Skin Toxicity Research Articles

Beacon: A phase II study of bevacizumab, atezolizumab, and cobimetinib in patients with recurrent, platinum resistant, high grade serous ovarian cancer.

5565 Background: Platinum resistant high grade serous ovarian cancer (HGSC) is associated with a poor prognosis and limited treatment options. Immune checkpoint inhibitors have failed to show significant impact in treatment of HGSC to date. Bevacizumab (anti-VEGF) and atezolizumab (anti-PDL1) have shown synergy in multiple cancer types. Cobimetinib (MEK inhibitor) may also potentiate immune responses, particularly by altering the tumour microenvironment. We sought to evaluate the efficacy of cobimetinib, bevacizumab and atezolizumab in women with platinum resistant HGSC. Methods: BEACON is a Phase II single arm study of cobimetinib (60mg oral D1-21 q 28-days), bevacizumab (5mg/kg IV q2w) and atezolizumab (840mg IV q2w from Cycle 2) in patients with platinum-resistant recurrent HGSC. Patients continued therapy until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) according to RECIST 1.1 at 24 weeks. Secondary endpoints included best overall response (BOR), safety, progression free survival, and response duration. Correlative studies on paired tumor biopsy and blood samples will explore molecular characteristics/subtypes and potential biomarkers of response as exploratory objectives. This study has now completed accrual and we present the 24-week response data, with a data cut off 21st December 2023. Results: Twenty-nine patients were enrolled between September 2018 and June 2023. Median age was 62 years (range 37 - 79) and 97% had received ≥ 2 prior lines of chemotherapy. The median number of cycles received was 3 cycles of atezolizumab and cobimetinib, and 4 cycles of bevacizumab. The ORR at 24 weeks was 21% [95% CI: 8-40], and a further 28% had stable disease as assessed per RECIST. Five patients (17%) have remained on study treatment for ≥ 52 weeks to date, suggesting that in some patients there was durable disease control. In terms of safety, 22 patients (76%) required a dose reduction in cobimetinib, mainly due to gastrointestinal and skin toxicity. Seventeen patients (59%) experienced a ≥Grade 3 treatment related adverse event, most commonly hypertension (6 patients, 21%). Two patients (7%) discontinued all study treatments due to toxicity. Conclusions: Preliminary results from this study show promising efficacy with the combination of atezolizumab, bevacizumab and cobimetinib in platinum resistant HGSC. Duration of response, progression free survival data and translational data exploring molecular characteristics will be presented as data matures. Clinical trial information: NCT03363867 . [Table: see text]

A phase 2, single arm, European multi-center trial evaluating the efficacy of afatinib as first line or later line treatment in advanced chordoma.

11517 Background: EGFR and Her2 overexpression in chordoma is well known, and chordoma cell-lines and mouse models were proven to be sensitive to EGFR inhibitor afatinib. This phase 2, single arm, European multi-center trial was designed to evaluate the efficacy of afatinib as first- or later-line tyrosine kinase inhibitor (TKI) treatment in advanced chordoma. Here we report efficacy and safety data. Methods: Eligible patients (pts) had locally advanced or metastatic, pathologically proven, EGFR expressing chordoma, not amenable for local therapies, with confirmed measurable and progressive lesions according to RECIST1.1. Pts were treated with afatinib 40mg/day in a 4 week cycle until disease progression (PD), unacceptable toxicity or withdrawal. Radiological tumor response assessment was performed every 3 cycles. The primary endpoint was response defined as progression free survival (PFS) rate ≥12 months (mos) for first-line cohort 1 and ≥ 9 mos for further-line treatment cohort 2, and change from baseline in EORTC QLQ- C30 and Brief pain inventory (BPI) questionnaires. Pts were enrolled using a Simon’s two-stage design, enrolling 13 patients in stage one, ≥3 patients with a PFS ≥ 12 or 9 mos were needed to enter stage two, where 43 pts total were to be enrolled, and ≥13 free from progression at 9 or 12 mos were required to meet the primary endpoint for success. Results: From Jun 2018 to Oct 2022, 47 pts were included. Four were ineligible for efficacy analysis (1 withdrawal, 3 stopped due to toxicity before first radiological evaluation). 34 entered cohort 1, 13 cohort 2. 31 (66.0%) were men, median age was 53 (range 28-85) years. 16 (34.0%) pts received prior systemic therapy (3 chemotherapy, 13 TKI, 2 immunotherapy, 2 other). The PFS rate at 12 mos was 40.0% in cohort 1 (12/30 pts), and 38.5% in cohort 2 (5/13 pts). Overall median PFS was 8.6 mos (95% CI 5.6-13.6); 9.1 mos (95% CI 5.8-16.6) in cohort 1 and 7.1 mos (95% CI 2.8-16.5) in cohort 2. Two pts remained on treatment at time of analysis. Best objective response by RECIST 1.1 was partial response in 4 pts (9.3%), stable disease in 33 (76.7%), PD in 5 pts (11.6%) and 1 (2.3%) unknown due to clinical progression. Median follow-up time was 23.7 mos (interquartile range 11.0-21.2). 16/47 pts (30.4%) experienced grade ≥3 adverse events (AEs). No grade 5 AEs related to afatinib were reported. Most common grade 3-4 afatinib-related AEs were skin toxicity (10.6% of pts), diarrhea (10.6%), mucositis (6.4%), hypertension (4.3%). Dose reduction was needed in 20/47 (42.6%) pts, and at least one dose interruption was needed in 31/47 (66.0%) pts. Conclusions: With a PFS rate at 12 mos of 40.0% in the first-line cohort and 38.5% at 9 mos in the further-line cohort, this phase 2 study met the PFS endpoint. QoLQ data will be provided at the conference . Partial response by RECIST was seen in 4/43 pts. Toxicity and dose reductions were relevant but manageable in most pts. Clinical trial information: NCT03083678 .

Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies.

Midline low-grade gliomas (mLGGs) of early childhood have a poorer prognosis compared with tumors of other localizations and in older patients. LGGs are associated with aberrant activation of RAS-RAF-MEK pathway, and pharmacological inhibition of the pathway has therapeutic promise. The aim of this study was clinical and molecular characterization of infantile mLGGs, with emphasis on the efficacy of targeted kinase inhibition. This study enrolled 40 patients with mLGG age <3 years. The majority of the patients (30/40) received first-line chemotherapy (CT) as per International Society of Paediatric Oncology LGG 2004 guidelines. In all patients, molecular genetic investigation of tumor tissue by polymerase chain reaction and RNA sequencing was performed. The median follow-up was 3.5 years. First-line CT failed in 24 of 30 recipients. The identified molecular profiles included KIAA1549::BRAF fusions in 26 patients, BRAF V600E in six patients, FGFR1::TACC1 fusions in two patients, and rare fusion transcripts in four patients. At disease progression, targeted therapy (TT) was initiated in 27 patients (22 patients received trametinib) on the basis of molecular findings. TT was administered for a median of 16 months, with partial response achieved in 12 of 26 (46%) patients in which response was evaluated. Severe adverse events were detected only on trametinib monotherapy: acute damage of GI or urinary mucosa complicated by hemorrhage and development of transfusion-dependent anemia in four patients and grade 3 skin toxicity in three patients. mLGGs of early childhood are often aggressive tumors, resistant to CT, and frequently require alternative treatment. The majority of patients harbor druggable molecular targets and respond to molecular TT.

A randomized trial of topical cannabis balms for the treatment of aromatase inhibitor–associated musculoskeletal syndrome (AIMSS).

e24129 Background: Aromatase inhibitors (AIs) are commonly used for postmenopausal women with hormone receptor positive breast cancer. Nearly 2 of 3 women on AIs complain of AIMSS leading to poor adherence. Preclinical and clinical pilot data suggest topical cannabinoids can reduce inflammation in arthritis. Methods: We conducted a randomized controlled trial assessing the feasibility and acceptability of two different topical medical cannabis balms for AIMSS. Women with stage 1-3 breast cancer with AIMSS [scoring 4 or higher on at least one of the four screening Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affectations of the Hands (M-SACRAH) questions] were eligible. Patients with skin lesions, use of any cannabis in prior 4 weeks, acupuncture, or plans to increase doses of other analgesics were excluded. Women were randomized 1:1 to cannabidiol (CBD) (2210mg CBD/ &lt; 0.3% THC) vs delta-9-tetrahydrocannabinol (THC) (375mg THC/ &lt; 20mg CBD) predominant balm. Participants enrolled in the Minnesota Medical Cannabis Program and were dispensed balms at state-registered dispensaries. 125cc of balm was applied 3 times daily to hands for 2 weeks. M-SACRAH, brief pain inventory (BPI), and NCI Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) measures were captured weekly. Results: 20 women were enrolled from one academic and one community oncology practice in Minnesota over a 10-month period. Reasons patients with AIMSS did not enroll included patient/clinician not interested, AIMSS not meeting M-SACRAH severity, and patient already using cannabis. Adherence to study protocol through week 2 was 85%. Mean age was 54 years, 85% White/15% Asian, 45% received adjuvant chemotherapy, and 50% reported no lifetime cannabis use. Participants reported improvement in M-SACRAH, BPI, and PRO-CTCAE pain scores from baseline to week 2 (Table 1). No skin toxicity was reported by patients. One patient discontinued balm due to greasy texture. Conclusions: Conducting a randomized trial of topical cannabis using state approved dispensaries is feasible. Both THC and CBD predominant topical balms are well tolerated and appear to reduce AIMSS severity in this pilot study of breast cancer survivors. Further confirmatory studies are warranted. Clinical trial information: NCT05935891 . [Table: see text]

Final analysis of the BIMES trial, a phase II single arm study assessing efficacy and safety of bintrafusp alfa in previously treated advanced malignant pleural mesothelioma (GECP 20/09).

8084 Background: Transforming growth factor β (TGF-β) is involved in tumor immune evasion and epithelial–mesenchymal transition (EMT). As TGF-β upregulation and EMT are associated with resistance to anti-PD1 therapy, we evaluated the efficacy of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in malignant pleural mesothelioma (MPM). Methods: Patients with advanced MPM who were previously treated with platinum-based chemotherapy were enrolled and received bintrafusp alfa 1200mg/m2 every 2 weeks until progression or for a maximum of two years. The primary objective was to determine the progression-free survival (PFS) by modified RECIST v1.1. assessed by the investigators. The expected median PFS was 4.5 months. Secondary objectives were overall response rate, duration of response, overall survival (OS) and safety. Results: Between October 2021 to March 2023, 47 patients were enrolled. Mean age was 70 years (41-84) and 36 (78.3%) were males. Most patients had epithelioid histology (82.9%) and had received only 1 prior line of therapy (84.8%). With a median follow-up of 11.5 months, 43 patients had disease progression and 24 patients died. The median number of doses administered was 4 (1-21) and reasons for treatment discontinuation were disease progression (82.6%), toxicity (6.5%), investigator decision (4.4%) and death (6.5%) by tumor progression. The median PFS was 1.9 months (95% CI 1.7 – 5.4) and the 6 month-PFS rate was 15.9%. Disease control rate was 34.8% (95% CI 22.2-49.9) consisting of 2 patients with partial response and 13 patients with stable disease as best response. The median OS was 11.9 months (95% CI 4.4 – not reached) and 6, 12 and 18-month OS rate was 65.3%, 46.5% and 26.6%, respectively. No significant differences in OS and PFS were observed based on MPM histological subtype. Grade 3-4 treatment-related adverse events occurred in 16 (34%) patients, anemia being the most common (n = 5); skin toxicity (n = 3); colitis (n = 2); adrenal insufficiency, acute kidney injury, allergic reaction, lipase, and amylase increased (n = 1 each). Conclusions: Bintrafusp alfa did not reach the expected efficacy in patients with advanced malignant pleural mesothelioma previously treated with platinum-based chemotherapy. Clinical trial information: NCT05005429 .

Real-world effectiveness and safety of amivantamab for exon 20 EGFR-mutant non-small cell lung cancer (NSCLC) in French early access program: Amexon 20 GFPC.

e20529 Background: Amivantamab is a bispecific EGFR/MET antibody approved for patients with NSCLC with EGFR exon 20 insertions. In France, early access has made it possible to use it as a second or further-line treatment after at least one line of chemotherapy. Methods: This is a retrospective multicentric cohort of consecutive patients with an adenocarcinoma and EGFR exon 20 insertions, who received at least one dose of amivantamab as part of the French early access program from September 3th, 2021 (date of approval in the French early access program) until April 30th, 2022. Patients gave consent for the data collection and were enrolled in 28 sites. Primary end point was Real world Progression free Survival (Rw PFS) and secondary endpoints were description of clinical characteristics, best response, duration of treatment, overall survival (OS), CNS activity, toxicities and subsequent treatment. Results: Thirty-nine patients received amivantamab in early French access. Median age was 60 years [39-83]; 64 % of patients were female and 54% never smoker; 33% had PS 2 or more and 66 % had brain metastasis at inclusion. Amivantamab was administered as a second or third line and more in 30% and 70% of patients respectively. Patients received a median number of 10 injections [1-47]. Overall, 37 patients were evaluable for response; response rate was 35 % and disease control rate (DCR) was 62%. After a median follow-up of 11.3 months [8-16.7], median Rw PFS and OS were 3.5 months [2.6-5.8] and 11.3 months [8-17.8] respectively. Rw PFS and OS at 6 months were 33.3% and 74.4% respectively. Duration of response was 5.8 months [2.3-11.9]. Overall, 23 patients were evaluable for CNS response; 26 % had CNS response and CNS DCR was 69%. Main sites of progression were lung (43%), bone (28%), liver (12.8%) and brain (10%). Grade III/IV adverse events were reported in 11 patients (28.2%), mainly skin toxicity (n = 5), infusion reaction (n = 2), digestive disorders (n = 1), interstitial pneumonia (n = 1), neurological disorders (n = 1), fever (n = 1). Amivantamab was permanently discontinued due to toxicities in 4 patients (10.3%). Subsequent treatment was administered to 21 patients (53.8%) after amivantamab, mostly consisting of mono chemotherapy (n = 13). Conclusions: Our real-world multicenter analysis showed that amivantamab was an effective monotherapy treatment in second line and after for patients with EGFR exon 20 insertions. No new toxicities were reported.

Nivolumab combined with radical chemoradiotherapy sparing concurrent cisplatin in high-risk locoregionally advanced nasopharyngeal carcinoma (PLATINUM): An investigator-initiated, open-label, multicenter, single-arm, phase II clinical trial.

6080 Background: The current standard therapy for locoregionally advanced nasopharyngeal carcinoma (LANPC) is radical chemoradiotherapy using induction chemotherapy plus concurrent chemoradiotherapy. However, concurrent cisplatin leads to severe acute (54.0–61.0%) and late (9.2–11.4%) toxicities. We hypothesized that nivolumab combined with radical chemoradiotherapy sparing concurrent cisplatin would obtain promising survival and low toxicity in high-risk LANPC. Methods: In this single-arm, phase II clinical trial (NCT03984357), patients with high-risk LANPC (T4N1M0 or T1–4N2–3M0) were recruited from 7 hospitals in China to receive nivolumab (360 mg once every 3 weeks for 3 cycles [Q3W x 3]) + induction chemotherapy (gemcitabine 1000 mg/m2 + cisplatin 80 mg/m2, Q3W x 3), followed by nivolumab (360 mg, Q3W x 3) + intensity-modulated radiotherapy (PGTVnx, 70Gy/33fx), and thereafter adjuvant nivolumab (480 mg, Q4W x 6). The primary end point was 3-year failure-free survival (FFS), defined as the time from enrollment to any disease failure or death. Secondary end points were safety and quality-of-life (QoL) assessed by cellphone-based EORTC/FACT questionnaires. Results: Between April 2020 and October 2020, 152 patients (median [IQR] age, 49 [39–56] years; 18.4% women) were included. After a median follow-up of 39 months (≥ 36 months, 89.5%), the 3-yr FFS was 88.8% (95% CI, 83.9–94.0%) and the 3-yr overall survival was 98.0%. Sixty (40.2%) patients had grade 3–4 acute treatment-related adverse events (trAEs) throughout treatment; 11 (7.2%) were associated with potential immunologic causes mainly involving hepatic (aspartate aminotransferase increased, 3.3%) and skin toxicities (rash/dermatitis, 2.0%). A total of 123 patients completed all required treatment, including 6 cycles of adjuvant nivolumab, with an overall compliance rate of 80.9%. The incidences of grade 3–4 acute trAEs in the induction, radiotherapy, and adjuvant phases were 30.2%, 16.7%, and 6.0%, respectively; compliance rates, 95.4%, 96.5%, and 91.8%, respectively. Eight (5.2%) patients had grade 3–4 late trAEs, e.g., hearing impaired (3.3%) and dry mouth (0.7%). No treatment-related death was observed. Patients had consistent negative changes in general QoL from baseline between the radiotherapy and induction phases, except for the domains of global health status and physical function/well-being, which were more common during the radiotherapy phase. Conclusions: Nivolumab incorporated into induction chemotherapy followed by radiotherapy has a promising efficacy and low toxicity for high-risk LANPC patients. A phase 3 non-inferior randomized clinical trial assessing PD-1 blockade plus this de-intensified radical chemoradiotherapy is underway (NCT04907370). Clinical trial information: NCT03984357 .

Factors derived from human exfoliated deciduous teeth stem cells reverse neurological deficits in a zebrafish model of Parkinson's disease

Background/purposeMesenchymal stem cells exhibit therapeutic efficacy for brain injury. This study examined the effect of mesenchymal stem cells derived from human exfoliated deciduous teeth (SHED) on alleviating symptoms of Parkinson's disease (PD). Materials and methodsSHED were isolated to examine the biosafety and bioavailability of stem cells derived from human exfoliated deciduous teeth-derived conditioned medium (SHED-CM) for the alleviation of PD symptoms in a 6-hydroxydopamine (6-OHDA)-induced PD zebrafish model. ResultsSHED-CM administration did not induce neurological, skin or muscle toxicity in control zebrafish at any dose, and estrogen equivalent testing showed no chronic toxicants. Induction of PD with 6-OHDA suppressed zebra SHED-CM was administered to zebrafish treated with 6-OHDA to induce PD symptoms. Similar to nomifensine, a drug with proven anti-PD potential, SHED-CM repaired the motor deficiencies in the zebrafish PD model. ConclusionOur results indicate the biosafety of SHED-CM and its therapeutic potential in treating PD in a zebrafish model.

Multi-ethnic genome-wide association study to identify a novel locus for susceptibility to immune-related adverse events from immune checkpoint inhibitors.

3090 Background: Immune-related adverse events (IrAEs) arising from immune checkpoint inhibitors (ICIs) can be unpredictable. As genomic variation underlies both disease susceptibility and drug responses, genomic markers may predict for the development of IrAEs. We perform a pioneering pharmacogenomic study across a multi-ethnic Asian patient population to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: From March 2018 – July 2023, cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital were recruited. IrAEs were characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed by SVS/HelixTree, PLINK and R. Genetic association was performed by logistic regression (additive model), accounting for all possible confounding factors. Bonferroni corrected P &lt; 1.28E-07 (0.05/390,925 SNPs passed QC) was considered statistically significant. Results: Genome-wide association study (GWAS) was conducted amongst 507 patients of Asian Ancestry (Chinese, Malay, Indian and Others). Median age was 63. Majority were male (66.5%), Chinese (76.7%), ECOG PS 0-1 (40.1%) and had stage IV cancer at diagnosis (67.2%). Non-small cell lung cancer (37.1%), renal cell carcinoma (12.2%) and hepatocellular carcinoma (7.7%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, durvalumab and atezolizumab, respectively (47.1%, 23.9%, 12.5%, 11.3%). 0.8% of patients received dual ICIs concurrently. Median duration of treatment was 142 days and median follow-up was 147 days. IrAEs were seen in 43.7% of patients. Skin (24.1%), endocrine (8.1%) and hepatotoxicity (6.1%) were the most common IrAEs. 4.9% of patients had grade ≥3 toxicity, of which skin (3.6%), hepatotoxicity (3.0%) and pulmonary toxicity (1.8%) were the most common. Multi-ethnic GWAS analysis identified one potential novel genetic locus associated with CTCAE grade ≥3 IrAEs. chr3:163402331 rs146525069; P = 7.29E-08, OR (95%CI) = 17.08 (5.40- 54.04); minor allele = A, 10.91% in Cases vs 0.71% in Controls. Conclusions: This pharmacogenomics GWAS uncovered a novel locus for susceptibility to serious immune-related adverse events from immune checkpoint inhibitors. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing. Our study provides a potential biological mechanism for IrAEs and a step towards more effective clinical translation of pharmacogenetic testing to personalize ICI use.

The IMRiS Trial: A Phase 2 Study of Intensity Modulated Radiation Therapy in Extremity Soft Tissue Sarcoma

PurposePrimary soft tissue sarcoma (STS) is rare, with many tumours occurring in extremities. Local management is limb-sparing surgery and pre-operative/post-operative radiotherapy (RT) for patients at high risk of local recurrence. We prospectively investigated late normal tissue toxicity and limb function observed after intensity modulated RT (IMRT) in extremity STS. Methods and MaterialsPatients with extremity STS, age ≥16 years. Two treatment cohorts: IMRT 50Gy in 25 × 2Gy fractions (pre-operative) or 60/66Gy in 30/33 × 2Gy fractions (post-operative). Primary endpoint was rate of ≥ grade 2 late subcutaneous fibrosis at 24 months after IMRT (RTOG late radiation morbidity scoring). ResultsOne hundred and sixty-eight patients were registered between March 2016-July 2017. Of those, 159 (95%) received IMRT (106, 67% pre-operative RT and 53, 33% post-operative RT) with a median follow-up of 35.2 months (IQR: 32.9 to 36.6); 62% male; median age 58 years. Of 111 patients assessable for primary endpoint at 24 months, 12 (10.8%, 95%CI: 5.7%-18.1%) had ≥ grade 2 subcutaneous fibrosis. The overall rate at 24 months of RTOG late skin, bone and joint toxicity was 7/112 (6.3%), 3/112 (2.7%) and 10/113 (8.8%), respectively, and for Stern's scale oedema was 6/113 (5.3%). More wound complications were observed with pre-operative than post-operative RT (29.2% vs 3.8%). Overall survival at 24 months was 84.6%, and local recurrence event rate at 24 months was 10%. ConclusionsThe rate of ≥ grade 2 subcutaneous fibrosis at 24 months after IMRT was 10.8%, consistent with other recent trials of IMRT, and lower than historical reported rates in patients treated with 3D-CRT. This trial provides further evidence for the benefits of IMRT in this patient population.

Genetic drivers of severe skin toxicity with immune checkpoint inhibitors (ICIs) in Asian patients.

2667 Background: ICIs may cause severe skin toxicity associated with significant patient (pt) impact. Published data suggests Asian pts might be at higher risk of skin immune-related adverse events (SirAEs). Variation in human leukocyte antigen (HLA) is known to predispose to autoimmune (AI) conditions, but there is limited data to understand genetic drivers of severe SirAEs. Methods: The incidence of severe SirAEs was correlated with 30 HLA alleles of interest in 2 cohorts totaling 18 Asian pts (Dermatitis bullous n=4, Erythema multiforme n=10, Stevens-Johnson syndrome n=3, Toxic skin eruption n=1) treated with atezolizumab (A) across tumor types as monotherapy or as part of combinations- 8 Japanese pts received A in a non-interventional study (trial ID: UMIN000048702) and 10 Asian pts were enrolled in Roche trials with A. Data from the 18 cases was compared to 3 different controls of Asian pts identified from Roche trials with A (i.e. pts without any irAEs n=148, pts without SirAEs n=225, pts without severe SirAEs n=390). For each HLA allele, positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity, (unadjusted) odds ratio (OR) and corresponding 95%-confidence interval (CI) were evaluated. Case-control populations were obtained by risk-set sampling with exact matching on indication, treatment arm and sex, and used in age-adjusted conditional logistic regression models to assess associations between each HLA allele and severe SirAEs. Results: There was an association between some HLA alleles and severe SirAEs, but sensitivity was low (&lt;30%) and 1-NPV was only slightly smaller than background prevalence. Results for five HLA alleles with OR&gt;1.5 in either the unadjusted or adjusted analysis compared to controls without severe SirAEs are presented in table. Results were consistent across the three control populations. Conclusions: Five HLA alleles previously reported in AI disorders were associated with severe SirAEs in Asian pts receiving A. Although the effect size is insufficient to be considered clinically relevant, further research is warranted to better characterize the pt-level drivers of severe SirAEs in Asians pts. Clinical trial information: UMIN000048702 . [Table: see text]

Correlation between irAEs and treatment efficacy of anti-PD-1 single agent in patients with recurrent/metastatic head and neck squamous cell carcinoma: A monocentric real-world observational study.

6029 Background: Immune-related adverse events (irAEs) are associated with efficacy of ICIs-based treatment in various cancer types. The aim of this retrospective study was to assess the relationship between irAEs and outcomes in patients with recurrent/metastatic Head and Neck squamous cell carcinoma (R/M-HNSCC) treated with immune checkpoint inhibitors (ICIs) monotherapy. Methods: We retrospectively reviewed data from patients with R/M HNSCC treated with ICIs single-agent between January 2018 and June 2023 at the Istituto Oncologico Veneto of Padua. Common Terminology Criteria for Adverse Events v.5.0 was used to assess irAEs evaluation. Patients were stratified into irAEs (any grade) and non-irAEs groups. Overall survival (OS) and progression free survival (PFS) were assessed using the Kaplan-Meier method. Univariate and multivariate Cox-regression were used to compare survival outcomes. The chi-square test was used to assess the association between irAEs and objective responses (ORR). Results: A total of 89 patients were eligible for the analysis. Patients with platinum-refractory disease received nivolumab (64 patients, 72%). All the 25 patients (28%) with platinum-sensitive disease were PD-L1 positive (CPS≥1) and received pembrolizumab as first line treatment for R/M disease. Median follow-up was 8.7 months. IrAEs (any grade) were observed in 60 patients (67%), including 9 patients (10%) with grade ≥3 AEs. The most common irAEs were endocrinopathies (35%), skin events (15%), hepatic events (13%), diarrhea/colitis (10%) and lipase/amylase elevation (10%). The ORR was higher in the irAEs group than in the non-irAEs group (19.5% vs 2%, p=0.017). PFS and OS were also significantly longer in the irAEs group: median PFS was 3.9 months vs 2.1 months (HR 0.48 95% CI 0.30-0.77; p=0.003) and median OS was 12.5 months vs 4.3 months (HR 0.36 95% CI 0.21-0.60; p=0.000). The statistically significant benefit for both PFS and OS was confirmed at the multivariate analysis (Table1). Patients who experienced endocrine-related irAEs (p=0.004), diarrhea/colitis (p=0.040) and lipase/amylase increase (p=0.005) had significantly longer OS than those without the corresponding toxicity. A positive trend was observed for skin toxicity (p=0.051). Conclusions: The occurrence of irAEs was a predictor of response and survival outcomes in patients with R/M HNSCC treated with ICIs single-agent.[Table: see text]

Results of a retrospective study on the efficacy and safety of alpelisib in patients with HR+/HER2- metastatic breast cancer in real-world clinical practice.

e13058 Background: The combination of alpelisib and fulvestrant is an optimal therapy option for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer with PIK3CA gene mutations. The aim of this work to retrospectively analyze the efficacy and safety of alpelisib in real-world clinical practice in patients with pre-treated luminal HER2– negative metastatic breast cancer. Methods: The study included an analysis of 33 patients with widespread luminal HER2- negative breast cancer with detected PIK3CA gene mutation. The median age was 57 ± 13 months (95% CI 52-62). In 12 (36.4%) patients, the PIK3CA gene mutation was detected in exon 9, and in 21 (63.6%) – in exon 20. Alpelisib was prescribed to pre-treated patients in different lines. Most women (32/33; 97%) had received ET combined regimens with CDK4/6 inhibitors before starting alpelisib therapy: 14 (42.4%) patients underwent palbociclib therapy in combination with fulvestrant; 4 (12.1%) – palbociclib with aromatase inhibitors; 13 (39.5%) – ribociclib in combination with fulvestrant; 1 (3.0%) – ribociclib with aromatase inhibitors. It is important to note that 63.6% of patients had previous progression on fulvestrant monotherapy and 72.7% on aromatase inhibitor therapy. Patients with luminal B-subtype of breast cancer dominated - 72.7% (24/33). Results: The median overall survival (OS) in this study was 14 ± 2.5 months (95% CI: 9-18.9), and the median progression-free survival (PFS) was 6 ± 2.7 months (95% CI: 0.7-11.3). The rate of objective response was 30.3%, and prolonged disease stabilization was observed in 24.2% of cases. Prognostic factors were brain metastases (increasing the risk of death by 18 times) and discontinuation of the drug for any reason (increasing the risk of death by 8 times). It should be noted that the main reason for discontinuation or disruption of the drug's timing was unmanageable toxicity. All patients registered adverse events of varying degrees, with 21 (63.6%) patients experiencing hyperglycemia (grade 3-4 – 30.3%) and 14 (42.4%) patients experiencing skin toxicity (grade 3-4 – 15.2%). In the SOLAR-1 study, the frequency of hyperglycemia was comparable (64.8%), and rash was noted in a third of all patients, which is comparable to our data. Conclusions: The results of using alpelisib with fulvestrant confirm its effectiveness in real-world clinical practice in patients with pre-treated HR+HER2- negative widespread breast cancer with the presence of somatic PIK3CA gene mutation. Brain involvement is an unfavorable prognostic factor in patients with PIK3CA mutation and increases the risk of death by 18 times, requiring the need to optimize the therapeutic algorithm, including through radiation methods. Discontinuation of the drug, which increases the risk of death by 8 times.

With eyes on the future: Prospective evaluation of immune-related adverse events in patients with lung cancer.

e23177 Background: Immune checkpoint inhibitors (ICIs) bear unique, time-dependent immune-related adverse events (irAEs). However, limited data exist regarding tolerability in real-world populations. We report interim, non-sex stratified results of the first study prospectively evaluating ICI tolerability in patients with lung cancer (LC) in a real-world setting. Methods: Recruitment began in July 2023 and is ongoing. The electronic Patient-Reported Outcomes version of the Common Terminology Criteria (PRO-CTCAE) was utilized to assess patients’ irAEs. Patients (pts) complete up to 6 questionnaires throughout their treatment plus an end of treatment evaluation. Inclusion criteria includes pts ≥18 years, with LC stage I to IV, receiving single-agent ICI at Dana-Farber Cancer Institute. Descriptive statistics summarized patients' demographics, clinical characteristics, and symptoms. Results: 36 pts were enrolled in the study as of January 23, 2024. 35 pts have completed their first PRO-CTCAE questionnaire; the median number of completed questionnaires was 2 (range: 1-6). Due to the current sample size, results reported reference pts’ first PRO-CTCAE assessment. 53% of pts identified as female, 92% identified as White, and 6% as Black (Table 1). 56% of pts (19/34) reported having shortness of breath (SOB), most of whom (63%; 12/19) reported having moderate to severe SOB that often (somewhat to very much; 42%; 8/19) interfered with daily activities; 21% of them (4/19) stated that the SOB had worsened since starting ICIs. Similarly, of the 54% (19/35) with a cough, 42% (8/19) reported a moderate to very severe cough and 16% (3/19) reported its worsening since ICI initiation. 14 pts reported anorexia secondary to treatment, with most of them (57%; 8/14) reporting that it interfered with daily activities. Most pts (79%; 27/34) noted some degree of lack of energy. Rates of skin toxicity were low, with only 6% (2/35) experiencing a rash after beginning ICIs. Many pts did not experience nausea, abdominal pain, or unexpected sweating (80%; 28/35, 83%; 29/35, 77%; 27/35). However, of the pts reporting nausea and abdominal pain, high severity of these symptoms was noted (43%; 3/7, 50%; 3/6). Other low frequency irAEs included diarrhea, dry mouth, and dysgeusia. Conclusions: SOB and cough were the most common symptoms experienced with high severity in this ongoing prospective evaluation of irAEs in pts with LC. Though nausea and abdominal pain were less common, when present, these symptoms were reported with high severity. Future data from this study will elucidate patient experiences with irAEs throughout their treatment course. [Table: see text]

Acute skin toxicity and self-management ability among Chinese breast cancer radiotherapy patients: a qualitative study

ObjectivesRadiation dermatitis is the most common reaction to radiotherapy, almost all breast cancer patients receive radiotherapy on an outpatient basis. Currently, there are no studies on the experience of radiation dermatitis and the ability to self-manage it. Therefore, we aimed to use qualitative approaches to gain a deeper understanding of the actual experiences and self-management ability in order to provide a reference for further improving the effectiveness of self-management and to optimize symptom management strategies.MethodsA descriptive qualitative study was conducted using purposive sampling to select 17 breast cancer patients undergoing radiotherapy. Semi-structured interviews were conducted from September to November 2023. The Colaizzi seven-step analysis method was used to classify the data into summarized themes.ResultsFour themes were identified from the interview responses: (1) multiple self-reported skin symptoms in breast cancer patients with radiation dermatitis; (2) the multidimensional impact on patient’s quality of life, especially pruritus, ulceration; (3) the ability to self-manage radiation dermatitis: strong mental toughness, positive response, and self-doubt; (4) challenges faced: concerns about radiotherapy side effects and recurrence, targeted symptom management and continuity of care after the radiotherapy.ConclusionsHealthcare professionals should consider patients’ self-reported symptoms when assessing radiation dermatitis. For pruritus and pain, we can enhance precision symptom management to improve patients’ quality of life. By utilizing information technology tools, we can increase breast cancer patients’ ability and confidence in managing radiation dermatitis effectively while enhancing accurate symptom management during radiotherapy.

The impact of bolus on clinical outcomes for post-mastectomy breast cancer patients treated with IMRT: data from China

PurposeThis study aims to investigate the effects of chest wall bolus in intensity-modulated radiotherapy (IMRT) technology on clinical outcomes for post-mastectomy breast cancer patients.Materials and methodsThis retrospective study included patients with invasive carcinoma ((y)pT0-4, (y)pN0-3) who received photon IMRT after mastectomy at the Affiliated Hospital of Qingdao University from 2014 to 2019. The patients were divided into two groups based on whether they received daily bolus application or not, and the baseline characteristics were matched using propensity score matching (PSM). Cumulative incidence (CI) of local recurrence (LR), locoregional recurrence (LRR), overall survival (OS) and disease-free survival (DFS) were evaluated with a log-rank test. Acute skin toxicity and late radiation pneumonia was analyzed using chi-square test.ResultsA total of 529 patients were included in this study, among whom 254 (48%) patients received bolus application. The median follow-up time was 60 months. After matching, 175 well-paired patients were selected. The adjusted 5-year outcomes (95% confidence interval) in patients treated with and without bolus were, respectively: CI of LR 2.42% (0.04–4.74) versus 2.38% (0.05–4.65), CI of LRR 2.42% (0.04–4.74) versus 3.59% (0.73–6.37), DFS 88.12% (83.35–93.18) versus 84.69% (79.42–90.30), OS 94.21% (90.79–97.76) versus 95.86% (92.91–98.91). No correlation between bolus application and skin toxicity (P = 0.555) and late pneumonia (P = 0.333) was observed.ConclusionsThe study revealed a low recurrence rate using IMRT technology. The daily used 5 mm chest wall bolus was not associated with improved clinical outcomes.

Delayed onset skin toxicity reaction after peripherally inserted central catheter rupture in lower extremities combined with chemotherapy.

Herein, we present a patient who was undergoing chemotherapy for bilateral breast cancer and experienced delayed-onset skin toxicity reactions after rupture of a peripherally inserted central catheter (PICC) in the lower extremities. The objective of this case report is to provide the necessary nursing assessment for the risk awareness of the PICC internal rupture and the occurrence of central venous catheter extravasation, as well as to strengthen the judgment of delayed skin toxicity of chemotherapeutic drugs. Rupture of the PICC in the lower extremities was primarily attributed to the use of a silicone catheter and an excessive puncture angle. The nature of docetaxel and partial catheter rupture caused drug extravasation, leading to delayed skin toxicity. The use of a polyurethane catheter reduces the incidence of catheter rupture; hence, silicon catheters should be avoided. The central venous catheter is also at risk for the extravasation of chemotherapeutic agents. Moreover, docetaxel-induced delayed skin toxicity, which has a high incidence, should be treated as expected. Nurses and clinicians should be aware of PICC internal rupture and central venous catheter extravasation to strengthen the judgment of delayed skin toxicity of chemotherapeutic drugs.

Continuous response despite reduced dose of trametinib as single agent in an adolescent with a relapsed disseminated pediatric low-grade glioma KIAA1549-BRAF fusion positive: a case report and review of the literature

Dissemination in pediatric low-grade glioma may occur in about 4%–10% of patients according to retrospective cohort studies. Due to its low incidence, there is no consensus on treatment for these patients. According to the constitutional activation of the MAPK/ERK pathway in these tumors, MEK inhibitors such as trametinib have been used successfully in the relapsed setting. Skin toxicity is frequent in patients receiving trametinib, normally mild to moderate, but sometimes severe, needing to discontinue the drug, limiting the efficacy in the tumor. There is not much information in the literature regarding whether reducing the dose of trametinib is able to maintain efficacy while, at the same time, decreasing toxicity. Here, we present an adolescent, with severe skin toxicity, whose trametinib dose was reduced by 50% and efficacy on the tumor continued while skin toxicity significantly decreased.

Rechallenge with Anti-EGFR Treatment in RAS/BRAF wt Metastatic Colorectal Cancer (mCRC) in Real Clinical Practice: Experience of the GITuD Group.

There are few third- and fourth-line therapeutic options for metastatic colorectal cancer (mCRC). In RAS/BRAF wild-type (wt) mCRC previously treated with anti-epidermal growth factor receptor (anti-EGFR) (first-line) and relapsed after a good response, retreatment with anti-EGFR (rechallenge) emerges as a therapeutic alternative. The aim was to show the activity and safety of anti-EGFR rechallenge in RAS/BRAF wt mCRC in real-world practice. A multicenter, retrospective, observational study (six hospitals of the Galician Group of Research in Digestive Tumors) was conducted. Adult patients with RAS/BRAF wt mCRC, evaluated by liquid biopsy, were included. They received anti-EGFR rechallenge (cetuximab, panitumumab) as monotherapy, or combined with chemotherapy, in third- or subsequent lines. Efficacy (overall response rate [ORR], disease control rate [DCR], overall survival [OS], and progression-free survival [PFS]) and safety (incidence of adverse events [AEs]) were assessed. Thirty-one patients were analyzed. Rechallenge (median 6 cycles [range 1-27], mainly cetuximab [80.7%]), started at a median anti-EGFR-free time of 18.4 months (1.7-37.5months) after two (38.7%) or more (61.3%) lines of treatment; 64.5% of patients received a full dose. Median OS and PFS were 9.8 months (95% confidence interval [CI] 8.2-11.4) and 2.6 months (95% CI 1.7-3.4), respectively. ORR was 10%, and DCR was 30%. The most common AEs were diarrhea (35.5%), anemia (29%), emesis (6.4%), and neutropenia (6.4%); <5% grade ≥3; 48.4% of patients reported anti-EGFR-related skin toxicity (grade >1). Hypomagnesemia required supplements in 29% of patients. Dose delays (≥3 days) and reduction (≥20%) were reported in 11 (35.5%) and seven patients (22.6%), respectively. In RAS/BRAF wt mCRC patients, an anti-EGFR rechallenge provides a feasible therapeutic option with clinical benefit (survival) and a manageable safety profile.

Dosimetric evaluation of different planning strategies for hypofractionated whole-breast irradiation technique

Purpose. The dose hotspot areas in hypofractionated whole-breast irradiation (WBI) greatly increase the risk of acute skin toxicity because of the anatomical peculiarities of the breast. In this study, we presented several novel planning strategies that integrate multiple sub-planning target volumes (sub-PTVs), field secondary placement, and RapidPlan models for right-sided hypofractionated WBI. Methods. A total of 35 cases of WBI with a dose of 42.5 Gy for PTVs using tangential intensity-modulated radiotherapy (IMRT) were selected. Both PTVs were planned for simultaneous treatment using the original manual multiple sub-PTV plan (OMMP) and the original manual single-PTV plan (OMSP). The manual field secondary placement multiple sub-PTV plan (m-FSMP) with multiple objects on the original PTV and the manual field secondary placement single-objective plan (m-FSSP) were initially planned, which were distribution-based of V105 (volume receiving 105% of the prescription dose). In addition, two RapidPlan-based plans were developed, including the RapidPlan-based multiple sub-PTVs plan (r-FSMP) and the RapidPlan-based single-PTV plan (r-FSSP). Dosimetric parameters of the plans were compared, and V105 was evaluated using multivariate analysis to determine how it was related to the volume of PTV and the interval of lateral beam angles (ILBA). Results. The lowest mean V105 (5.64 ± 6.5%) of PTV was observed in m-FSMP compared to other manual plans. Upon validation, r-FSSP demonstrated superior dosimetric quality for OAR compared to the two other manual planning methods, except for V5(the volume of ipsilateral lung receiving 5 Gy) of the ipsilateral lung. While r-FSMP showed no significant difference (p = 0.06) compared to r-FSSP, it achieved the lowest V105 value (4.3 ± 4.5%), albeit with a slight increase in the dose to some OARs. Multivariate GEE linear regression showed that V105 is significantly correlated with target volume and ILBA. Conclusions. m-FSMP and r-FSMP can substantially enhance the homogeneity index (HI) and reduce V105, thereby minimizing the risk of acute skin toxicities, even though there may be a slight dose compromise for certain OARs.