Temporary Authorization For Use Research Articles

Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer: Real-life data from the temporary use authorization program in France.

Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T-DXd) in France based on DESTINY-Breast01 trial which demonstrated its efficacy and safety in HER2-positive metastatic/unresectable breast cancer after ≥2 anti-HER2-based regimens received at metastatic stage. This multicenter real-world early access program included HER2-positive metastatic/unresectable breast patients pretreated with at least two lines of anti-HER2 regimens who received T-DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks. Four hundred and fifty-nine patients (median age, 58 years; hormone receptor-positive, 67%; brain metastases, 28.1%) received T-DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2-22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow-up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T-DXd treatment was 3.4 (range, 0-7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD-related death. In this early access program in patients with heavily pretreated HER2-positive metastatic/unresectable breast cancer, T-DXd had antitumor activity with a similar response to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed.

Gemtuzumab Ozogamicin for Patients with Newly Diagnosed CD33 Positive Acute Myeloid Leukemia: Results from a French Retrospective Observational Study

Introduction: Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate targeting CD33 with a calicheamicin derivative payload. GO is approved in France in combination with daunorubicin and cytarabine for treatment-naïve patients aged ≥15 years with de novo CD33-positive acute myeloid leukemia (AML). Before the European Medicines Agency granted marketing authorization in 2018, GO was available in France with an authorization for temporary use (ATU) for specific patients since 2010, and between 2018 and 2019 as part of a “post-ATU” cohort until its reimbursement. This study aimed to describe the real-world use, effectiveness, and safety of GO in treatment-naïve patients with CD33-positive AML in France, as requested by the French Transparency Commission. Methods: This retrospective, multicenter, observational study included all patients in the French ATU and post-ATU cohorts treated between 01 December 2014 and 31 October 2022. Patient and disease characteristics, treatment (dose/combination), response outcomes, and adverse events (AEs) of interest were described. Prognostic factors for event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS) were identified using Cox proportional hazard models. Results: Overall, 113 patients were included (ATU cohort, N=62; post-ATU cohort, N=51). The median age when GO was initiated was 63.0 years (range, 19-91); 54.9% (n=62) of patients were male; 81.8% (n=72/88) had an ECOG performance score 0-1, and 65.3% (n=64/98) had favorable risk according to the ELN classification 2017 ( Table). During the first induction treatment, most patients (98.1%; n=105/107) received GO in association with other agents, most commonly cytarabine and daunorubicin (60.0%; n=63/105). Most patients (78.5%, n=84/107) received 3 doses of GO during first induction. In all cases, patients received GO in second (7.1%; n=8) or subsequent (2.7%; n=3) induction courses - always in association with cytarabine and with or without daunorubicin/other agents. GO was given during the first, second, and subsequent consolidation treatment in 46.9% (n=53), 32.7% (n=37), and 2.7% (n=3) of patients, respectively, usually with cytarabine with or without daunorubicin. After a median follow-up of 44.6 months (95% CI, 33.8-69.3), 78.6% (n=88/112) of patients responded post-induction - of these, 72.3% (n=81) achieved a complete response (CR) and 6.3% (n=7) achieved a CR without platelet recovery. Minimal residual disease was evaluable in 46 patients; 52.2% (n=24) achieved a CR without minimal residual disease. Median EFS was 13.1 months (95% CI, 9.9-17.5); EFS by ELN risk group is shown in the Table. Median RFS was 17.5 months (95% CI, 12.6-35.6) and median OS was 49.8 months (95% CI, 21.8-not estimable; Figure). After a median period of 13.0 months (range, 3.0-33.0) following GO treatment, 31.5% (n=35/111) of patients received a hematopoietic stem cell transplant. Older age predicted shorter OS (hazard ratio [HR] 1.1 [95% CI, 1.0-1.1]; p<0.001). Having an FLT3TKD mutation (HR 4.1 [95% CI, 1.4-12.4]; p=0.013) or adverse cytogenetic classification (HR 13.0 [95% CI, 2.3-73.8]; p=0.015) predicted shorter EFS. Having ECOG-PS ≥2 (HR 6.6 [95% CI, 1.8-24.5]; p=0.005) or adverse cytogenetic classification (HR 72.7 [95% CI, 7.6-699.1]; p=0.001) predicted shorter RFS. AEs of interest were reported for 38.9% (n=44) of patients; 13.3% (n=15) were serious and 26.6% (n=30) were treatment-related (TRAE). The most common AEs were thrombocytopenia (21.2%; n=24), pyrexia (4.4%; n=5), and hepatic cytolysis (3.5%; n=4). AEs of special interest included persistent thrombocytopenia (15.9%; n=18), severe hemorrhage (5.3%; n=6), and veno-occlusive disease/sinusoidal obstruction syndrome (0.9%; n=1). Overall, 46.9% (n=53) patients died, with relapse or progressive disease accounting for 41.5% of deaths (n=22/53). Two (1.8%) patients died from TRAEs (laryngeal edema/pulmonary alveolar hemorrhage and hepatic cytolysis). Conclusions: GO was predominantly administered according to its indication. Response rates were similar to those reported in the pivotal ALFA-0701 study. Median OS was longer in this study than in ALFA-0701 (49.8 vs 27.5 months), although median RFS and EFS were reduced. No new safety signals were reported. Overall, GO appears safe and effective in real-world practice when added to induction therapy for treating patients with de novo CD33-positive AML.

1404P Clinical characteristics and therapeutics sequences of KRAS G12C metastatic non-small cell lung cancer (mNCSLC) patients treated by sotorasib in the French pre-marketing authorization (MA) early access program (cohort temporary authorization of use, cATU)

1404P Clinical characteristics and therapeutics sequences of KRAS G12C metastatic non-small cell lung cancer (mNCSLC) patients treated by sotorasib in the French pre-marketing authorization (MA) early access program (cohort temporary authorization of use, cATU)

Real-world dostarlimab use in advanced/recurrent endometrial cancer in France

In October 2020, the French Health Authority granted early access outside of the clinical trial setting for dostarlimab, a programmed death-1 inhibitor. Dostarlimab was approved by the European Medicines Agency (in April 2021) as monotherapy for patients with post-platinum mismatch repair deficient/microsatellite instability-high advanced/recurrent endometrial cancer, based on the results of the GARNET trial (NCT02715284). This was a real-world descriptive analysis of patients granted cohort temporary authorization of use to receive dostarlimab between November 2020 and June 2021. Physicians could complete follow-up forms at each treatment cycle to provide clinical information, safety, and efficacy data. Safety and disease progression data were also captured through pharmacovigilance reports. Of 95 temporary authorization of use requests made by 80 oncologists in 59 French hospitals, 87 patients were eligible, and 80 received≥1 dose of dostarlimab. Based on treatment response assessments received (n=43), the mean (standard deviation) time from treatment initiation to response evaluation was 11 (6) weeks. The disease control rate (complete plus partial responses plus stable disease rates) was 56% (n=24/43), and the overall response rate was 35% (n=15/43); both consistent with those reported in the GARNET trial. No new safety signals were reported. The enrolment of 80 patients in an 8-month period highlights the need for access to novel treatment regimens in France for these patients post-platinum. Prospective randomized studies are ongoing to assess the efficacy and safety of dostarlimab and other checkpoint inhibitors as first-line treatment in patients with endometrial cancer.

Access to innovation through clinical trials and the national early access program for patients with lung cancer in France: focus on atezolizumab and durvalumab.

Tumor genomic profiling and PD-L1 testing mean lung cancer management can be tackled through a personalized approach. Targeted therapies and immunotherapy are necessary to improve survival and preserve the patients' quality of life. Early access to innovation before marketing authorization (MA) is possible in France through clinical trials and an early-access program called a Temporary Authorization for Use (ATU), which is a unique regulatory system in Europe. This study aims to assess the impact of early access to innovation through clinical trials and ATUs in thoracic oncology. Data from clinical trials between 2018 and 2021 and ATUs between 2005 and 2019 were collected internally and assessed for drugs in thoracic oncology, with specific focus on 2 ATUs, respectively, atezolizumab and durvalumab. From 2018 to 2021, the National Agency for the Safety of Medicines and Health Products authorized 145 clinical trials in lung cancer. Between 2005 and 2019, 19 drugs obtained an EU MA or an MA extension for a therapeutic indication in lung cancer. During this period, 11 of these drugs were granted an ATU, corresponding to 6851 patients treated. Of this total number of patients, data were collected for 33.1% and 71.2%, who received durvalumab and atezolizumab, respectively. Real-life efficacy data were consistent with the clinical trial data. Over the past 15years, clinical trials and the French early access program have allowed considerable early access to therapeutic innovation in real life for patients, especially in thoracic oncology.

553P Real-world data on dostarlimab in post-platinum mismatch repair deficient (dMMR)/ microsatellite instability high (MSI-H) advanced/recurrent (A/R) endometrial cancer: Descriptive analysis of the French cohort temporary authorization of use (ATU)

Dostarlimab is an anti-PD-1 antibody approved by the EMA in April 2021 as monotherapy for patients (pts) with dMMR/MSI-H A/R endometrial cancer (EC) that have progressed on/after platinum-based therapy, based on the results of the GARNET trial1 (NCT02715284). The French Health Authorities granted early access for dostarlimab in this setting in Oct 2020.

Survival, cost and added therapeutic benefit of drugs granted early access through the French temporary authorization for use program in solid tumors from 2009 to 2019.

Decisions on market authorization (MA) and reimbursement have different durations across countries because of health technology assessment (HTA) procedures and negotiations between manufacturers and national authorities. To overcome this delay, France has implemented a Temporary Authorization for Use (ATU) program that allows early access to drugs before MA, in order to treat patients with unmet medical needs. The objectives of our study were to establish the added therapeutic benefit (ATB) of ATUs for solid tumors and to investigate the correlations between three tools evaluating ATB and survival outcomes and drug costs. Data on ATUs granted from January 2009 to December 2019 to treat solid tumors were analyzed. An assessment of their ATB was conducted using the American Society of Clinical Oncology‐Value Framework (ASCO‐VF), the European Society for Medical Oncology‐Magnitude Clinical Benefit Scale (ESMO‐MCBS) and the French HTA criterion, clinical added value (CAV). The latter score determines reimbursement and national market access. Thirty‐five drugs in 39 indications were granted ATUs. All of them obtained MA and derived a clinical benefit to be reimbursed by the Social Security. Twenty‐eight (71.8%) had CAV compared to preexisting therapies. 24/38 (63.2%) had a 4‐5 ESMO‐MCBS score and 19/33 (57.6%) had an ASCO‐VF score over 45. No correlations were found between cost, PFS, OS, CAV and ASCO‐VF score, while high ESMO‐MCBS scores were correlated to OS. In conclusion, many patients were treated with innovations before MA thanks to ATU, although there are discrepancies between ATB scales, hence the importance of international collaboration in the evaluation of innovative therapies.

PB1805: INSIGHTS FROM ORAL AZACITIDINE EARLY ACCESS PROGRAM IN FRANCE: PATIENT POPULATION WITH ACUTE MYELOID LEUKEMIA RECEIVING ORAL-AZA FOR MAINTENANCE OF COMPLETE REMISSION AFTER INDUCTION CHEMOTHERAPY

Background: While many older patients with acute myeloid leukemia (AML) reach complete remission (CR) with intensive chemotherapy (IC), ~80% will ultimately relapse. Treatment options in relapse settings are limited and outcome is usually poor. The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial evaluated oral azacitidine (Oral-AZA; formerly CC-486), a hypomethylating agent, in patients with AML in first remission (CR1) after IC, who were not eligible for hematopoietic stem cell transplantation (HSCT). Unprecedentedly in AML, maintenance treatment with Oral-AZA was associated with significantly longer overall survival and relapse-free survival compared with placebo. Therefore, Oral-AZA received a marketing authorization in the EU as maintenance therapy in adult patients with AML who achieved CR or CR with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment and who are not candidates for, including those who choose not to proceed to, HSCT. Also, French health Authority enabled an early access to Oral-AZA in this indication via a Temporary Authorization for Use (ATU) that started in June 2021. Aims: The aim of the study was to describe the characteristics of patients with newly diagnosed AML who received Oral-AZA for maintenance of CR/CRi after IC and consolidation treatment, who were not eligible for HSCT and were enrolled into ATU in France. Methods: ATU is a French early access allowing administration of the drug under a Therapeutic Use Protocol approved by health authorities. Data presented in this abstract were collected on a declaratory basis and were not monitored. A total of 52 patients were included in 32 centers across France and treated with Oral-AZA during the period from 09-Jun-2021 to 14-Sep-2021. Oral-AZA monotherapy was administered at 300mg once daily for 14 days per 28-days cycle. Results: Overall, 52 treated patients were included with a median age of 67.5 years [range: 35-85]. Regarding Performance Status, 22/52 (42.3%) had an ECOG 0, 25/52 (48.1%) 1 and 5/52 (9.6%) ≥2. The majority (43/52 [82.7%]) had a diagnosis of de novo AML, and the genetic risk (according to ELN2017 criteria) was favorable for 13/52 (25.0%), intermediate for 22/52 (42.3%) and adverse for 17/52 (32.7%) of the patients. Most of the patients had received 1 cycle of IC induction (45/52 [86.5%]). The induction regimen was 3 + 7 for 42/52 (80.8%) patients, among those, 3 (5.8%) received midostaurin along with the 3 + 7. Also 7/52 (13.5%) received CPX-351 as induction regimen. The median number of consolidation cycles was 2 [range: 0-6]; 8/52 (15.4%) patients did not receive any consolidation and 6/52 (11.5%) had >3 cycles of consolidation. The majority of patients (27/52 [61.4%]) received IDAC consolidation. The median time between AML diagnosis and Oral-AZA ATU request approval was 6.8 months [range: 1-98]. Because of the limited time frame of the ATU, follow-up is available for 14/52 patients, and the median follow-up is 21.8 days [range: 1-35]. During the follow-up period, one patient had a temporary interruption of Oral-AZA treatment due to grade 4 neutropenia. There was no reported permanent discontinuation of treatment related to an adverse event. Summary/Conclusion: The characteristics of the patients included in the Oral-AZA Early Access Program in France are in line with European label. These real-life results bring new insights in this population of patients who are not eligible to HSCT with high unmet need to prolong CR1. No unexpected safety signal was registered. Updated results will be presented at the meeting.

Survival in adult patients with BRAFV600 mutation-positive advanced melanoma: a noninterventional ambispective study of patients with cobimetinib combined with vemurafenib during the French early access program: MELANIS study.

Cobimetinib combined with vemurafenib was available in France in 2015 through a 'Temporary Authorization for Use' program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5-20.7). Brain metastasis ( P < 0.001), ECOG index ≥2 ( P = 0.007), and hepatic impairment ( P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2-8.4). ECOG index ≥2 ( P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.

Long-term prophylaxis with lanadelumab for HAE: authorization for temporary use in France

BackgroundHereditary angioedema (HAE) is associated with a heavy burden of illness.ObjectiveTo evaluate use of lanadelumab in a French Authorization for Temporary Use (ATU) program.MethodsATU requests were made between October 12, 2018, and March 13, 2019; patients were followed through September 23, 2019. At entry, patients received lanadelumab 300 mg every 2 weeks. HAE attack characteristics were evaluated at day (D) 0 and months (M) 3 and 6. Patients completed the Angioedema Quality of Life (AE-QoL) questionnaire at initiation and monthly and the Angioedema Activity Score questionnaire daily in 28 day cycles (AAS28).ResultsIn total, 77 patients received ≥ 1 lanadelumab dose; 69 had ≥ 1 quarterly follow-up visit (analyzed population). Mean (standard deviation [SD]) lanadelumab exposure was 240.4 (53.7) days. Lanadelumab dose was modified in 12 patients (mostly to every 4 weeks). For the analyzed population, compared with attacks/month (mean [SD]) within 6 months before ATU (2.68 [2.54]), fewer attacks occurred between initiation and first visit (0.16 [0.42]; P < 0.001) or last visit (0.16 [0.42]; P < 0.001); D15 and last visit (0.15 [0.41]); and D70 and last visit (0.17 [0.70]). AE-QoL total and domain scores were significantly higher at initiation versus M3 and M6; 55% and 65% of patients, respectively, achieved a minimal clinically important difference from D0 to M3 and D0 to M6. Proportion of patients with AAS28 of 0 was higher during M3 (90%) and M6 (83%) than initiation (59%). The most frequently reported adverse events included headache (7.3%) and injection site pain (6.3%).ConclusionsLanadelumab reduced attack rates, improved quality of life, and was generally well tolerated.

Effective Letermovir Prophylaxis of CMV infection post allogeneic hematopoietic cell transplantation: Results from the French temporary authorization of use compassionate program.

We report the results of the French Temporary Authorization of Use (ATU) compassionate program of letermovir for primary prophylaxis conducted in 21 transplant centers. Patients were CMV seropositive allogeneic hematopoietic cell transplantation recipients and at high risk for CMV infection. Primary prophylaxis was defined as initiation of letermovir between day 0 and day +28 post-transplant. Between November 2017 and January 2019, 96 patients with a median age of 56 years received letermovir and follow-up data were available for 78 patients. The median time from transplant to letermovir initiation was 4 days, and the median duration of exposure to letermovir was 78 days, with 57 patients still on treatment at the cutoff date. Letermovir was temporarily discontinued in 4 patients (5.1%) and stopped in 39 patients (50.0%), in most cases due to planned end of treatment (n=16, 20.5%). Fifteen patients (19.2%) each presented one positive CMV PCR, in median 13 days after letermovir initiation. Clinically significant CMV infection was reported in 5 patients (6.4%). No CMV disease was reported. At least one adverse drug reaction was reported for 12 patients (15.4%). In this early access program, letermovir was effective with comparable results of the phase 3 study with a low rate of clinically significant CMV infection, including in patients who were at high-risk for CMV infection.

Abstract P2-13-26: Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France

Abstract Background Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of an HER2-directed antibody and a topoisomerase I inhibitor covalently linked via a tetrapeptide-based cleavable linker. In DESTINY-Breast01, tolerability and efficacy of T-DXd including overall response rate, progression-free survival, duration of response and overall survival have been demonstrated for HER2-positive metastatic and/or unresectable BC in patients (pts) relapsing after 2 or more anti-HER2-based regimens. In France, rapid and fair access to innovative drugs outside clinical trials, prior to their marketing authorization in a given indication, is granted by the French Health Agency, ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé), through cATU program. Here we report first real world evidence data from cATU program in HER2+ BC pts treated with T-DXd. Methods T-DXd 5.4mg/kg was given intravenously in monotherapy every 3 weeks in HER2-positive metastatic and/or unresectable BC pts who had previously received at least 2 lines of anti-HER2 regimens in the metastatic setting. Eligible pts needed to have normal neutrophil count and no left ventricular dysfunction. Pts with active or history of interstitial lung disease (ILD), pneumonitis, severe pulmonary disease were excluded. Clinical, biological and safety data were collected until the end of cATU, as well as treatment response according to RECIST 1.1., dose modification, treatment interruption and discontinuation. Analysis was performed on March 31th, 2021 on the basis of available collected data. Results From September 30th, 2020 to March 31th, 2021, 155 centers requested at least one ATU for a total of 539 adult pts; 468 requests were accepted and 71 were refused as they did not meet eligibility criteria. T-DXd was received by 459 pts with the following characteristics: 99.1% were women, median age was 58 years, 90.4% had a ECOG score of 0-1, 98.9% had initial HER2-positive BC (IHC 3+ or IHC 2+/ISH+), 67% were hormone receptor positive. The main sites of metastases were bones (57.3%), lymph nodes (51.6%), lungs (36.2%), liver (33.1%), brain (28.1%) and cutaneous/subcutaneous (13.9%). Median time between initial diagnosis of primary BC and inclusion was 6.6 years (range: 6.6 months - 33.9 years). 81.7% of pts had previously received radiotherapy and 76.5% underwent surgery. The median number of prior cancer regimens in the metastatic setting was 4 (range: 2-22). 21.1% received 2 prior lines of metastatic treatments, 19.6% received 3 lines and 59.3% received 4 lines or more. 94.8% pts received prior trastuzumab emtansine, and 79.3% had prior pertuzumab. During follow-up, data on tumor assessment were available for 160 pts. Of these, 56.7% had complete or partial response and 12.1% had progression. Of the 459 treated pts, 97 pts (21.1%) experienced ≥ 1 Adverse Drug Reaction (ADR) including 41 pts (8.9%) with ≥ 1 serious ADR. Most frequent ADRs were related to gastrointestinal toxicity (35.4%). During cATU, 17 cases (3.7%) with ILD or considered as ILD were reported but no cases had a fatal outcome (only grade 1 or 2 when reported by physicians). 13 fatal cases were reported (no drug-related deaths, attributed by physician). ADRs leading to T-DXd discontinuation were reported in 4 pts (0.9%). Dose reductions were reported in 17 pts (3.7%) and 21 pts (4.6%) had temporary interruptions. Conclusions We report here the first real world data from the French cATU in HER2-positive BC pts treated by T-DXd. The enrolment of 468 pts in 6 months illustrated the unmet medical need for this population. T-DXd had antitumor activity with a similar response rate to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed. Citation Format: Thierry Petit, Nawale Hajjaji, Eric-Charles Antoine, Marc-Antoine Benderra, Michel Gozy, Cyril Foa, Jean-Loup Mouysset, Julien Grenier, Mireille Mousseau, Audrey Mailliez, Mahasti Saghatchian, Emma Lachaier, Isabelle Desmoulins, Audrey Hennequin, Patricia Maes, Delphine Loirat, Francesco Ricci, Véronique Diéras, Dominique Berton, Florence Lai Tiong, Luis Teixeira, Nadine Dohollou, Christelle Lévy, Thomas Bachelot, Jean-Yves Pierga. Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-26.

Délais administratifs des RTU, effet sur l’accès à l’innovation dans le mélanome

Melanoma has benefited in recent years from therapeutic innovations, which have improved overall survival of patients. France has developed a regulatory arsenal allowing faster access to innovative drugs before marketing authorization: temporary authorization for use (ATU) and temporary recommendation for use (RTU). We describe here the decision-making processes that led to the non-publication of the decree on the funding of three RTU in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib, and we analyse the fate of these drugs in order to quantify the potential loss of chance. On 03AUG2018, the French National Agency for Medicines and Health Product Safety (ANSM) published 3 RTU in order to give rapid access to major innovations in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib. These drugs have respectively demonstrated reductions in the risk of recurrence by 35%, 43% and 55% for target populations of 2200, 1900 and 650 patients per year. Despite a favourable opinion on reimbursement from the French National Authority for Health (HAS), the decrees on reimbursement will never be published, prohibiting the use of these products before the marketing authorisation, and depriving many patients of a potential cure. Despite a favourable opinion from scientists and health agencies for the rapid availability of a drug, the French public health code does not systematically imply access to a therapeutic innovation. The reform of access to innovation implemented on 01JUL2021 may help tackle this issue.

First Evaluation Switching From Ropivacaine to Highly Concentrated Bupivacaine in Intrathecal Mixtures for Cancer Pain

Intrathecal drug delivery is widely used for intractable cancer pain treatment. A combination of drugs with morphine and bupivacaine is recommended in first line therapy. In France, we use ropivacaine 10mg/mL instead of bupivacaine 5mg/mL, the only concentration available. Bupivacaine 40 mg/mL has been available in France only since July 2020 under temporary authorization of use. The main objective of the study was to evaluate the safety, efficacy by pain assessment, to analyze drug dosage changes, to report adverse events (AEs) and conversion ratios switching from ropivacaine to bupivacaine. Secondary objective was to evaluate costs differences. We conducted this retrospective follow-up monocentric study within the Institut de Cancérologie de l'Ouest (ICO) Pain Department in Angers, France. We included 14 patients aged 18 years and above, implanted with an Intrathecal Drug Delivery Systems (IDDS) for cancer pain treatment and followed up at ICO from July 2020 to February 2021 after switching from ropivacaine to bupivacaine. We used a continuous infusion mode and Bolus could be added through Personal Therapy Manager (PTM). The median conversion ratio between ropivacaine and bupivacaine was 0.68 (0.65; 0.69) and resulted in no significant change in numeric rating scale evaluation (p=0.10). We observed moderate and rapidly reversible AEs such as clinical hypotension (29%) and motor block after bolus (21%). The estimated median hospital cost per day was significantly lower (p=0.05) for the bupivacaine refills than for the last ropivacaine pump refill, decreasing from US$ 61.7 (49.6; 70.5) to US$ 50.4 (45.9; 60.4). The median reimbursement per day from the National Health Insurance (NHI) was three times lower for bupivacaine pump refill when compared to the last ropivacaine pump refill (p < 0.01), decreasing from US$ 179.10 (156.79; 182.91) to US$ 64.59 (59.85; 71.89). Switching from ropivacaine to bupivacaine in IDDS appears more efficacious while remaining just as secure, and at lower cost.

Moving somatic gene editing to the clinic: routes to market access and reimbursement in Europe

Somatic gene editing (SGE) holds great promise for making genetic therapy possible for many monogenic conditions very soon. Is our current system of European market authorization and reimbursement ready for the expected tsunami of gene therapies? At a recent workshop of the Netherlands ZonMw consortium on ethical, legal, and social implications of personalized medicine, we discussed the current possibilities for bringing new gene therapies to the clinic. In Europe, it is not yet clear whether the route via the European medicines agency as an advanced therapy medicinal product is the most appropriate for evaluation of highly personalized SGE applications, although this may optimally guarantee safety and effectiveness. Compassionate use may ensure faster access than the centralized procedure but does not stimulate the commercial development of products. Prescription to named patients may only provide adequate access for single patients. Temporary authorization of use may allow access to medication half a year before formal market authorization has been granted, but may also have large budget impacts. Magistral compounding under a hospital exemption may be an attractive solution for rare, tailor-made applications at an acceptable price. To approve local experimental use of a therapy on a case-by-case basis may be fast, but does not guarantee optimal safety, effectiveness, and broad implementation. We argue that alternative routes should be considered for products developed for a market of large groups of patients versus unique personalized treatments. A balance between scientific evidence for safety and effectiveness, affordability, and fast access may demand a range of alternative solutions.

Esketamine in patient with treatment resistant depression: Outcome of the temporary authorization for use programme in France

IntroductionEsketamine nasal spray has been developed for patients with treatment resistant depression.ObjectivesA cohort Temporary Authorization for Use (ATUc) allowed to collect for a 6-month period the first data in real lifeMethodsOn 02/08/2019 the French National Agency for Medicines and Health Product Safety granted an early access program for Esketamine nasal spray framed by a specific protocol for patients without therapeutic alternatives. Each treatment request was approved based on inclusion and exclusion criteria. Clinical evolution, treatment management and safety were then spontaneously reported by psychiatrists.Results From 09/23/2019 to 03/25/2020, 66 patients were treated. The median age was 53 years and 41 (62.1%) were females. At treatment request, 52 patients (79%), presented a severe current depressive episode based on clinical judgment. The median duration of the disease was 12.2 years and the current episode was 2.6 years. Since the beginning of the current depressive episode, all patients (66) were prescribed ≥2 antidepressants (mean 4.2). Esketamine was initiated in a complete hospitalization setting in 27 patients (55.1%) and in day hospitalization in 22 patients (44.9%).Safety profile was consistent with the one described during clinical study. The most frequently adverse events reported (&gt;10%) were dizziness, sedation, sleepiness, anxiety and dissociation. Most of them appeared after treatment administration and were transient.ConclusionsATUc ended on 12/18/2019 after Marketing Authorization granted by European Medicines Agency. Data reported by French psychiatrists are the first collected in this specific population and provide descriptive information on patient characteristics, burden of disease; Esketamine management and practical use at hospital levelDisclosureData analysis performed by RCTs and poster conception coordinated by Medergy and funded by Janssen

Which drugs to treat Adenovirus infections?

Human adenoviruses (HAdV) infections are generally mild and resolve spontaneously in immunocompetent individuals. However, HAdV infections can have a major clinical impact in immunocompromised patients. HAdV infections are associated with high morbidity and mortality in recipients of allogeneic stem cell transplants, particularly children. There are currently no drug approved for the treatment of HAdV infections. Nevertheless, some nucleotide analogues are used under temporary authorization for use, such as cidofovir or brincidofovir. Cidofovir inhibits the replication of HAdV but its nephrotoxicity and its low tissue concentrations severely limit its use. Brincidofovir, a cidofovir prodrug, with a better bioavailability and no nephrotoxicity was evaluated in the treatment of HAdV infections, but its development was recently stopped and it is currently no longer available in ATU. Other molecules with anti-HAdV activity are still in early stages of development. Adoptive immunotherapy by adenovirus-specific T-cell transfer is an interesting option but should be anticipated in patients with high risks of disseminated infections. Given the small therapeutic panel available, it is critical to continue the search for new anti-HAdV molecules, which remains mainly conducted by academic laboratories.

827P First real-life data on olaparib in 1st line (1stL) maintenance BRCA1/2 mutated epithelial ovarian cancer (EOC) in France: Descriptive analysis of 201 patients (pts) enrolled in the cohort temporary authorization for use (ATUc)

827P First real-life data on olaparib in 1st line (1stL) maintenance BRCA1/2 mutated epithelial ovarian cancer (EOC) in France: Descriptive analysis of 201 patients (pts) enrolled in the cohort temporary authorization for use (ATUc)

Review of Scorpion Stings and Snakebites Treated by the French Military Health Service During Overseas Operations Between 2015 and 2017

Depending on their theatre of operation, French soldiers may potentially be exposed to scorpion stings and snakebites. Following the recommendations of a French military health service (FMHS) technical committee for envenomation, the FMHS provides antivenoms appropriate to each deployment. This work aimed to evaluate this risk of envenomation and to assess the antivenoms used by the FMHS in operational theatres since the creation of this committee in 2015. Cases were identified based on a review of temporary authorization of use application forms for the use of antivenom. Data were collected retrospectively from these forms, and prescribing physicians were contacted for any missing data. Between 2015 and 2017, 28 requests for temporary authorization of use were identified: 19 for Scorpifav (Sanofi-Pasteur, Lyon, France) and 9 for Fav-Afrique (Sanofi-Pasteur). The FMHS treated 15 soldiers and 4 civilians for scorpion envenomation with Scorpifav: 15 in Mali, 3 in Chad, and 1 in Niger. Systemic signs were observed in 7 patients. Two soldiers and 7 civilians were treated with Fav-Afrique for ophidian envenomation: 5 in Djibouti, 3 in Mali, and 1 in the Republic of Côte d'Ivoire. These 28 patients were treated without sequelae. Other than moderate erythema that resolved with an antihistamine, no adverse effects were reported. Medical evacuation to France was unnecessary. This study shows that the risk of envenomation for soldiers on deployment is low but real. Antivenoms used by the FMHS were efficient and well tolerated, preserving the operational capacity of deployed troops.

Real-world data of cabozantinib in patients with VEGF-refractory metastatic renal cell carcinoma (mRCC): Results from the French Early Access Program (CABOREAL).

683 Background: Cabozantinib (Cabo) is approved in Europe for the treatment of mRCC in first line and after failure of tyrosine kinase inhibitors (TKI). We report the results from real-world use of Cabo in the French Early Access Program (EAP) (CABOREAL [NCT03744585]). Methods: Data were retrospectively collected from 26 centers. Patients (pts) were treated with Cabo during the Temporary Authorization for Use (ATU) period from Sep 12, 2016 to licensing in Feb 19, 2018. Pts were eligible after 2 prior VEGFR TKI unless clinical decision for 2nd line (L). The aim was to evaluate the use and activity of Cabo in real-life conditions. Overall survival (OS) was calculated from initiation of Cabo. Results: Overall, 410 pts were included. Median age was 63 years, 85% had clear-cell histology, 41% and 32% were intermediate/poor IMDC risk, respectively. Pts were mostly ECOG 1 (42%) or 2 (30%); 229 (56%) pts had bone metastasis (mets). Median follow-up was 14.4 months (m). Cabo was used as 2L, 3L and 4L or beyond for 101 (25%), 137 (33%) and 172 (41%) pts respectively; 204 pts (50%) were pretreated with nivolumab (Nivo). Activity results and dose reduction are summarized in the table. Starting dose was 60 mg (290 pts, 71%), 40 mg (109 pts, 27%) and 20 mg (8 pts, 2%). Treatment interruption occurred for 267 pts (65%), dose modification for 240 pts (59%) and schedule change for 64 pts (16%). Median daily dose was 40 mg/day. Treatment discontinuation occurred for 348 (85%) pts, with 86 (25%) due to adverse events. Notably, 184 (54%) pts received a subsequent systemic therapy. Conclusions: We report the largest real-world study of Cabo in mRCC to date. CABOREAL demonstrates that using dose modification, median Cabo duration was 7.6 m in a heavily pretreated population, with the longest treatment duration in patients with prior Nivo exposure. Clinical trial information: NCT03744585. [Table: see text]