Effectiveness of Siponimod with Up to 2 Years of Treatment in a Real-World Setting in People with SPMS: Analysis from the Novartis Global Managed Access Program.

4577 Background: Nivolumab showed a survival benefit in a randomised phase III trial in pre-treated mRCC. The EAP provided the opportunity to treat patients (pts) in real world clinical practice before market availability of the drug clinical practice. The aim of this analysis was to evaluate the safety and activity of nivolumab in a real world setting. Methods: Nivolumab was available upon physician request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for mRCC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks. Pts included in the analysis had received ≥ 1 dose of nivolumab and were monitored for adverse events using CTCAE v.4.0. Results: Totally, 389 pts were enrolled in the EAP across 95 Italian sites, median age was 65 years (range, 34-85) with 70 (18%) aged ≥ 75 yrs. Pts had a clear-cell RCC in 92% of cases, bone metastases in 50% and brain metastases in 8%, and received more than one previous line in 79% of cases. At the time of this analysis, median number of doses received was 10 (1-31) and 82 (21%) pts were treated beyond progression. Among 389 pts, 18 pts (5%) discontinued treatment due to AE. The best overall response rate was 17% including one complete and 66 partial responses, whereas 121 (31%) had stable disease. With a median follow-up of 7 months (range, 1 to 16), 6-month and 9-month survival rates were 83% and 77%, respectively. Response and survival rates were comparable among pts regardless age, presence of brain or bone metastases and number of prior therapies. Conclusions: This EAP represents the most extensive reported real-world experience with nivolumab in pre-treated RCC pts. These first data seem to confirm efficacy and safety data of the pivotal trial in a real world setting. Results in patient populations poorly (elderly or bone metastases) or not represented at all (brain metastases) in the pivotal trial encourage the use of nivolumab in these subgroups of RCC pts.

e17061 Background: ThePhase 3 VISION trial demonstrated that [177Lu]Lu-PSMA-617 prolonged overall survival (OS) in metastatic-castration resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSi). The expanded access program (EAP) (NCT04825652) was opened to provide access to [177Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. The VISION trial required strict inclusion and exclusion criteria, which may not represent the patient population encountered in clinical practice. This study aimed to evaluate the efficacy and safety profile of [177Lu]Lu-PSMA-617 in a real-world setting within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP between May 2021 and March 2022 at four institutions in the United States with available toxicity and outcome data were included. Outcome measures included overall survival (OS), ≥50% PSA decline rates (PSA-RR), and incidences of toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Differences in baseline characteristics, toxicity, and PSA-RR between the EAP and VISION were evaluated using a t-test of proportions. Results: 117 patients with mCRPC were eligible and included. Patients enrolled in the EAP were similarly pretreated with taxane-based chemotherapy regimens (>1 taxane: 47% vs 40%; p=0.16) and more heavily pretreated with ARSi (>1 ARSi: 70% vs 46%; p<0.001). EAP patients had similar levels of ≥3 grade anemia (18% vs 13%; p=0.15), thrombocytopenia (13% vs 8%; p=0.13), and neutropenia (3% vs 3%; p=0.85) and higher levels of ≥3 grade lymphopenia (34% vs 8%; p<0.001). Patients treated within the EAP experienced numerically shorter OS (median OS: 13.7 vs 15.3 months) and similar PSA-RR (40% vs 46%; p=0.29). Median follow-up was numerically shorter in the EAP compared with VISION (14.7 mo vs 20.3 mo). Conclusions: mCRPC patients treated with [177Lu]Lu-PSMA-617 in a real-world setting were more heavily pretreated with ARSi, had a similar safety profile, and experienced numerically shorter OS and similar PSA-RR compared with VISION trial patients. A major limitation of this study is that we did not have access to individual patient data from the VISION trial, so we were not able to assess whether differences in OS between VISION and the EAP were statistically significant.

ABSTRACTObjective: The objective of this study was to evaluate the efficacy and safety of rituximab (RTX) treatment given off-label to Cypriot patients with multiple sclerosis (MS).Methods: Clinical data from 30 MS patients ever treated with off-label RTX until mid-2018 at the Cyprus Institute of Neurology and Genetics were retrospectively collected and reviewed. The heterogeneous patient cohort included patients with relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS). Outcome data (relapse rate and EDSS progression) as well as adverse effects for patients with a follow-up period of >12 months (n = 13) were recorded.Results: Following RTX administration, all patients with RRMS remained relapse free and had a stable or slightly improved EDSS score (mean EDSS before treatment = 6, mean EDSS at 12 months = 4.75). Patients with SPMS had a significant reduction in their relapse rate and a stabilization or slight improvement of their EDSS scores (mean EDSS before treatment = 6.25, mean EDSS at 12 months = 5.5). Only one of the patients with PPMS had a follow-up period of >12 months and his EDSS score remained unchanged. Rituximab infusions were generally well tolerated; there were only seven grade 3 or 4 adverse events recorded.Conclusion: Our results are in agreement with larger retrospective studies in which it was demonstrated that RTX was well tolerated and effective in treating RRMS and SPMS patients by reducing relapse rate and stabilizing disease.

Background: Changes in relapse activity during secondary progressive multiple sclerosis (SPMS) need to be accurately characterized in order to identify patients who might benefit from continuing disease-modifying therapies. Objective: To describe relapse occurrence in patients with SPMS during long-term follow-up and assess its impact on disability worsening. Methods: This retrospective cohort study included 506 patients. We assessed the influence of relapses on time from SPMS onset to an Expanded Disability Status Scale score of 6 (EDSS 6), and on irreversible worsening of EDSS scores across different periods. Results: The annualized relapse rate (ARR) decreased with patient’s age (mean reduction of 43% per decade) and SPMS duration (mean reduction of 46% every 5 years). Post-progression relapses were associated with shorter time from secondary progressive (SP) phase onset to EDSS 6 (hazard ratio (HR) = 1.29, 95% confidence interval (CI) = (1.01, 1.64)). Relapse occurrence during the first 3 years and 3–5 years after SP onset was associated with an increased risk of irreversible EDSS worsening (OR = 3.12 (1.54, 6.31) and 2.04 (1.16, 3.58)). This association was no longer significant after 5 years. Conclusion: The occurrence of relapses was a marker of short-term disability progression during early SPMS, but did not have decisive impact in later SPMS.

Cyclophosphamide (CYC) is an alkylating agent with immunosuppressive effect by inhibiting DNA synthesis and producing apoptosis used in many autoimmune diseases, including multiple sclerosis (MS). Here, we analyze the efficacy of CYC treatment in relapsing-remitting (RRMS) and active secondary progressive MS (SPMS) in our center with a monthly scheme. Patients with MS treated with CYC and a follow up of at least 36months were eligible for inclusion. All participants had received a standard CYC regimen. The EDSS score mean annualized relapse rate (ARR) and progression index (PI) were measured as efficacy outcomes at 12, 24, and 36months. Outcomes were also analyzed comparing disease course and activity. A total of 16 patients were included (50% male, 18.75% RRMS and 81.25% SPMS). EDSS remained stable along the follow-up period, with 62.5% improving or maintaining the same EDSS score at 12months. PI decreased 14% and 21% at 12 and 24-36months of follow-up, respectively. ARR decreased 20% after 12months, 19% after 24months, and 30.23% after 36months. Median differences in ARR were higher in patients with high relapse activity (0.60 vs 0.07, p = 0.001) and malignant course (0.60 vs 0.17, p = 0.027). PI also differed with higher mean differences in patients with high relapse activity (0.70 vs 0.03, p = 0.016) and malignant course (1.17 vs 0.03, p = 0.003). CYC continues to be a valid therapeutic option, especially in regions with limited access to high-efficiency therapies particularly in patients with high relapsing activity and malignant course.

ABSTRACTObjective:The PACIFIC trial established standard therapy for patients with unresectable stage III NSCLC who did not progress after platinum-based concurrent chemoradiation therapy. However, real-world data, particularly from Latin America, remain limited. The LACOG 0120 study aimed to evaluate the efficacy and safety of consolidation therapy with durvalumab in a real-world setting in Brazil. Methods:Patients with unresectable stage III NSCLC who received chemoradiotherapy followed by durvalumab consolidation therapy through an expanded access program were evaluated. The primary objective was to assess progression-free survival (PFS). Secondary endpoints included overall survival (OS), treatment compliance, and safety, with a focus on the incidence and severity of immune-mediated adverse events (NCT04948411). Results:Thirty-one patients from seven centers were evaluated. Median follow-up was 50.3 months (95% CI: 48.6-54.4). Median PFS was 9.9 months (95% CI: 7.3-52.4), with a 36 month-PFS of 34.5% (95% CI: 17.7-52.1). Median OS was 34.9 months (95% CI: 26.0-NR), and the 36 month-OS was 46.3% (95% CI: 25.7-64.6). Durvalumab was administered for a median of 17 cycles (10 to 24), with 45.2% of patients completing the planned therapy. The main reason for discontinuation was disease progression. Treatment-related adverse events of any grade occurred in 12 patients (38.7%), with grade 3 events reported in two (6.5%). Pneumonitis was observed in 4 patients (12.9%) - grade 3 in 1 patient. Conclusions:PFS was lower in this analysis compared to the PACIFIC trial; however, OS was similar, indicating comparable efficacy in a real-world setting among Brazilian patients with unresectable stage III NSCLC. No new safety concerns were identified.

<h3>Objective:</h3> To describe demographic and clinical characteristics and characterize change in Expanded Disability Status Scale (EDSS) score in people living with secondary progressive multiple sclerosis (plwSPMS) receiving siponimod under the managed access program (MAP; Global Siponimod MAP cohort [BAF2001M cohort]). <h3>Background:</h3> Siponimod significantly reduced the risk of confirmed disability progression and worsening of cognitive processing speed vs placebo in the phase 3 EXPAND trial (NCT01665144). However, real-world effectiveness data for siponimod remain scarce. <h3>Design/Methods:</h3> The BAF2001M cohort is an umbrella program to facilitate access to siponimod when marketing authorization is pending (under physician request) in the absence of acceptable alternative treatments. The program started in March 2019 and is ongoing. The target population included adult patients with SPMS and an EDSS score &lt;7 from March 2019 to January 2021. After January 2021, access to the MAP required SPMS with active disease. Treatment selection and patient monitoring were based on physician assessment. Baseline characteristics included country, age, sex, relapse, MRI activity in the last 2 years, EDSS, and cognition evaluation. <h3>Results:</h3> A total of 632 cases were analyzed (153 excluded from analysis due to local country restrictions). Mean (SD) age was 52.3 (8.7) years, 60% of patients were female, and median (IQR) EDSS was 5.5 (4.5–6.5). Prior to siponimod start, ~51% experienced a relapse in the last 2 years, 54% had previous cognitive evaluation, and 52% had an MRI scan in the last 2 years (48% showed activity). Mean change in EDSS from baseline was approximately −0.02/−0.03 at Months 6, 12, 18, and 24 (not significantly different vs baseline). Approximately 94% (140/149) of patients improved or were stable at Month 24. <h3>Conclusions:</h3> Most plwSPMS demonstrated improved or stabilized EDSS scores over 2 years. This population was older than the EXPAND study population and around half demonstrated relapse/MRI activity. Results support the effectiveness of siponimod in SPMS. <b>Disclosure:</b> Dr. Mavrikis Cox has received personal compensation for serving as an employee of Novartis Pharmaceuticals. Dr. Mavrikis Cox has stock in Novartis Pharmaceuticals. Virginia DeLasHeras has nothing to disclose. Dr. Ryan has received personal compensation for serving as an employee of Novartis. Mrs. Istrate has nothing to disclose. Soudeh Ansari has received personal compensation for serving as an employee of Novartis. Sophie Arnould has nothing to disclose. Dr. Piani Meier has received personal compensation for serving as an employee of Novartis. Dr. Piani Meier has received personal compensation for serving as an employee of Merck Group.

Secondary progressive multiple sclerosis: A national consensus paper on diagnostic criteria

To determine the factors, if any, that are associated with the efficacy of "off-label therapies" (OLTs) for multiple sclerosis (MS). Consecutive patients (N = 174) with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) with relapses, on OLTs with a generic formulation of azathioprine, mycophenolate mofetil, or rituximab biosimilar for ≥2 years were included. Annualized relapse rate (ARR) and expanded disability status score (EDSS) 1 year before and ≥2 years after starting OLTs were recorded. Optical coherence tomography (OCT) was done at baseline and at the end of the study. During a median period of 4.1 years (2.4-24), ARR reduced in all (P < 0.0001) and EDSS improved in RRMS (P < 0.0001) patients but not in SPMS (P < 0.31) patients. Good responders were those who had RRMS (P = 0.001, odds ratio [OR] 0.04, 95% confidence interval [CI] 0.01-0.15), female gender (P 0.008, OR 6.67, 95% CI 1.7-26.8), and had early access to OLT (P = 0.006, OR 1.2, 95% CI 1.05-1.40). Baseline peripapillary retinal nerve fiber layer thickness identified the risk of conversion to SPMS (P < 0.01, OR 1.03; 95% CI 1.01-1.06). This limited prospective study suggests that early identification of patients who could potentially respond to unconventional but accessible therapies may be valuable in the treatment of MS, particularly in resource-poor regions.

P3.02b-077 Osimertinib Expanded Access Program for Previously Treated Patients With Advanced EGFR T790M Mutation-Positive NSCLC: Topic: EGFR Clinical

To evaluate clinical and MRI effects of natural interferon beta treatment in both relapsing-remitting (RR) and secondary-progressive (SP) multiple sclerosis patients. A double-blind, randomized trial of natural interferon beta (nIFN-beta) in 58 ambulatory patients with RR and 40 with SP multiple sclerosis. Forty-nine patients (29 RR and 20 SP) were treated with intramuscular nIFN-beta6 MIU three times a week for 24 months and 49 control patients were treated with placebo. Primary clinical endpoints were differences in exacerbation rates and proportion of patients remaining exacerbation-free. There were no significant baseline differences between the treated and placebo groups. In the treated RR group a significant reduction in exacerbation rate, an increase in the probability of remaining exacerbation-free, and an improvement in mean EDSS were found at 24 months. MRI activity and total lesion burden were significantly reduced in treated RR patients. In the SP group, nIFN-beta produced a significant reduction in EDSS score, a significant reduction in active lesion number, a marginally significant favourable difference in total lesion burden but no significant effect on the number of gadolinium-enhancing lesions. Side effects were transient and mild in treated patients. These observations confirm that nIFN-beta is a promising and well-tolerated treatment for either RR or SP MS patients.

A population-level analysis of convalescent plasma use and COVID-19 mortality in the USA revealed an inverse correlation and an estimate that recent declines in plasma use could have resulted in about 30,000 excess deaths.

The COVID-19 pandemic has triggered an extensive need for new therapeutics and there has been widespread use of unapproved/repurposed medicines. Several countries have regulations for access to unapproved medicines, known as compassionate use, managed/expanded access or emergency use. The Novartis Managed Access activity for COVID-19 delivered unapproved/repurposed medicines to nearly 6,000 patients over a 6-month period. With the rapid growth of such access mechanisms to address COVID-19, a better understanding of these channels is required.

PND36 Real-World Evaluation of Patients Affected By Multiple Sclerosis (MS), Relapsing-Remitting Multiple Sclerosis (RRMS) or Secondary Progressive Multiple Sclerosis (SPMS) in Italy: Prevalence, Pharmaco-Utilization and Cost Analysis

Compassionate use (CU) is a treatment option for patients with serious or life-threatening medical conditions that provides access to locally unlicensed medications (generally free of charge) when all available treatment options have been exhausted and enrollment in a clinical trial is not possible. To examine the disparity in CU access observed across countries and explore the key driving factors. This study analyzed all Novartis CU requests (for individual/named patients and cohort programs) received between January 1, 2018, and December 31, 2020, and investigated selected country-specific factors for association with request activity. Data analysis was performed from February 2021 to February 2022. Country-specific request activity was quantified using request counts and rates per million population and examined in stratified and multivariable analyses (negative-binomial regression) for association with the following covariates: existence of local CU regulations and their public availability, clinical trial activity, population size, and gross domestic product. During the 36-month observation period, 31 711 CU requests were received from 110 countries, 23 194 (73%) of which came from only 10 high-income countries. All high-income countries combined accounted for 27 612 (87%) of all requests, while lower-middle-income and low-income countries contributed only 1021 (3%). Of all requests, 29 870 (94%) were from countries with CU regulations made publicly available on the internet, and higher request activity was demonstrated in countries conducting more clinical trials. Presence and public availability of CU regulations, population size, gross domestic product, and clinical trial activity were independently associated with the CU request activity in multivariable analysis. In this cohort study analyzing Novartis CU requests over a 3-year period, existence and public availability of CU regulations and local clinical trial activity were positively associated with higher CU request rates. The analysis also identified an association between macroeconomic factors and CU request activity, despite the generally free provision of unlicensed therapeutic products. Similar analyses of other comparable experiences are needed to supplement these initial observations. Ultimately, better understanding of factors associated with CU request activity would translate into improved early access to novel lifesaving products for patients with unmet medical needs around the world.