in their management. In this paper, we review the current understanding of the mechanistic drivers of immune-related skin toxicities with a focus on inflammatory, immunobullous and melanocyte/pigment-related reactions. We detail the specific immune-based mechanisms that may underlie different cutaneous reactions. We also discuss potential mechanisms as they relate to extracutaneous irAEs and the lessons learned from these, the potential overlap with cutaneous irAEs, techniques to study differences in immune-related vs. de novo skin reactions, and how treatment of these AEs impacts cancer treatment, patient quality of life and overall survival. An improved understanding of the mechanistic basis of cutaneous irAEs will allow clinicians to develop and use blood-based biomarkers that could help ultimately predict onset and/or severity of these irAEs, and to implement rational mechanistic-based treatment strategies that are targeted to the irAEs while potentially avoiding reducing the anti-tumour effect of ICIs.

Feasibility Trial of IMPT to Reduce Toxicity in Anal Cancer Patients

<h3>Purpose/Objective(s)</h3> The purpose of this prospective trial was to assess patient and physician reported toxicity in anal cancer patients undergoing definitive chemoradiation with intensity modulated proton therapy (IMPT). <h3>Materials/Methods</h3> Patients with AJCC v8 Stage II-III disease were treated with IMPT using a multi-field, split-target technique using robust optimization with dose prescribed as per RTOG 0529 (50.4-54 Gy). All patients received two cycles of 5-fluorouracil and Mitomycin concurrently with radiation. Toxicity was assessed at baseline, weekly during chemoradiation and in follow-up using physician graded CTCAE v 4.0 and PRO-CTCAE for relevant domains (17 items). The primary endpoint was to define point estimates and 95% CI for ≥ grade 2/3 GI, GU, Dermatologic, and Hematologic toxicity within 90 days from treatment. The proportion of PRO-CTCAE questions scored ≥ 3 for each domain was compared to baseline. Survival outcomes were assessed using the Kaplan-Meier method. The proportion of ≥ grade 2 and ≥ grade 3 toxicities were compared to historic IMRT patients treated on RTOG 0529 using Fisher's exact test. <h3>Results</h3> Fourteen patients were enrolled from 2017-2020. The median age was 56 (range 31-85) with 50% female participants. Eleven patients (79%) had Stage III disease. The respective T/N stages are T2 (n=5, 36%), T3 (n=7, 50%), T4 (n=1,7%), N0 (n=2,14%), N1 (n=9,64%), and N2 (n=3,21%). All patients completed prescribed treatment with 1 patient requiring a treatment break. <b>Table 1</b> shows rates of ≥ grade 2/3 CTCAE events for IMPT. Rates of patient reported Derm and GU toxicity were low at baseline with a peak at week 6 (91% and 58% PRO-CTCAE items ≥grade 3, respectively) and normalization to baseline 3 months after IMPT. In contrast, the proportion of high grade PRO-CTCAE GI scores was 40% at baseline which persisted through 1 year post treatment. A complete clinical response at 6 months was observed in 11 patients (79%). The median overall survival was not reached with a median follow-up is 32.5 months. The 2 years overall, progression-free, and colostomy free survival was 92%, 64%, and 85%, respectively. Median time to progression was 9 months with local only (n=2,14%), local and distant (n=2,14%) and distant (n=1,7%) recurrence patterns. <h3>Conclusion</h3> In this single arm trial, rates of clinician reported toxicity with IMPT were similar to IMRT. High grade PRO-CTCAE events were common during IMPT. GU and Derm events normalized at 3 months from treatment but high-grade GI symptoms persisted to12 months and were similar to baseline. Additional measures are needed to minimize acute and chronic toxicity related chemoradiation.

The diverse landscape of dermatologic toxicities of non-immune checkpoint inhibitor monoclonal antibody-based cancer therapy.

Since their first approval 25 years ago, monoclonal antibodies (mAbs) have become important targeted cancer therapeutics. However, dermatologic toxicities associated with non-immune checkpoint inhibitor (non-ICI) mAbs may complicate the course of cancer treatment. Data on the incidence and types of these reactions are limited. A comprehensive review was conducted on dermatologic toxicities associated with different classes of non-ICI mAbs approved for treatment of solid tumors and hematologic malignancies. The review included prospective Phase 1, 2, and 3 clinical trials; retrospective literature reviews; systematic reviews/meta-analyses; and case series/reports. Dermatologic toxicities were associated with several types of non-ICI mAbs. Inflammatory reactions were the most common dermatologic toxicities, manifesting as maculopapular, urticarial, papulopustular/acneiform, and lichenoid/interface cutaneous adverse events (cAEs) with non-ICI mAbs. Immunobullous reactions were rare and a subset of non-ICI mAbs were associated with the development of vitiligo cAEs. Dermatologic toxicities of non-ICI mAbs are diverse and mostly limited to inflammatory reactions. Awareness of the spectrum of the histopathologic patterns of cAE from non-ICI mAbs therapy is critical in the era of oncodermatology and oncodermatopathology.

215 (PB095) - OQL036 topical gel inhibits the skin toxicity associated with 5-fluorouracil/capecitabine: results from in vitro and in vivo preclinical studies

Background: Hand-Foot Syndrome (HFS) is a dermatological toxicity induced by capecitabine (CAP)/fluorouracil (5FU). HFS is related to damage of palmar/plantar epidermal/dermal cells by 5FU, and inflammation-mediated by cyclooxygenase-2 pathways. We hypothesize applying OQL036 a topical gel prodrug metabolizing to thymidine (TdR) and naproxen (NAP) may alleviate HFS toxicity associated with CAP/5FU.

Management of cutaneous toxicities under amivantamab (anti MET and anti EGFR bispecific antibody) in patients with metastatic non-small cell lung cancer harboring EGFR Exon20ins: towards a proactive, multidisciplinary approach

Contexte.The Epidermal Growth Factor Receptor (EGFR) is mutated in 10–15% of patients with lung adenocarcinoma. At metastatic stage EGFR tyrosine kinase inhibitors (TKIs) are used front line for patients harboring targetable mutations. Novel anti-EGFR therapies are being developed. Amivantamab is a bispecific anti-EGFR and anti-MET antibody with expected skin toxicities. ObjectiveWe developed here guidelines for prevention and treatment of cutaneous toxicities under amivantamab according to our experience at Institut Curie. Materiel & MethodThe first patients with metastatic lung cancer harboring EGFR Exon20ins mutation, included in the phase 1 CHRYSALIS trial and cured at Institute Curie from November 1st 2019 until December 31st 2021 were selected for this work. Retrospectively, all cutaneous adverse events were registered and classified according to the CTCAE 6.0 classification, and actions we implemented to minimize and treat these adverse events were collected. We then developed guidelines based on these datas. ResultsA total of seven patients started amivantamab as monotherapy. The two most frequent dermatological adverse events were: acneiform rash and paronychia (100 % of patients). Other adverse events presented by the patients were reported: modification of hair growth with hypertrichosis in 50 % of men (n = 1/2) and hirsutism in 80 % of women (n = 4/5); skin abrasion of the scalp in 71 % (n = 5/7); and skin fissure in 57 % (n = 4/7). We recommend first a rigorous inspection of the skin and teguments to determine the risk rate to have dryer skin under treatment; second a prevention of paronychia/acneiform rash/and skin fissures with prophylactic tetracycline, skin moisturizing, and hygienic measures starting at least 14 days before treatment initiation; third a particular attention to the psychological impact of skin toxicities with access to psychological support. ConclusionWe propose here guidelines for the management of dermatological toxicities under amivantamab with a multidisciplinary approach for the proactive management of cutaneous toxicities with a focus on preventive actions.

EP08.02-040 Dacomitinib Induced Febrile Neutropenia: a Rare Serious Adverse Event

Dacomitinib, a second-generation oral irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has improved overall survival in metastatic non-small lung cancer patients harbouring EGFR mutations. The common adverse reactions associated with dacomitinib are diarrhoea and dermatological toxicities while severe febrile neutropenia has not been reported in literature.

Dermatological toxicity of acute lymphoblastic leukemia treatment by protocol ALL IC-BFM 2002

Background. Аcute lymphoblastic leukemia (ALL) in children is not only the most common but also potentially curable disease in 8590% cases. The other side of high effectiveness of modern treatment protocols their toxicity. Inspite of skin and mucosal toxicity is not a life threatening condition, it requires a supportive care to prevent infectious complications, which prolong hospitalization, administration of antibacterial, antifungal and in some cases antiviral drugs.&#x0D; Aim. To study skin and mucosal toxicity in patients with ALL, treated by ALL IC-BFM 2002 protocol.&#x0D; Materials and methods. One hundred and nineteen pediatric patients with primary diagnosed ALL were enrolled the study. All the patients were treated by ALL IC-BFM 2002 protocol. Toxicity assessment was performed on each step by the scale of National Cancer Institute (NCI) USA, 2d version.&#x0D; Results. The most often variants of skin and mucosal toxicity during ALL IC-BFM 2002 protocol were found on protocol mM/M, based on high-dosed methotrexate. In 42.1% stomatitis 2st. was diagnosed on methotrexate dose 5000 mg/m2, 3st. 15.8%, 4st. 5,3%. Methotrexate dosed 2000 mg/m2 coused stomatitis 3 st. in 6.3%, in other patients stomatitis was 12st. Exfoliative dermatitis was in 1 (1%) case with prolonged methotrexate elimination. Block polychemotherapy used in high risk group of patients was complicated with stomatitis 34 st. in 90%. In 20% naso-gastral catheter was performed and in 25% used partial/hole parenteral nutrition support. Alopecia was reversible and observed in 100% patients. Protocols I, II and maintenance treatment were free of clinically significant skin and mucosal toxicity.&#x0D; Conclusion. The skin and mucosal toxicity profile of ALL IC-BFM 2002 protocol was tolerable. Hole volume of supportive care, preventing and treatment of dermatological toxicity of chemotherapy can prevent of severe skin and mucosal toxicity (soft tissue infections, sepsis, metabolic disorders).

Association of genetic polymorphisms of CYP3A4 and CYP2D6 with gefitinib-induced toxicities.

Dermatological, gastrointestinal and hepatic toxicities are the most common adverse events associated with gefitinib use. Gefitinib is metabolized by cytochrome P450. Inconsistent associations of single nucleotide genetic polymorphisms of CYP450 and gefitinib-induced adverse effects were reported. We aim to investigate the association between CYP450 genetic polymorphism and the development of gefitinib-associated adverse events. A retrospective cohort study of Chinese patients with metastatic nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations who received first-line gefitinib treatment was conducted. Single nucleotide polymorphisms (SNPs) of CYP2D6, CYP3A4 and CYP3A5 were assayed using a multiplex SNP microarray. Risks of development of gefitinib-induced toxicities associated with different SNPs were determined. Among the 152 patients treated with gefitinib, 52 (34.2%) had gefitinib-induced hepatotoxicity, 113 (74.3%) had cutaneous reactions and 53 (34.9%) had gastrointestinal adverse effects. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes were significantly associated with hepatic, cutaneous and gastrointestinal adverse effects [odds ratio (OR) 3.773; (95% confidence interval {CI},1.046-13.610; P = 0.043), 3.368 (95% CI, 1.000-11.345; P = 0.050) and 20.000 (95% CI, 2.381-167.965; P = 0.006), respectively]. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes may be associated with increased risks of gefitinib-induced toxicities in the liver, skin and gastrointestinal tract.

NS-001: Characterization and management of oral and dermatological toxicities in patients receiving the CD3 X GPRC5D bispecific antibody talquetamab for the treatment of relapsed/refractory multiple myeloma

NS-001: Characterization and management of oral and dermatological toxicities in patients receiving the CD3 X GPRC5D bispecific antibody talquetamab for the treatment of relapsed/refractory multiple myeloma

Safety Assessment on Serious Adverse Events of Targeted Therapeutic Agents Prescribed for RAS Wild-Type Metastatic Colorectal Cancer: Systematic Review and Network Meta-Analysis.

Despite substantially elevated risk of serious adverse events (SAEs) from targeted therapy in combination with chemotherapy, comprehensive pharmacovigilance research is limited. This study aims to systematically assess SAE risks of commonly prescribed targeted agents (bevacizumab, cetuximab, and panitumumab) in patients with rat sarcoma viral oncogene homolog (RAS) wild-type metastatic colon cancer. Keyword searches of Cochrane Library, Clinical Key and MEDLINE were conducted per PRISMA-NMA guidelines. Frequentist network meta-analysis was performed with eight randomized controlled trials to compare relative risk (RR) of 21 SAE profiles. The risks of hematological, gastrointestinal, neurological SAE were insignificant among targeted agents (p > 0.05). The risk of serious hypertension was substantially elevated in bevacizumab-based chemotherapy (p < 0.05), whereas panitumumab-based chemotherapy had markedly elevated risk of serious thromboembolism (RR 3.65; 95% CI 1.30–10.26). Although both cetuximab and panitumumab demonstrated increased risk of serious dermatological and renal toxicities, panitumumab-based chemotherapy has relatively higher risk of skin toxicity (RR 15.22; 95% CI 7.17–32.35), mucositis (RR 3.18; 95% CI 1.52–6.65), hypomagnesemia (RR 20.10; 95% CI 5.92–68.21), and dehydration (RR 2.81; 95% CI 1.03–7.67) than cetuximab-based chemotherapy. Thus, further studies on risk stratification and SAE management are warranted for safe administration of targeted agents.

Case report: Zanubrutinib-induced dermatological toxicities: A single-center experience and review

Zanubrutinib, a next-generation non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, shows great efficacy in the treatment of B cell malignancies. Some patients may experience a series of side effects after the treatment of zanubrutinib. Grade 4 dermatological toxicities are rare, which present as severe rash and skin infection. Herein, we retrospectively reported the grade 4 dermatological toxicities of zanubrutinib in three consecutive patients. They were treated with zanubrutinib 160 mg twice daily orally. One patient was diagnosed with Primary Breast Diffuse Large B-cell Lymphoma(PB-DLBCL) and two patients were diagnosed with Chronic Lymphocytic Leukemia(CLL). Within one month after zanubrutinib treatment, all three patients developed grade 4 dermatological toxicities, including bruising, maculopapular rash, petechiae, ecchymosis, hemorrhagic blister, acne-Like rash, papulopustular rash, and skin infections. Zanubrutinib was discontinued in two patients due to unacceptable dermatological toxicities. Safety data from pre-licensing clinical trials showed that zanubrutinib-related side effects were frequent but well tolerated. To date, no severe dermatological toxicities were reported. The majority of patients can be relieved with symptomatic treatment, but a very small percentage of patients may face discontinuation of the drug.

Optimizing Multidisciplinary Treatment-Related Adverse Effects Detection and Reduction in Patients Undergoing Active Cancer Treatments in Ambulatory Infusion Centers.

The objective of this study was to describe the implementation of an interdisciplinary supportive care program for treatment-related adverse effects (TRAEs) of patients with cancer in two ambulatory infusion centers affiliated with a major health system. A management program of TRAEs was developed on the basis of the collaboration between oncologists, infusion center oncology nurses, and a board-certified oncology clinical pharmacist for patients with cancer in two outpatient infusion centers. Patients received multidisciplinary interventions or oncologist-driven interventions on the basis of their reported symptoms during their cancer treatments. They were followed prospectively at regular intervals for further symptom management interventions. To evaluate this program, a retrospective chart review was performed, and data were collected regarding the number and nature of these TRAEs. The outcomes of their interventions were assessed up to 3 months since initial encounters. Data for patient satisfaction were also collected before and after implementation of the program. A total of 308 patients received 469 interventions initiated either by the multidisciplinary team or by oncologists over a 3-year period. Compared with oncologist-led interventions, multidisciplinary interventions were statistically significant in the number of interventions (P = .004; 95% CI, 17.9 to 36.2) and in reducing occurrences of TRAEs (P = .03; 95% CI, 33.8 to 72.4) such as dermatological toxicities, diarrhea, immune-related adverse effects, mucositis, and nausea or vomiting after 1-month follow-up. Multidisciplinary team captured approximately 40% of TRAEs of all grades that were escalated to oncologists for further management, which led to an overall improvement in management of TRAEs. Multidisciplinary care for patients in infusion centers led to improvement in treatment-related toxicities.

A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study final results.

LBA3513 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. pathologic complete remission (pCR) can be considered as surrogate endpoint of efficacy of treatment in terms of disease-free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multicentre study in patient with locally advanced rectal cancer who receive standard concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is the proportion of pCRs after at least 1 cycle of durvalumab; secondary endpoints are the proportion of clinical complete remissions (cCRs) after at least 1 cycle of durvalumab, the proportion of adverse and serious adverse events (NCI CTCAE v5.0). The sample size has been estimated by using the optimal Simon’s two-stage design assuming a null pCR proportion of 0.15 and an alternative pCR percentage of 0.30 (alpha = 0.05, power = 0.80). If more than 4 pCRs were observed in the first 19 enrolled patients, 36 additional patients were to be accrued for a total of 55 evaluable patients. The null hypothesis is rejected if ≥ 13 pCRs are observed in 55 patients. Results: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were evaluable for study objectives. Fifty-two of 55 treated patients received all 3 infusions of durvalumab. After treatment, a clinical response percentage of 81.8% was observed; 3 patients had progression of disease due to local and/or metastases before surgical intervention. Eighteen patients achieved complete pathological response (32.7%), confirmed by central revision. Near complete regression, moderate and minimal regression were observed in 14 (25.5%), 9 (16.4%) and 11 (20.0%) patients respectively. Regarding toxicity, 23 patients (41.8%) had adverse events (AEs) related to durvalumab treatment. Two patients (1.8%) discontinued durvalumab for toxicity. Grade 3 AEs occurred in 4 (7.3%) patients (diarrhea, skin toxicity, transaminase increase, lipase increase and pancolitis). No Grade 4 toxicity was observed. In 20 patients (36.4%) G1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypo-thyroidism), dermatologic toxicity (skin rash) and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). Conclusions: This study met its primary endpoint showing a promising activity of neoadjuvant chemo-radiotherapy plus durvalumab in terms of pCR rate and a safe toxicity profile. Clinical trial information: NCT04083365.

OTHR-13. Effectivity and toxicity of off-label treatment with Trametinib monotherapy or in combination with Dabrafenib in children with relapsed or refractory brain tumor

INTRODUCTION: Most pediatric low grade gliomas, and a substantial part of PXAs, have a BRAF alteration/activated MAPK pathway. This group often requires several lines of therapy, which coincides with significant morbidity. There is growing evidence that molecular targeted treatment may be beneficial for this population. Here we report the toxicity and efficacy of patients treated off-trial with either trametinib monotherapy or in combination with dabrafenib. METHODS: We performed a single-center retrospective chart review of all neuro-oncological patients who received trametinib monotherapy or in combination with dabrafenib (compassionate-use) in the Princes Maxima Center between April 1st, 2018 and December 31st, 2021. RESULTS: 22 patients (ages 1-21 years) were included of whom 14 received trametinib monotherapy (BRAF-KIAA fusion, n=10) and eight received trametinib/dabrafenib combination therapy (BRAFV600 mutation, n=8). All patients on trametinib monotherapy (n=14) developed skin problems such as rash (100%), dry skin (86%), paronychia (71%) and eczema (64%). Eight patients (57%) had at least one adverse event (AE) ≥grade 3. Patients on trametinib and dabrafenib showed similar toxicity, although with lower prevalence and no paronychia. One patient (13%) had an AE ≥grade 3. Median treatment time of trametinib was 514 days (IQR 455) and for trametinib and dabrafenib 360 days (IQR 512). Five patients (36%) on trametinib are still on treatment and nine patients (64%) stopped treatment due to e.g. tumor progression or toxicity. All patients on trametinib and dabrafenib are still on treatment. Best overall response of trametinib monotherapy (n=14 evaluated) was observed as partial response (50%), stable disease (33%) and progressive disease (17%). Combination therapy (n=7 evaluated) brought 100% partial response. CONCLUSION: Dermatological toxicities are mostly seen in trametinib monotherapy or in combination with dabrafenib. Despite moderate toxicity patients seem to benefit from treatment. Results suggest that combination therapy has a more favorable toxicity profile than monotherapy.

LGG-34. Nephrological impact of BRAF inhibitors in a pediatric population of central nervous system tumors: a single institution experience

BRAF inhibitors (iBRAF) are under investigations in ongoing clinical trials for pediatric brain tumor treatment. Preliminary data regarding the pediatric population report pyrexia, hematological, dermatological, cardiac, and ophthalmic toxicities among the most common adverse events. Acute kidney injury (AKI), mainly due to tubular interstitial injury, has been reported in the adult population. With our study we want to contribute to a more comprehensive knowledge of the short- and long-term nephrological adverse effects of iBRAF in a pediatric population. We collected and reviewed clinical and laboratory data of all patients treated with iBRAF for pediatric central nervous system tumors at our Institution and available for publication. AKI was monitored through serial creatinine measurements, kidney function with estimated glomerular filtration rate (eGFR) and kidney injury with creatinuria/proteinuria ratio. Tubular injury was evaluated with fractional excretion of sodium, potassium and magnesium and with glycosuria. Moreover, urine was examined to detect presence and morphology of erythrocytes. Eight patients were identified, 3 females; median age at treatment start was 9 years (range 2,75 – 18,75). Six patients with BRAFV600E–mutated pediatric Low-Grade Glioma were treated with Vemurafenib, 1 patient with BRAFV600E-mutated pediatric High-Grade Glioma was treated with Vemurafenib and 1 patient with BRAFV600E-mutated Langerhans Cell Histiocytoses was treated with Dabrafenib. Seven patients were considered for analysis. After a median follow up of 3,83 years (range 2,25 – 6,58) no AKI was reported and all patients but two retained normal eGFR at last follow up. No tubular and glomerular injury laboratory findings were detected, and erythrocytes in the urine resulted always below the upper limit of normality. CONCLUSIONS: iBRAF were not associated with AKI and tubular injury. Nevertheless, some data, namely significative decrease of eGFR in two out of seven patients, warrants further investigations.

Toxicities of anti-VEGF therapies used in metastatic renal cell carcinoma: A real-world experience.

e16533 Background: Tumor endothelial proliferation inhibition using vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) have revolutionized metastatic renal cell carcinoma (mRCC) therapy. We retrospectively analyzed data on various anti-VEGF adverse events (AEs) utilizing the FDA Adverse Events Reports System (FAERS). Methods: We examined the FAERS public dashboard data on VEGF inhibitors’ reported AEs for the years 2019-2021. Data analyzed using descriptive statistics. Results: A total of 34,651 AEs were identified for anti-VEGF therapies, of which 29,328 (84.6%) were serious and 5,830 (16.82%) reported deaths (Table). Lenvatinib has most reported serious hemorrhagic events and thyroid impairment in 5.5% and 1.2%, respectively, and least (3.4%) reported dermatologic toxicity (including Hand-foot skin reaction, depigmentation, and rash. Cabozantinib has most (2.8%) reported gastrointestinal (GI) perforation and fistula. Pazopanib has most bone marrow suppression (BMS)—neutropenia, leukopenia, thrombocytopenia, and anemia (43.3%), dermatologic toxicity (25.8%), hepatotoxicity—jaundice, elevated transaminases, hyperbilirubinemia, hepatic encephalopathy, coagulopathy, ascites, and/or hepatorenal syndrome (23.9%), arterial thromboembolic events (ATE)—comprising cerebral infarction, ischemic stroke, transient ischemic attack, myocardial infarction, angina (19.8%), proteinuria and nephrotic syndrome (NS; 10.4%), pulmonary toxicity—interstitial lung disease, and pneumonitis (7.2%), posterior reversible encephalopathy syndrome (PRES; 4.9%), cardiotoxicity—cardiac failure (3.1%), and tumor lysis syndrome (TLS; 0.9%). Sunitinib has most reported osteonecrosis of the jaw AEs (ONJ; 37.3%), QT Prolongation and various arrhythmias (11.9%), severe hypertension (SHTN—including accelerated, urgency, and emergency; 10.0%), and aortic complications—including aortic aneurysm, dissection, and rupture (3.1%). Conclusions: Pazopanib has most while axitinib has least reported BMS, ATE, and pulmonary AEs. Cabozantinib has most reported GI AEs and sunitinib has most reported ONJ, SHTN, QT prolongation, arrhythmias, and aortic complications. With expanding treatment landscape for mRCC, this study helps shed light on the different anti-VEGF toxicity profiles and would therefore support treatment decision making.

Intensity-Modulated Radiotherapy Associated With Improved Survival Outcome in Anal Cancer.

PurposeTo describe the survival and toxicity outcome from a single-centre experience in patients with squamous cell cancer of the anal canal (SCC-AC), related to the impact of technological advances in diagnostics and radiation techniques.Material and MethodsA retrospective cohort study was performed after the approval of the institutional ethical committee (EK 478-21). We identified 142 patients in our registry, who received radical treatment for SCC-AC between 2000 and 2020. Fifty-five patients had FDG PET/CT for initial staging and target volume delineation, 87.33% received concomitant chemoradiotherapy (CRT), 64 patients were treated with 3-dimensional conformal radiotherapy (3DRT) between 2000-2009, and 78 patients with intensity-modulated radiotherapy (IMRT) between 2009-2020. Endpoints for the analysis included locoregional relapse-free survival (LRFS), disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). Acute and late toxicities were also reported.ResultsAt a median follow-up of 31.2 months, the median overall survival was 135 months, 5-year LRFS was 73.1%, 5-year DFS was 65.3%, and 5-year CSS was 75.3%. The use of IMRT was associated with shorter treatment duration. In the univariate analysis, IMRT was associated with significantly improved DFS and CSS for the whole cohort and significantly improved DFS, OS, and CSS for patients who received CRT. In the multivariate analysis, IMRT was associated with the improvement of all survival paraments. The use of FDG PET/CT did not translate into an improvement in the survival outcomes in both univariate and multivariate analyses. Grade-3 and more dermatological toxicities occurred less frequently, but hematological toxicities were more frequent in the IMRT-group. Late side effects and colostomies were less frequently reported in the IMRT group.ConclusionThe use of IMRT in the management of SCC-AC was associated with improvement of the oncological outcomes with improved toxicity profiles in this long-term single-centre experience.