Compassionate Use Research Articles

Real-world experience of larotrectinib in children, adolescents and young adults with TRK fusion solid tumors in France.

10056 Background: Larotrectinib is an FDA and EMA approved TRK inhibitor for TRK fusion solid tumors in patients with locally advanced or metastatic disease, or where surgical resection is likely to result in severe morbidity. Here we report the real-world activity and safety data on compassionate use and post-marketing authorization of larotrectinib collected in the SACHA-France study (NCT04477681), following the French Health Technology Assessment institution (HAS) request. Methods: All larotrectinib prescriptions made in France outside clinical trials since April 2019 for patients’ < 25 years-old were registered in the SACHA-France study. Safety and activity data were collected, with data cut-off of 23/01/2024. SACHA-France is open in all 31 French Society of Pediatric Oncology (SFCE) centers, it is approved as a real-world data source by the HAS and supported by the French National Agency for the Safety of Medicines and Health Products (ANSM). Results: 21 patients were included (4 compassionate use, 17 post-marketing authorization). Main cancer types were soft-tissue sarcomas (n=13, of them 7 infantile fibrosarcoma), followed by central nervous system (CNS) tumors (n= 7), and other solid extra-CNS tumors (n=1). All patients except one had a TRK fusion tumor: NTRK3 (n=10), NTRK2 (n=6, all CNS tumor) and NTRK1 (n=4). Median age at start of larotrectinib was 2.8 years (range: 0.2 -21.1). Ten patients had received no prior systemic therapy. Main reasons to start larotrectinib were to avoid mutilating surgery (n=9) and disease progression (n=9). Best objective response was reported as partial response in 13 out of 19 patients with evaluable disease (10/12 patients with soft tissue sarcomas, 2/6 patients with CNS tumors), with median time to response of 57 days. Of them, five patients with soft tissue sarcomas achieved a complete response after non mutilating surgery. Median treatment duration was 219 days (range: 10-1368, 5 patients still on therapy). Seven patients with soft tissue sarcomas stopped larotrectinib, after a median duration of 242 days (range: 122-1190), three of them after tumor surgery; none presented with tumor recurrence (follow-up: 350 days; range 40-636). At data cut-off, 8 patients had disease progression on-therapy (5/7 CNS tumors, 3/13 soft tissue sarcomas), with a NTRK resistance mutation identified in 2 out 3 patients with tumor biopsy. Adverse drug reaction (ADR) were reported in 2/21 patients (9%), including a grade 2 weight gain and a grade 3 neutrophil count decreased (1 patient each). Both ADRs were expected and required neither corrective treatment nor action on larotrectinib. Conclusions: Our real-world data confirm the favorable safety profile of larotrectinib with rapid and durable tumor-agnostic efficacy.

Baseline PSMA PET/CT as a predictive biomarker for toxicity and patient-reported outcomes in mCRPC patients undergoing 177Lu-PSMA radioligand therapy.

e17058 Background: The phase III VISION trial demonstrated that 177Lu-PSMA-617 (PSMA-RLT) prolonged overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). Common side effects of PSMA-RLT include xerostomia, bone pain, and myelosuppression. The objective of this study is to evaluate the role of baseline PSMA PET/CT (bPET) in predicting hematologic toxicity and patient-reported outcomes in mCRPC patients undergoing PSMA-RLT. Methods: Patients treated with 177Lu-PSMA-617 in the Expanded Access Program at UCLA with available bPET, toxicity data, and patient-reported outcomes (BPI, FACT-P, and Xerostomia Questionnaire) were included in this retrospective analysis. TRAQinform IQ technology (AIQ Solutions-Madison, WI) was used to conduct region of interest (ROI)-based analyses at bPET. SUVmean, SUVmax, volume (cm3), and total lesion PSMA (TLP; SUVmean x volume) of the whole-body tumor burden, healthy bone, and the salivary glands were extracted. We evaluated the following associations: 1) Whole-body tumor parameters on bPET with time to worsening of FACT-P scores (defined as a decrease of >10 points from baseline) and time to first occurrence of Grade 3 or 4 hematologic toxicity (Multivariate Cox regression model); 2) Healthy bone parameters on bPET with time to worsening of BPI Pain Severity and Pain Interference scores (defined as a 30% increase or at least 2 points from baseline) and time to first occurrence of Grade 3 or 4 hematologic toxicity (Multivariate Cox regression model); 3) Salivary gland parameters on bPET with Xerostomia Questionnaire scores (Mixed-effect linear regression model). Results: 61 mCRPC patients were included. When evaluating associations between healthy bone SUVmean, SUVmax, and TLP with time to first occurrence of Grade 3 or 4 hematologic toxicity, baseline hemoglobin was associated with a longer time to first occurrence (HR = 0.61, p = 0.005; HR = 0.59, p = 0.002; HR = 0.62, p = 0.005 respectively). When evaluating associations between bPET and time to worsening of FACT-P scores, whole-body tumor SUVmean, SUVmax, and TLP were associated with a longer time to worsening (HR = 0.74, p = 0.033; HR = 0.82, p = 0.01; HR = 0.91, p = 0.028 respectively). When evaluating associations between salivary gland SUVmean, volume, SUVmax, and TLP with Xerostomia Questionnaire scores, the number of cycles was associated with higher scores (mean estimate: 0.63, p = 0.003; mean estimate: 0.64, p = 0.003; mean estimate: 0.64, p = 0.003; mean estimate: 0.63, p = 0.003 respectively). Conclusions: In this retrospective analysis of 61 mCRPC patients treated with PSMA-RLT, bPET parameters were generally not predictive of hematologic toxicity or patient-reported outcomes. Of note, whole-body tumor SUV was associated with a longer time to worsening of FACT-P scores. Validation in a larger, prospective cohort is warranted.

Efficacy and toxicity of [177Lu]Lu-PSMA-617 for metastatic castration-resistant prostate cancer in a real-world setting: Results from the U.S. Expanded Access Program and comparisons with phase 3 VISION data.

Efficacy and toxicity of [¹⁷⁷Lu]Lu-PSMA-617 for metastatic castration-resistant prostate cancer in a real-world setting: Results from the U.S. Expanded Access Program and comparisons with phase 3 VISION data.

Mind the gap: Estimating the opportunity lost due to the gap between FDA and EMA cancer drug approvals.

11030 Background: Drug regulators operate on their own timelines to assess the safety and efficacy of new drugs and/or extensions to existing indications, such that there are delays between regulators. During such a gap, patients in the “early” domain have access to the approved drug, while those in the “late” domain do not, outside of compassionate use. Our study aimed to quantify the “opportunity lost” for new therapies approved by FDA and EMA, assuming patients in the late domain receive standard-of-care (SOC) therapy – which is presumably inferior to the new drug – during the gap. Methods: Anticancer drugs approved by both FDA and EMA were identified through the HemOnc knowledgebase. Inclusion criteria included: 1) drugs approved in both domains based on the same randomized clinical trial (RCTs) for the same indication; 2) a primary time-to-event endpoint; and 3) a quantitated median time-to-event for the primary endpoint. For each included trial, the approval gap between FDA and EMA in days and the ratio of approval gap to median control arm time-to-event duration was calculated. A ratio ≥2 implies that, on average, no late domain patients starting treatment in the first half of the gap would be expected to have access to the new drug prior to an event. Results: Of 60 eligible RCTs, 59 had calculable median event durations. 25 (42%) had a primary overall survival endpoint; the most common surrogate endpoint was progression-free survival (PFS; 29/59; 49%). The median (interquartile range [IQR]) approval gap was 186 (124-271) days, with FDA being the first approver in 56/59 (95%) cases. The median (IQR) ratio of approval gap to median control arm event duration was 0.63 (0.35-1.11). Drugs with ratio ≥2 (Table) were targeted or immunotherapies; 7/8 (88%) were approved with PFS endpoint; 5/8 (62.5%) were approved for second line or later. Conclusions: Our study shows that FDA approves most drugs prior to EMA and a nontrivial number of patients may experience progression or death events while awaiting access to anticancer therapies already approved in another domain. The analysis does not take into consideration scenarios in which the new therapy is inferior to SOC or delays in patient access (due to slow uptake; regulatory barriers [in Europe/UK]; or patient affordability [in US]). Further regulatory collaboration (e.g., Project Orbis) between FDA and EMA could help to reduce and potentially ameliorate this differential in access to new cancer drugs in the future. [Table: see text]

A multicohort platform trial to improve drug access for pediatric cancer patients in Japan: The PARTNER trial (NCCH2220).

TPS10079 Background: In Japan, there are no pediatric regulations that encourage drug development for pediatric cancer, such as Pediatric Investigation Plans (PIPs) which are mandated in Europe, or the RACE Act in the U.S. Therefore, there are fewer early-phase clinical trials and approved drugs for pediatric cancer than in Western countries. In addition, because there is no rapid compassionate use program, there are delays when using an unapproved drug. According to a report from the Japanese cancer genome profiling (CGP) testing data center, C-CAT, 51.3% of pediatric patients with solid tumors had targetable genetic abnormalities. However, only 5.8% of them had access to the recommended molecular targeted therapy (Tanimura K. et al., presented at the Japanese Society of Pediatric Hematology and Oncology annual meeting 2022). Thus, Japanese pediatric patients with relapsed or refractory solid tumors have limited access to novel drugs, even if they have druggable mutations. Therefore, we designed a platform study (NCCH2220, PARTNER trial) to rapidly deliver molecularly targeted drugs based on CGP testing. Methods: This study has two objectives: first, to administer some drugs to pediatric patients that are not approved for pediatric cancer in Japan. These drugs have been shown to be safe in pediatric patients in foreign countries and are expected to be effective. Second, to evaluate the safety and efficacy of the drug in Japanese pediatric patients and, if necessary, its pharmacokinetics. These data will be used for potential future regulatory filings. This is an open-label, multicenter, multicohort study. Eligible patients are aged 0–29 years with diseases having no standard therapy, which are refractory, or when there is intolerance to standard therapy. The study drug must be recommended for the patient by CGP testing or approved for pediatric use for their disease in the U.S. or Europe, or approved in Japan for use in adults only. The drugs are used as monotherapy in the study. The study schedules follow a master protocol. Up to 30 patients can be enrolled in each cohort. The primary endpoint is the incidence of dose-limiting toxicity in each cohort. The secondary endpoints are the incidence of adverse events, the overall response rate, and, if necessary, the pharmacokinetics in each cohort. As of January 2024, the study had five treatment cohorts with the following agents: imatinib, pazopanib, ruxolitinib, trametinib, and atezolizumab. Additional cohorts will be added. We started planning the study in November 2022, and enrollment began on January 18, 2024. This platform trial has enabled us to deliver drugs to patients more quickly and efficiently than by conducting individual early-phase trials for each drug. Clinical trial information: jRCTs031230544 .

Project Facilitate: An analysis of the increased utilization in the oncology single patient expanded access pathway.

11029 Background: FDA Oncology Center of Excellence’s (OCE) Project Facilitate (PF) was launched in June 2019 in response to perceived barriers providers face when accessing Expanded Access (EA). PF staff provide step-by-step support to oncology healthcare providers requesting use of investigational drugs to treat their patients with cancer. Since launch, PF has received an increased number of oncology single patient EA applications each calendar year. An analysis of single patient investigational new drug applications (IND) received was performed over each calendar year, starting June 1, 2020. Methods: Data was extracted from PF’s central database between June 1, 2020 and December 31, 2023. Data collected included IND receipt date, granting date, status, application type, indication, drug name, address of requestor, and patient demographics. The starting date of June 1, 2020 was chosen since it was when PF staff officially started performing clinical review of applications. Results: Of the 2791 oncology single patient expanded access applications extracted, there were 681 (24.4%) emergency INDs (eIND) and 2110 (75.6%) non-emergency single patient INDs (SPI). Applications received by calendar year increased since June 1, 2020 to December 31, 2020 (397, 14.2%), 2021 (682, 24.4%), 2022 (822, 29.5%), and 2023 (890, 31.9%). The top-3 disease areas requested include high grade glioma (262, 9.4%), multiple myeloma (213, 7.6%), and melanoma (186, 6.7%). The top-3 disease areas requested in pediatric patients < 17 years of age (568, 20.4%) include AML (88, 15.5%), high grade glioma (85, 15%), and ALL (47, 8.3%). Race and ethnicity information was provided in 32 applications containing white/Caucasian (24, 75%), Black or African American (4, 12.5%), Asian (2, 6.25%), and Hispanic or Latino (2, 6.25%). Applications were received from 46 states and 1 US territory, Puerto Rico. The top 3 states requestors resided in were CA (346, 12.4%), NY (317, 11.4%), and TX (276, 9.9%). Although rare, 22 (0.79%) applications were denied or placed on clinical hold most commonly due to curative or established therapies being available. Conclusions: Project Facilitate saw a 20.4% increase in oncology single patient expanded access requests received from calendar year 2021 compared to 2022 and an 8.3% increase from 2022 to 2023, equaling a 30.4% increase in 2023 compared to 2021. [Table: see text]

Impact of next generation sequencing in high grade glioma management.

e14031 Background: Recent advances in genomic profiling have improved our understanding of the molecular pathogenesis of high grade gliomas. Increased availability of high-throughput Next Generation Sequencing (NGS) allows the identification of genetic alterations which could direct personalized cancer treatments for HGG patients. Methods: All patients with high grade glioma (WHO Grade ≥3 glioma by 2016 or 2022 classification) in our institution, who underwent NGS testing between 2019-2023, were identified from a prospectively maintained electronic database. NGS results, from the Oncomine Precision Assay, a multi-gene panel which tests for 50 different mutations, were collated. Medical records were systematically reviewed to collect demographic, treatment and survival data. Alterations detected on NGS were characterized using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Results: 53 patient samples underwent NGS testing (34 males [64%]; 19 females [36%]). Median age at diagnosis was 52 years (range: 20-72 years). Thirty patients (57%) had an ECOG PS 1 at first clinical review. 18 tumors (34%) were found to have MGMT promoter hypermethylation. 28 patients (53%) were found to have potentially actionable alterations according to the ESCAT scale; 19 (35%) EGFR mutations (ESCAT IIIA level evidence) were detected, 5 PIK3CA (9%) mutations (ESCAT IIIA), 3 FGFR3 (6%) alterations (ESCAT IIB), 2 patients with CDK 4 (4%) copy number gain (ESCAT IIIA), 2 PTPRZ1-MET (4%) fusions (ESCAT IIIA) and 1 BRAF V600E (2%) mutation (ESCAT IB). 4 patients were found to have multiple mutations on NGS. 1 sample had insufficient tissue for analysis. 2 patients (4%) were considered for targeted therapy based on NGS results (1 BRAF V600E mutation and 1 FGFR3 alteration) but both deteriorated in advance of commencing treatment. One patient received nivolumab for MSI-H recurrent GBM (ESCAT IIIB) but progressed within 3 months of commencing treatment. Conclusions: Despite advances in our understanding of the pathogenesis of these high grade gliomas and improved awareness of molecular targets, the delivery of targeted therapy to patients with HGG remains challenging. Rapid access to targeted therapy via compassionate access programmes and improved availability and access to clinical trials for patients with rare cancers and molecular alterations, is paramount.

Plastic Surgery Outreach Clinics Expand Access to Cleft and Craniofacial Care in Mississippi

Abstract Accessing treatment at ACPA (American Cleft Palate-Craniofacial Association)–approved centers is challenging for individuals in rural communities. This study aims to assess how pediatric plastic surgery outreach clinics impact access for patients with orofacial cleft and craniosynostosis in Mississippi. An isochrone map was used to determine mean travel times from Mississippi counties to the sole pediatric hospital and the only ACPA-approved team in the state. This analysis was done before and after the establishment of two outreach clinics to assess differences in travel times and cost of travel to specialized plastic surgery care. Two sample t-tests were used for analysis. The addition of outreach clinics in North and South Mississippi led to a significant reduction in mean travel times for patients with cleft and craniofacial diagnoses across the state's counties (1.81 hours vs 1.46 hours, P < 0.001). Noteworthy travel cost savings were observed after the introduction of outreach clinics when considering both the pandemic gas prices ($15.27 vs $9.80, P < 0.001) and post-pandemic prices ($36.52 vs $23.43, P < 0.001). The addition of outreach clinics in Mississippi has expanded access to specialized healthcare for patients with cleft and craniofacial differences resulting in reduced travel time and cost savings for these patients. Establishing specialty outreach clinics in other rural states across the United States may contribute significantly to reducing burden of care for patients with clefts and craniofacial differences. Future studies can further investigate whether the inclusion of outreach clinics improves follow-up rates and surgical outcomes for these patients.

Effect of DeltaRex-G ± DeltaRex-G Plus (an FDA-approved drug) on advanced chemoresistant pancreatic cancer, sarcoma, and breast cancer.

e15086 Background: Expanded access for DeltaRex-G, a tumor targeted retrovector encoding a CCNG1 inhibitor, is being studied for advanced cancers. Methods: 137 archived tumor specimens were analyzed with AI RNA sequencing to identify CCNG1 expression levels, reported as: Low = 17%, Medium-low = 17%-49%, Medium-high = 50%-83%, High = 83%. Nine patients with advanced solid malignancies, whose CCNG1 levels were identified, received DeltaRex-G (2-3 x 10e11 cfu/dose one to three times a week), either without an FDA-approved drug, or with an FDA-approved drug (“DeltaRex-G Plus”). Overall survival, duration of treatment, and responses were evaluated. Results: All analyzed tumors showed enhanced CCNG1 expression. Thirty (22%) tumors exhibited High CCNG1 expression, 48 (35%) showed Medium-High CCNG1 expression, 53 (39%) displayed Medium-Low CCNG1 expression, and six (4%) had Low CCNG1 expression. One hundred (73%) patients had metastatic disease, and 37 (27%) had localized disease. There was no correlation between CCNG1 expression and disease stage. Four patients with advanced pancreatic cancer (n = 1), Stage 1 HR+Her2+ invasive breast cancer (n = 1), Stage 1 triple negative breast cancer (n = 1), and squamous cell carcinoma of skin (n = 1), received DeltaRex-G alone or DeltaRex-G Plus between 2008 and 2021 and are alive 15, 3, 2.5, and 2.5 years since treatment initiation, respectively. Retrospective analysis of their respective tumors showed CCNG1 expression levels of 24%, 23%, 74%, and 40%. Three of the patients are in sustained remission and the patient with squamous cell carcinoma had a partial response. Of the five patients currently being treated with DeltaRex-G Plus: one patient with advanced breast cancer had a partial response (n = 1), one patient with advanced pancreatic cancer (n = 1) and three patients with soft tissue sarcoma (n = 3) had stable disease. Four of five patients had previously progressed with standard doses of chemotherapy. All patients are alive from 11 to 22 weeks since treatment initiation. No serious treatment-related adverse events have been reported. Conclusions: Taken together, the data shows that (1) 100% of 137 tumors tested have enhanced CCNG1 expression, further reinforcing the 2021 FDA-CBER authorization for use of DeltaRex-Plus, and (2) DeltaRex-G Plus is a promising therapy for advanced pancreatic cancer, sarcoma, and breast cancer. Randomized Phase 2/3 studies are warranted to confirm the efficacy and safety of DeltaRex-G Plus. Clinical trial information: NCT04091295 .

Patients (pts) with R/R large B-cell lymphoma (LBCL) treated with lisocabtagene maraleucel (liso-cel) nonconforming product (NCP) under the Expanded Access Protocol (EAP).

7026 Background: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product indicated for the treatment of adults with R/R LBCL. Liso-cel NCP is defined as any product wherein one or both of the CD8 or CD4 cell components did not meet ≥ 1 of the commercial release specifications but met EAP release criteria and was considered appropriate for infusion. Methods: This is a prospective, multicenter EAP study of pts with R/R LBCL intended to receive commercial liso-cel but were treated with NCP due to manufacturing outcomes. Data from United States pts are reported here. The study comprised a pretreatment period for pt evaluation, a treatment period, which started at the first dose of lymphodepleting chemotherapy and continued through NCP administration at Day 1, and the posttreatment period, which followed pts up to 3 months after NCP administration for safety and disease status. Study objectives were safety (primary endpoint) and effectiveness by ORR and CR rate assessed by the treating physician per Lugano 2014 criteria (secondary endpoint). Due to the 3-month follow-up, duration of response, PFS, and OS analyses could not be estimated. Results: A total of 167 United States pts (third-line or later, n = 145; second line, n = 22) were included in the analysis set (data cutoff: 11/20/2023), which included pts who were infused and completed 3 months of follow-up (n = 134) or discontinued participation or died before 3 months (n = 33). Median (IQR) time from leukapheresis to NCP infusion was 50 d (44–58). Median age was 69 y (range, 29–87), 57% male, 42% diffuse LBCL (DLBCL) not otherwise specified, and 29% transformed DLBCL. The most frequent types of NCP (≥ 10 cases) were CD4 low T-cell lineage purity (n = 37 [22%]), CD4 low or high vector copy number (n = 31 [19%]), CD4 low transduction frequency (n = 24 [14%]), or CD8 high interferon-γ (n = 12 [7%]). Bridging therapy was reported in 31% of pts. In the total population (N = 167), cytokine release syndrome was reported in 42% of pts (1% grade ≥ 3), neurological events in 8% (4% grade ≥ 3), immune effector cell–associated neurotoxicity in 2% (1% grade ≥ 3), prolonged cytopenia in 40% (grade ≥ 3 on or after Day 29), grade ≥ 3 infections in 14%, infusion-related reactions in 1% (grade ≥ 3), and second primary malignancy in 1% (none grade ≥ 3). Thirteen pts died because of: AEs (n = 6), disease progression (n = 5), or unknown reasons (n = 2). Of 118 efficacy-evaluable pts for best overall response in the first 3 months, ORR was 71% (95% CI, 62–79); 53% had a CR (95% CI, 43–62) and 19% had a PR (95% CI, 12–27). Conclusions: These data add to current clinical experience with liso-cel, show that pts with R/R LBCL can derive clinical benefit from receiving NCP without compromising safety, and provide important evidence to facilitate clinical decision-making. Clinical trial information: NCT04400591 .

The impact of expanded access programs for systemic anticancer therapy in an Irish cancer centre

BackgroundExpanded access programs (EAPs) allow cancer patients with unmet clinical need to obtain access to pre-authorisation treatments. There is no standardised process for implementing these programs nationally, and real-world data on their impact is lacking.AimsThis study aimed to evaluate the prevalence of such EAPs and their impact in a cancer centre.MethodsData relating to adult cancer patients treated via EAPs from 2011 to 2021 in three Cork university hospitals was collated. Descriptive statistics were employed to get an overview of the impact these programs currently have on cancer care provision.ResultsWe identified 193 patients who accessed EAPs during the study period, availing of 33 separate drugs for a total of 50 different cancer indications. The prevalence of EAP usage was shown to have been trending upwards in recent years with a total of 189 programs being accessed throughout the period. Drugs provided were from a number of different anti-cancer drug classes, particularly targeted therapies (n = 18) and immune checkpoint inhibitors (n = 17). Cancers from a wide range of both solid and liquid tumour types were treated with EAP drugs, and patients treated were from across a broad spectrum of ages (26–82, SD 11.99).ConclusionsEAPs have an increasing role in accessing novel cancer therapies in our community and by extension nationally. Equity of EAP access would be facilitated by a national registry of available agents which we have established. Assessment of their benefits and toxicities would be enhanced by the requirement for a real-world database as a condition of EAP approval.

Stereotactic Magnetic Resonance-Guided Daily Adaptive SABR (SMART) for Localised Non-Metastatic Pancreatic Cancer: First Reported Clinical Outcomes From the UK

AimsPrognosis of locally advanced pancreatic cancer (LAPC) remains poor with limited therapeutic options. Radiation therapy in pancreatic cancer has been restricted by the disease's proximity to radiosensitive organs at risk (OAR). However, stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) has demonstrated promise in delivering ablative doses safely. We sought to report clinical outcomes from a UK-based Compassionate Access Programme that provided access to SMART to patients with LAPC. Materials and methodsThis was a registry retrospective study conducted at a single centre with access to SMART. Patients with LAPC were treated with prescription dose of 40 Gy in 5 fractions. The planning objective was that 98% of PTV received ≥95% of the prescribed dose, prioritising duodenal, stomach and bowel UK SABR consortium constraints. Daily online adaptation was performed using magnetic resonance guidance and on-table re-optimisation. 0–3 months and > 3-month post-treatment-related toxicities, local progression-free survival, metastatic-free survival and overall survival were evaluated. Results55 patients were treated with SMART at our institution from 2020 to 2022. Median follow-up from date of diagnosis was 17 months (range 5–37 months). Median age was 69.87% of patients underwent induction chemotherapy. 71% of patients reported 0–1 grade acute toxicity only. No grade >3 acute toxicity was reported. 5 patients (9%) reported a grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal stricture). No grade >3 toxicity after 3 months was reported. 6 (10%) of patients had grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal haemorrhage). Median local PFS post diagnosis was 17 months (95% CI 15.3–18.7). Median OS post diagnosis was 19 months (95% CI 15.9–22.1). One-year local control post SMART was 65%. ConclusionThis is the first UK-reported experience of MR-guided daily adaptive pancreatic SABR. SMART shows promise in delivering ablative doses with acceptable toxicity rates and good clinical outcomes.

#2187 Rare disease, novel approach: C3GN and Iptacopan case report

Abstract Background and Aims C3 glomerulonephritis (C3GN) is a rare disease characterised on biopsy by proliferative lesions of predominant C3 deposition on immunofluorescence, particularly deposits within the mesangium and capillary walls. Dysregulation of the alternative complement pathway is thought to be the underlying mechanism [1]. There are no approved treatments for C3G and prognosis is poor, with 50% progression to kidney failure over 10 years and similar rates of transplant loss due to disease recurrence. Iptacopan (a selective Factor B complement inhibitor) is proposed to suppress key enzymes involved in the alternative pathway cascade [2]. It is being studied in clinical trials of C3G [3]. We sought to describe our experience in diagnosing and managing a 25-year-old with C3GN who presents with nephrotic syndrome, hypertension, and a reduction in his estimated glomerular filtration rate (eGFR) with a novel small molecule therapeutic. Method This report charts the clinical course of one male patient over 11 months from presentation with C3GN, to the introduction of immunosuppression and of Iptacopan, and the assessment of his response to the foregoing. The patient consented to the publication of his case. Results A 25-year-old male with a background of autism spectrum disorder was referred to his regional nephrology service due to reduction in his eGFR and proteinuria. His creatinine was 158 µmol/L with an eGFR was 51.8 ml/ml/1.73 m2 (CKD-EPI equation); urinary protein creatinine ratio (uPCR) 500 mg/mmol; urinary albumin creatinine ratio (uACR) 400.2 mg/mmol. Serum album 32g/L. His C3 0.22 (normal range 0.82–1.85 g/L); C4 0.27 (normal 0.15–0.53 g/L). A renal biopsy was performed which demonstrated diffuse MPGN dominant C3 staining; cholesterol crystals; and moderate to severe chronic tubulointerstitial damage. 1 mg/kg oral prednisolone with mycophenolate mofetil (MMF) titrated up to a dose of 1g twice a day was initiated. As he was established on the therapy his eGFR rose back to 57.9 ml/min over approximately 8 weeks from a nadir of 33.8 ml/min. Following initial weaning of his prednisolone dose, his eGFR dropped back down to 29.7 ml/min with a creatinine of 250 µmol/L. With involvement and clinical support from the National Renal Complement Therapeutics Centre an application was made to Novartis for the compassionate use of Iptacopan which was commenced early August 2023 (he would not have been eligible for recruitment into any current clinical trials). His latest eGFR is 47.5 ml/ml/1.73 m2 with a uACR of 9.1 mg/mmol and normal C3 and C5b-9 levels after 5 months of Iptacopan. His prednisolone dose is 10 mg. MMF continues at 2g total dose. Conclusion Iptacopan has so far resulted in the normalisation of serum C3 levels, reduction of uACR and stabilisation of serum creatinine as we have reduced the prednisolone dose.

#1640 Alternative complement pathway disorders in the transplant setting—experience from a large volume center

Abstract Background and Aims Complement alternative pathway disorders, atypical hemolytic-uremic syndrome (aHUS) and C3 glomerulopathy (C3G), are rare diseases with a high rate of recurrence after kidney transplantation. Due to limited availability of testing, patients may go undiagnosed, indicating testing during pretransplant evaluation. Posttransplant thrombotic microangiopathy (TMA) is a rare complication of transplantation. A large number of post transplant TMAs is regarded as secondary, either to immunosuppressive drugs or transplant itself. In select cases, complement alternative pathway disorders analysis is warranted. Method We retrospectively reviewed all patients in whom complement system diagnostic work-up was performed in the transplant setting in our center, from 2017 to 2022. Complement system analysis in isolated histological TMA of the allograft, without extrarenal manifestations and with known cause of native kidneys ESRD, was not performed routinely. Patients in whom alternative pathway disorders were confirmed were compared with those with no abnormalities detected by complement system analysis. Results 12 patients were identified, 75% male, median age 39.5 years (IQR 28-60.25). 8 patients were evaluated before transplantation. 4 of the 8 patients were referred for transplantation with diagnosed aHUS. Genetic testing was used for recurrence risk stratification. In living donor transplantations 2 donors were tested as well. One patient was referred from a neighboring resource poor country and was not on eculizumab therapy. He was homozygous for a high risk causative mutation. He was declined for living related donor kidney transplant, due to risk to the donor and unavailability of eculizumab. Compassionate use request was initiated. One patient was referred as possible C3G and repeat complement analysis revealed elevated C3Nef. Out of 3 patients, previously diagnosed as CKD of unknown origin or immune complex-mediated membranoproliferative glomerulonephritis, 2 were diagnosed during pretransplant evaluation: one as C3G and the other as aHUS. 4 patients were evaluated posttransplant. One analysis was performed due to recurrent C3G of the allograft, with confirmed competent dysregulation. 2 analyses were in liver transplant recipients, both with systemic TMA. Severe overactivation with consumption of complement was proven in one and treated with eculizumab. The characteristics of patients with diagnosed disorders of the complement system and those without are shown in Table 1. Conclusion Transplant physicians should keep a high volume of suspicion for complement dysregulation disorders, both during the pretransplant work-up and when evaluating TMA and recurrent GN posttransplant. Special caution should be advised when a patient is referred as chronic GN, MPGN or unknown cause ESKD at a young age.

The economic impact of 14 compassionate use programs for medicines in Italy, in the perspective of the National Health Service

Background: Compassionate use programs (CUP) for medicines allow patients, not recruited in trials, accessing medicines before marketing approval. The evidence on the economic impact of CUP is limited to one paper that did not include the possible long-term economic impact of medicines used in CUP compared to alternative treatments, like avoided hospitalization costs. This paper aims at covering this information gap, updating and integrating the existing evidence, with a cost analysis in the perspective of the Italian National Health Service (SSN). Methods: Data were retrieved from the Roche CUP Database, the peer-reviewed literature (e.g. published cost-effectiveness studies, if any), the gray literature (e.g. regional documents for the alternative treatment cost) and unpublished data (e.g. cost-effectiveness analysis provided for price and reimbursement negotiation for medicines in CUP). Results: We retrieved data from 14 CUPs and 3,485 patients (70% affected by tumors) (Jan 2015-August 2022). The alternative treatment mean cost per patient ranged from € 11.1 k to € 18.8 k. The net economic benefit ranged from € 47 million to € 75 million (€ 13.5 k-€ 21.5 k per patient). Avoiding alternative treatments mostly contributes to the economic benefit. The long-term economic impact accounted for 20/30% of the net economic impact. The net economic benefit for cancer drugs ranged from € 12.6 million to € 40.0 million. Conclusions: Despite research limitations, this paper provides additional evidence on the economic impact of CUP in Italy. This could represent the first step of a broader analysis of the economic impact of early access schemes for drugs.

Safety and efficacy of narsoplimab in pediatric and adult patients with transplant-associated thrombotic microangiopathy: a real-world experience

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication following hematopoietic stem cell transplantation (HSCT). No approved treatments are currently available. This study presents real-world data obtained with narsoplimab, a human immunoglobulin G4 monoclonal antibody that inhibits MASP-2, the effector enzyme of the lectin pathway of the complement system. Between January 2018 and August 2023, 20 (13 adult and 7 pediatric) patients diagnosed with TA-TMA received narsoplimab under an ongoing compassionate use program. The diagnosis was based on internationally defined criteria for pediatric and adult patients. Fifteen patients fulfilled the criteria recently established by an international consensus on TA-TMA. Nineteen patients exhibited high-risk characteristics. Thirteen patients (65%) responded to narsoplimab, achieving transfusion independence and significant clinical improvement. The one-hundred-day Overall Survival (OS) post-TA-TMA diagnosis was 70%, and 100% for responders. Narsoplimab proved to be effective and safe in the treatment of high-risk TA-TMA, with no increased infectious complications or other safety signals of concern across all age groups. The high response rates and the encouraging survival outcomes underscore the potential of narsoplimab as a valuable therapeutic option, particularly for high-risk cases.

Phage Therapy for Cardiac Implantable Electronic Devices and Vascular Grafts: A Targeted Literature Review.

Infections of cardiac implantable electronic devices (CIEDs) and vascular grafts are some of the most dreaded complications of these otherwise life-saving devices. Many of these infections are not responsive to conventional treatment, such as systemic antibiotics and surgical irrigation and debridement. Therefore, innovative strategies to prevent and manage these conditions are warranted. Among these, there is an increasing interest in phages as a therapeutical option. In this review, we aim to collect the available evidence for the clinical application of phage therapy for CIED and vascular graft infections through literature research. We found 17 studies for a total of 34 patients. Most of the indications were left ventricular assist device (LVAD) (n = 20) and vascular graft infections (n = 7). The bacteria most often encountered were Staphylococcus aureus (n = 18) and Pseudomonas aeruginosa (n = 16). Clinical improvements were observed in 21/34 (61.8%) patients, with microbiological eradication in 18/21 (85.7%) of them. In eight cases, an adverse event related to phage therapy was reported. Phage therapy is a promising option for difficult-to-treat CIED and vascular graft infections by means of an individualized approach. Clinical trials and expanded access programs for compassionate use are needed to further unveil the role of phage therapy in clinical application.

Compassionate use of cefiderocol in a complex case of extensively drug-resistant Acinetobacter baumannii fracture-related infection: a comprehensive approach and multidisciplinary management.

Fracture-related infections (FRI) pose a difficult management problem, as they require numerous surgical interventions and extended antibiotic treatments, especially when a multidrug-resistant organism is involved, with a paucity of available literature that provides guidance. A 42year-old male presents an open diaphyseal tibia and fibula fracture, complicated by soft tissue necrosis and infections caused by extensively drug-resistant Acinetobacter baumannii (XDR-Ab). Initially treated with a damage control external fixator, the patient underwent multiple surgical procedures, including radical debridement, negative pressure wound therapy, external fixator revisions and reconstructive surgery using a latissimus dorsi free flap. The emergence of colistin resistance in the Acinetobacter baumannii strain led to the compassionate use of cefiderocol, finally achieving clinical cure. This case report is one of the firsts that highlights the potential efficacy of cefiderocol in treating challenging bone and joint infections sustained by XDR-Ab. The successful outcome also emphasizes the importance of a comprehensive, multidisciplinary approach in achieving favorable results in complex FRI.

Effectiveness and Safety of OnabotulinumtoxinA in Adolescent Patients with Chronic Migraine.

Chronic migraine (CM) significantly affects underage individuals. The study objectives are (1) to analyze the effectiveness and safety of onabotulinumtoxinA (BTX-A) in adolescents with CM; (2) to review the literature on BTX-A use in the pediatric population. This prospective observational study included patients under 18 years old with CM treated with BTX-A (PREEMPT protocol) as compassionate use. Demographic, efficacy (monthly headache days-MHD; monthly migraine days-MMD; acute medication days/month-AMDM) and side effect data were collected. A ≥ 50% reduction in MHD was considered as a response. Effectiveness and safety were analyzed at 6 and 12 months. A systematic review of the use of BTX-A in children/adolescents was conducted in July 2023. In total, 20 patients were included (median age 15 years [14.75-17], 70% (14/20) females). The median basal frequencies were 28.8 [20-28] MHD, 18 [10-28] MMD and 10 [7.5-21.2] AMDM. Compared with baseline, at 6 months (n = 20), 11 patients (55%) were responders, with a median reduction in MHD of -20 days/month (p = 0.001). At 12 months (n = 14), eight patients (57.1%) were responders, with a median reduction in MHD of -17.5 days/month (p = 0.002). No adverse effects were reported. The literature search showed similar results. Our data supports the concept that BTX-A is effective, well tolerated, and safe in adolescents with CM resistant to oral preventatives.

Expanded Access Programme for the use of tecovirimat for the treatment of monkeypox infection: A study protocol for an Expanded Access Programme.

Monkeypox is a viral zoonotic disease commonly reported in humans in parts of Central and West Africa. This protocol is for an Expanded Access Programme (EAP) to be implemented in the Central African Republic, where Clade I monkeypox virus diseases is primarily responsible for most monkeypox infections. The objective of the programme is to provide patients with confirmed monkeypox with access to tecovirimat, a novel antiviral targeting orthopoxviruses, and collect data on clinical and virological outcomes of patients to inform future research. The study will be conducted at participating hospitals in the Central African Republic. All patients who provide informed consent to enrol in the programme will receive tecovirimat. Patients will remain in hospital for the duration of treatment. Data on clinical signs and symptoms will be collected every day while the patient is hospitalised. Blood, throat and lesion samples will be collected at baseline and then on days 4, 8, 14 and 28. Patient outcomes will be assessed on Day 14 -end of treatment-and at Day 28. Adverse event and serious adverse event data will be collected from the point of consent until Day 28. This EAP is the first protocolised treatment programme in Clade I MPXV. The data generated under this protocol aims to describe the use of tecovirimat for Clade I disease in a monkeypox endemic region of Central Africa. It is hoped that this data can inform the definition of outcome measures used in future research and contribute to the academic literature around the use of tecovirimat for the treatment of monkeypox. The EAP also aims to bolster research capacity in the region in order for robust randomised controlled trials to take place for monkeypox and other diseases. {2a & 2b}: ISRCTN43307947.