French Early Access Program Research Articles

Abstract P1-18-28: Phase IV study evaluating effectiveness and safety of talazoparib in patients with locally advanced or metastatic HER2 negative breast cancer and a BRCA1 or BRCA2 mutation (ViTAL)

Abstract Background: Talazoparib (TALA) is a highly potent PARP inhibitor that has demonstrated clinical benefit in the phase III EMBRACA trial for patients with germline BRCA1 or BRCA2-mutation and a locally advanced or metastatic HER2 negative (HER2-) breast cancer (BC). Methods: ViTAL is an ambispective, multi-center longitudinal, phase IV study that aims to ensure the effectiveness and safety of TALA in the real-world setting among patients with locally advanced or metastatic HER2- BC, with somatic or germline BRCA mutation (sBRCA or gBRCA). This study includes two cohorts: - Cohort 1: patients treated through the French Early Access Program from November 2018 to September 2019. Inclusion of patients with sBRCA mutation was allowed. - Cohort 2: patients treated according to the European Marketing Approval granted 21/09/2021. The primary endpoint is Time to Treatment Discontinuation (TTD) for TALA defined as Time between the date of first dose of TALA and the date of last dose or death. Results: We present the results of Cohort 1 in which includes 85 patients. Patients’ characteristics are as follows: median age 50 years; 46% triple negative BC and 54% ER+ BC; 47% BRCA1-mutated and 53% BRCA2-mutated; 94% gBRCA and 6% sBRCA; 95% ECOG PS 0 or 1; 31% premenopausal status; 40% de novo metastatic BC (mBC). Visceral, bones and central nervous system metastases were found in 61%, 54% and 11% of patients, respectively. No breast or ovarian cancer in first degree relative was found in 35 patients (41%). The median number of prior cytotoxic regimen was 2, 15% were chemo-naïve for mBC; 35% received prior platinum in the neoadjuvant, adjuvant or metastatic setting. For patients with ER+/HER2- mBC the median number of prior endocrine therapy was 2 and 74% of these patients received a CDK4/6 inhibitor prior to TALA. The median follow-up was 17.4 months [range 15.7-20.5]. Of 85 treated patients, 66 patients (78%) experienced permanent discontinuation of TALA due to progressive disease (88%), toxicity (8%), cancer-related death (3%), or other reasons (1.5%). The median TTD for TALA was 9.0 months [range 6.0-11.0] with 35% of patients still in under treatment at 12 months. At least one adverse event (AEs) was recorded in 71% of patients. Hematologic AEs (any grade) occurred in 44% of patients (anemia for 26%, thrombocytopenia for 9%, neutropenia for 8%). The most common non-hematologic AEs were alopecia (6%) and asthenia (5%). Related serious hematologic AEs occurred in 7 (8%) patients including 6 (7%) with anemia. Related serious non-hematologic AEs (vomiting, pyelonephritis) were seen in 2 patients (2%). AEs associated with temporary drug interruption, dose modification and permanent drug discontinuation occurred in 32 (38%), 16 (19%), and 5 (8%) patients respectively. After discontinuation of TALA, 83% of patients received a subsequent treatment with a TTD of 2.4 months [range 1.7-3.3]. The most common subsequent treatments were non-platinum chemotherapy (64%) and platinum therapy (24%). Conclusions: The TTD of 9 months is consistent with the outcomes and safety results of the EMBRACA study. ViTAL, the first real-word study with TALA confirms its interest in locally advanced or metastatic HER2- BC. Analysis of Cohort 2 will occur when data are mature. (Ref Litton JK, Rugo HR, Ellt J et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018; 379:753-763. Citation Format: Delphine Loirat, Marie Duboys de Labarre, Christine Essner, Ioana Hrab, Jean-Christophe Thery, Christelle Jouannaud, Cristian Villanueva, Perrine Vuagnat, Pauline Soibinet-Oudot, Anne Creisson, Audrey Mailliez, Jean-Loup Mouysset, Laura Salabert, Nadine Dohollou, Jean-David Fumet, Thibault De La Motte Rouge, Jean-Michel Vauthier, Maylis Decrop, Pascal Pujol. Phase IV study evaluating effectiveness and safety of talazoparib in patients with locally advanced or metastatic HER2 negative breast cancer and a BRCA1 or BRCA2 mutation (ViTAL) [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 P1-18-28.

Nationwide Real-Life Safety and Treatment Exposure Data on Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III, Locally Advanced, Non-small Cell Lung Cancer: Analysis of Patients Enrolled in the French Early Access Program.

Consolidation immunotherapy with the PD-L1 inhibitor durvalumab following concurrent chemoradiotherapy (cCRT) has shown a significant survival improvement and is now a standard of care in patients with unresectable stage III or non-operable non-small cell lung cancer (NSCLC). In this early access program cohort, demographic, disease characteristics and safety data were collected for 576 patients from 188 centers, who received durvalumab 10mg/kg intravenous infusion every 2weeks, until disease progression or unacceptable toxicity or for a maximum of 12months following cCRT. Durvalumab exposure data were available for 402 patients. Overall, 576 patients were included, 72.9% were men, median age 64.0years, 52.3% had a stage IIIB disease. PD-L1 status captured in 445 (77%) patients was positive (48.1%), negative (32.6%), unknown (19.3%). At the end of cCRT, adverse events (AEs) all grade ≤ 2, were reported in 22.7% of patients, mainly esophagitis (6.3%). The main reasons of discontinuation were completion of the planned 12months of consolidation treatment (42.1% patients), disease progression (28.6%) and adverse events (19.5%). Treatment completion was similar in PDL-1 positive and PDL-1 negative patients groups. 20.7% patients had a SAE drug reaction and 17.7% stopped treatment mainly due to SAE. ADR rate and early treatment discontinuation were higher in patients > 70years old. Death due to AEs occurred in 7 patients, 2 had interstitial lung disease. Safety data with durvalumab consolidation after cCRT in a large cohort of patients with stage III NSCLC are reported in this real-life cohort. Consistent data were reported both in the PD-L1 positive and PD-L1 negative NSCLC patients in daily practice.

Kte-X19 in Relapsed or Refractory Mantle-Cell Lymphoma, a “Real-Life” Study from the Descar-T Registry and Lysa Group

Kte-X19 in Relapsed or Refractory Mantle-Cell Lymphoma, a “Real-Life” Study from the Descar-T Registry and Lysa Group

Demographic characteristics of the 1902 transthyretin amyloid cardiomyopathy patients treated by tafamidis through the French early access program

Abstract Background Transthyretin amyloidosis (ATTR) is a rare and serious, systemic disease characterized by deposits of amyloid fibrils in various tissues and organs. Tafamidis meglumine is a potent and selective stabilizer of TTR, indicated since 2011 in the treatment of neurological forms of the disease. The French “Agence Nationale de Sécurité du Médicament et des produits de santé” (ANSM) granted a temporary recommendation for use (RTU) on November 28th 2018, based on ATTR-ACT, the pivotal trial results, and designed to enable use of tafamidis meglumine in ATTR cardiomyopathy (ATTR-CM) patients with NYHA I, II and III before marketing authorization. This RTU has been a unique opportunity in France to collect real world data of ATTR-CM patients treated by tafamidis meglumine. Objective We aimed to describe the characteristics of ATTR-CM patient treated by tafamidis in the setting of the RTU, over 2 years from November 28th 2018 to November 27th 2020. Methods Demographic and clinical data about the diagnosis pathway of patients included in the RTU were prospectively collected using questionnaires, as requested by ANSM to be completed by physicians at the time of tafamidis prescription. A second version of the inclusion form, introduced in May 2020, has allowed collection of additional clinical information. Results Overall, 1902 ATTR-CM patients have been included by 189 physicians from 107 centers. Nine centers included each at least 50 patients, accounting for 1092, or 57.4% of all patients. The median age of the patients was 82 years (IQR=9 years), 82% were male, and, 12.4%, 58.8% and 28.7% of patients had a NYHA class of I, II and III, respectively. For almost all patients, the diagnosis of restrictive/infiltrative heart failure was based on heart MRI and/or echocardiography (98.5%; among the 601 patients included from May 2020 28.8% had both exams, 69.7% echo only and 1.6% MRI only), the infiltrative nature of the cardiomyopathy had been confirmed by bone scintigraphy (99.3%), and the absence of light chains had been confirmed by protein electrophoresis or Bence Jones proteinuria (96.6%). Genetic test was performed in 1205 patients (69.4%). Out of the 884 patients who had a genetic test result available at the time of initial prescription, 762 (86.2%) were affected with the wild-type form and 122 (13.8%) with the hereditary form. Among the 601 patients included from May 2020, a hospitalization for cardiovascular condition within the 6 months preceding tafamidis initiation was reported for 22.3% of them, and tafamidis was initiated within 12 months after diagnosis for 92% of them (only 8% initiated the treatment beyond that period). Conclusion The RTU program has provided 1902 ATTR-CM patients with early access to tafamidis over 24 months, in France. Overall, as compared to patients included in ATTR-ACT, the pivotal trial, RTU patients were older, the proportion of wild-type was slightly higher, and NYHA distributions were similar. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Early access program sponsored by Pfizer

1080P HORIZON: Final results from a 5-year ambispective study of 705 patients who initiated pembrolizumab for advanced melanoma in the French early access program

Based on early data, compassionate use of pembrolizumab (PEM) was granted to patients (pts) with advanced melanoma (unresectable or metastatic) in a French early access program (06/2014 – 09/2015). To explore real-world evidence (RWE), enrolment for this multicenter retro and prospective cohort study began in 06/2016. We present final results for effectiveness among this population.

1200P BrigALK2 study: A multicentric real-world study evaluating brigatinib in ALK positive advanced pre-treated non-small cell lung cancers: Long-term follow-up with focus on lorlatinib efficacy after brigatinib

Brigatinib is a next-generation ALK inhibitor (ALKi) approved in ALK+ advanced NSCLC (aNSCLC) pretreated with crizotinib and in first-line setting. The objective of BrigALK study was to assess efficacy of brigatinib during the French early access program (FEAP).

Alpelisib and fulvestrant efficacy in HR-positive HER2-negative PIK3CA-mutant advanced breast cancer: Data from the French early access program.

1064 Background: In 11.2018, the PIK3CA-inhibitor alpelisib was made available in France through an early access program (EAP), in combination with fulvestrant in pre-treated PIK3CA-mutant, HR-positive, HER2-negative advanced breast cancer (ABC) patients. Patients had to received two or more prior systemic treatments for ABC, including an aromatase inhibitor and a CDK4/6 inhibitor in the absence of contraindications. This retrospective real-life, EAP-based study aimed to assess the efficacy and safety of alpelisib/fulvestrant combination in the post CDK4/6 inhibitor setting. Methods: The IRB-approved protocol and call for data were sent on 10.2020 to the cancer centers which participated the most in the EAP prospective registry. Eligible patients were women who started alpelisib/fulvestrant between 11. 2018 and 10.2020 as part of the EAP (which excluded patients with visceral crisis or inflammatory BC). Alpelisib and fulvestrant were used at standard doses. Primary endpoint was PFS by local investigators using RECIST1.1. Secondary endpoints included objective response rate and safety (NCI CTCAE v5.0). Results: 10 centers provided individual data regarding 209 consecutive patients. Patients had received a median number of 4 (1-14) previous systemic treatments for ABC, including CDK4/6 inhibitors, chemotherapy, fulvestrant (alone or in combination) and everolimus for 206 (98.8%), 159 (76.1%), 163 (78%) and 123 (58.8%) patients, respectively. With a median FU of 7.0 months, median PFS was 4.0 months (95%CI [3.5;5.0]) and 35.4% of 164 evaluable patients had an objective response. After stratification on the number of prior lines of treatment, prior exposure to everolimus had no impact on PFS (mPFS in the 123 patients pretreated with everolimus: 4.0m, 95%CI [3.5-5.5]). Of note, this population was enriched in patients who had a long disease control by everolimus (median time spent on everolimus: 7.0m, range (6.5-9.0)). In multivariable analysis, characteristics significantly associated with longer PFS were PS < 3 (HR = 0.03, 95%CI [0.02-0.29]) and prior treatment with fulvestrant (HR = 0.53, 95%CI [0.32-0.89]). N = 81(38.8%) patients discontinued alpelisib due to adverse events (AEs). Most frequent grade 3/4 AEs were hyperglycemia, skin rash, diarrhea and fatigue occurring in 13.4, 8.1, 4.8 and 1.9 % of patients, respectively. Conclusions: Despite heavy pre-treatments, alpelisib +fulvestrant had a clinically relevant efficacy in the French EAP population. Interestingly, prior treatment with either everolimus or fulvestrant did not overtly impair alpelisib-fulvestrant efficacy. The best treatment sequence for PI3KCA/mTOR inhibitors could be examined in future trials in PIK3CA-mutant ER+/HER2- ABC patients.

PNS87 360 VIEW of the French EARLY Access Program

PNS87 360 VIEW of the French EARLY Access Program

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]

PNS52 ASSESSMENT OF THE IMPACT OF THE LEVEL OF ASMR ON THE DRUG'S PRICE AND ITS NEGOTIATION TIME WITH THE HEALTH AUTHORITIES IN TREATMENTS THAT BENEFITED FROM THE FRENCH EARLY ACCESS PROGRAM

The price and time to market for a new drug are two major issues for the pharmaceutical industries in France. This study assessed the correlation between the added medical value (ASMR, a criterion assessed and rated from I to V by the HAS and used to determine the price) and the price and its negotiation time for drugs having entered the French Early Access Program (ATUc). For this study, we selected the drugs from the ATUc program as of January 1, 2014. For each product, we compared when possible, its price in the ATUc program with the one obtained when it entered the French market. Moreover, we recorded the time between the granting of the ASMR and the awarding of the price. Finally, we sorted the data by ASMR level and calculated the average price reductions and negotiation times for each group. There was no drug with an ASMR I level and only one drug with an ASMR II level, so we did not consider them. A correlation was found between the ASRM level, the price and its trading time. The higher the level of ASMR, the less the delta between its price in ATUc and its negotiated price is important and the longer the negotiation time. For ASMR III, IV and V, the price deltas were respectively -8.5%, -17% and -20.2% and the negotiation times were respectively 581.6 days, 558 days and 306.5 days. This study allows us to anticipate the average time required to negotiate prices with the authorities and the price decrease to be expected compared to the price set in the ATUc.

1344P - Outcomes of advanced melanoma patients who discontinued pembrolizumab (pembro) after complete response (CR) in the French early access program (EAP)

BackgroundInformation on outcomes after cessation of anti-PD-1 mAb for CR are scarce outside KN-001 & 006 trials. We investigated these outcomes in the French pembro EAP, where pts were less selected than in registration trials. MethodsA multicenter ambispective cohort of advanced melanoma pts initiating pembro between May 2014-Sept 2015 (CCTIRS, #15.640) was searched for pts who achieved CR. Overall and progression-free survivals with Log rank tests were used to compare curves. Results687 pts (159 with brain metastases) were included from 41 centers, which covered 75% of French pembro EAP. 79 pts (13%) achieved CR, among whom 68 (10%) stopped pembro for CR. Compared with the remaining 619 pts surveyed, these 68 pts had lower baseline serum LDH levels (54.5% vs 73.8%, respectively, were normal, p=0.016), lower ECOG PS (ECOG 0 for 298 (52.6%) and 54 (80.6%), respectively, p=0.001), and fewer metastatic sites (p=0.003). Of note, 10% of these 68 pts had >3 metastatic sites, 10% had brain metastases, 53% had 2010 AJCC stage M1c melanoma, and 67% had received previous treatment for advanced melanoma (mainly ipilimumab). Frequency of BRAFV600, NRAS, and c-kit mutation status was not different between pts who did or did not achieve CR. Median duration on pembro in these 68 pts was 21.2 m (range: 2.5-48.4, SD 10.0). Pembro was used alone to achieve CR in 79% of pts, while 4% received concurrent radiotherapy alone, 10% concurrent surgery alone, and 6% both treatments. At the cut-off date (13/09/2018), after a median follow-up since pembro initiation of 36.3 m and of 15.3 m since pembro cessation (2-31, SD 8.3), only 3% of pts experienced melanoma recurrence. Median recurrence-free survival was not achieved. These 2 pts received radiotherapy, with one partial response achieved. 5 pts died, with 2 deaths unrelated to melanoma (1 lymphoma, 1 chylothorax), 1 related to melanoma progression, and 2 of unknown causes. ConclusionsIn this large real-life cohort, 10% of pts reached CR and discontinued pembro. All but 3% were recurrence-free after a median 15.3 m of treatment, thus validating the discontinuation of anti-PD1 in complete responders. Clinical trial identificationCCTIRS, #15.640. Editorial acknowledgementRIC-Mel network and their team. Legal entity responsible for the studyMSD France. FundingMSD France. DisclosureP. Saiag: Honoraria (self), Advisory / Consultancy: MSD. L. Mortier: Honoraria (self), Advisory / Consultancy: MSD. C. Dutriaux: Honoraria (self), Advisory / Consultancy: MSD. L. Benmahammed: Full / Part-time employment: MSD. O. Morsli: Full / Part-time employment: MSD. C. Train: Full / Part-time employment: ClinSearch. A. Spampinato: Full / Part-time employment: MSD. M.T. Leccia: Honoraria (self), Advisory / Consultancy: MSD. N. Meyer: Advisory / Consultancy: MSD. J.J. Grob: Honoraria (self), Advisory / Consultancy: MSD.

Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study)

ObjectivesBrigatinib is a next-generation ALK inhibitor initially developed in ALK-positive NSCLC pretreated with crizotinib. Materials and MethodsThis retrospective multicentric study analyzed ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS). Results104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors (mainly crizotinib then ceritinib). At brigatinib initiation, 59.1% had performance status 0–1, 51.9% had ≥ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (95% CI, 0.06–20.7) months. Median PFS was 6.6 (4.8–9.9) months for the entire population. For patients who received 2, 3–4 and >4 lines of treatment before brigatinib, PFS was 4.3 (2.5–8.9), 10.4 (5.9–13.9) and 3.8 (0.8–7.4) months, respectively. In the 91 evaluable patients, disease control rate was 78.2%. From brigatinib start, median overall survival was 17.2 (11.0–not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Median OS from the diagnosis of NSCLC was 75.3 (38.2–174.6) months. ConclusionThese real-world results confirm the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-positive advanced NSCLC.

Real-Life Efficacy of Osimertinib in Pretreated Octogenarian Patients with T790M-Mutated Advanced Non-small Cell Lung Cancer.

The resistance mutation T790M is reported in 50-60% of patients pretreated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Osimertinib has been approved in these patients, but data in octogenarians remain rare. The objective of this retrospective analysis was to evaluate in real life the efficacy of osimertinib in a population of octogenarian patients. This retrospective multicentric study included pretreated octogenarian patients with EGFR T790M-mutated advanced non-small cell lung cancer (NSCLC) in the setting of the French early access program for osimertinib. The primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation. In total, 43 patients were included (mean age 84.6years; women 90.7%: adenocarcinoma 100%; never smokers 90.5%; at osimertinib initiation: performance status ≥ 2, 42.4%; stage 4, 93.0%; brain metastases 16.3%). Patients received a median of two lines of treatment before osimertinib initiation, and all received first- or second-generation EGFR TKIs before osimertinib (first line in 79.1%). Osimertinib was used as a second-line treatment in 41.9% of cases and third line or more in 58.1%. Median PFS was 17.5 (95% confidence interval [CI] 12.2-19.0) months for the entire population: 20.6 (95% CI 18.8-not reached) months in patients with brain metastases and 16.7 (95% CI 10.4-18.9) months in patients without (p = 0.1). There was no significant difference for osimertinib treatment as second or third line or more (17.1 vs. 18.6months, respectively). OS was 22.8 (95% CI 15.7-not reached) months from osimertinib initiation. The efficacy of osimertinib as second-line treatment or more in octogenarian pretreated patients with EGFR T790M-mutated advanced NSCLC in a real-life setting was similar to that in randomized controlled trials.

Brigatinib in pretreated patients with ALK-positive advanced NSCLC.

9045 Background: Brigatinib is a next-generation ALK inhibitor initially developed in pre-treated ALK+ NSCLC. Data on the efficacy of brigatinib in real world remain rare. Methods: This retrospective multicentric study analyzed ALK-+ advanced NSCLC patients pretreated with at least two tyrosine-kinase inhibitors, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: 104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors, mainly crizotinib then ceritinib in 93% patients. At brigatinib initiation, 59.1% had performance status 0-1, 51.9% had ≥ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (0.06–20.7) months. Median PFS was 6.6 (95% CI, 4.8–9.9) months for the entire population. In the 91 evaluable patients, disease control rate was 78.2% (stable, 28.2%; partial response, 45.7%; complete response, 4.3%). From brigatinib start, median overall survival was 17.2 (95% CI:11.0–not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Ten (9.6%) patients had treatment discontinuation due to intolerance or patient request. Median OS from the diagnostic of NSCLC was 75,3 (95% CI, 38,2-174,6) months. Conclusions: This study confirms the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-+advanced NSCLC. These real-world results are consistent with clinical data reported in clinical trials.

Long-term efficacy of anti-PD1 therapy in Hodgkin lymphoma with and without allogenic stem cell transplantation

IntroductionLong-term efficacy of anti-PD1 therapy and the need for a consolidation with allogenic haematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). MethodsWe retrospectively analysed 78 patients with R/R HL treated with nivolumab in the French Early Access Program and compared their outcomes according to subsequent allo-HSCT. ResultsAfter a median follow-up of 34.3 months, the best overall response rate was 65.8%, including 38.2% complete responses (CRs). The median progression-free survival (PFS) was 12.1 months. Patients reaching a CR upon nivolumab had a significantly longer PFS than those reaching a partial response (PR) (median = not reached vs 9.3 months, p < 0.001). In our cohort, 13 patients who responded (i.e. in CR or PR) to nivolumab monotherapy underwent consolidation with allo-HSCT. Among responding patients, none of those who underwent subsequent allo-HSCT (N = 13) relapsed, whereas 62.2% of those who were not consolidated with allo-HSCT (N = 37) relapsed (p < 0.001). There was no difference in overall survival (OS) between the two groups. Five of 6 patients who were not in CR at the time of transplantation (4 PRs and 1 progressive disease) converted into a CR after allo-HSCT. ConclusionMost patients with R/R HL treated with anti-PD1 monotherapy eventually progressed, notably those who did not achieve a CR. Patients undergoing consolidation with allo-HSCT after anti-PD1 therapy experienced prolonged disease-free survival compared with non-transplanted patients, but this difference did not translate into a benefit in OS. This information should be considered when evaluating the risk/benefit ratio of allo-HSCT after anti-PD1 therapy.

Superiority of Allogenic Stem Cell Transplantation after Anti-PD1 Therapy over Anti-PD1 Monotherapy Alone in Relapse/Refractory Hodgkin Lymphoma: Real World Evidence from the French Early Access Program

Background: Nivolumab demonstrated remarkable activity in patients with relapse or refractory (R/R) Hodgkin lymphoma (HL). However, long term efficacy and the need for a consolidation with allogenic stem cell transplantation remain unclear.Patient and method: We retrospectively analyzed 78 patients with R/R HL treated with nivolumab in the French Early Access Program and compared their outcome according to subsequent alloHSCT.Results: After a median follow-up of 31.5 months, the best overall response rate was 64%, including 37.3% complete response (CR). The median progression-free survival (PFS) was 12.1 months and median overall survival (OS) was not reached. At 3 years, PFS and OS rates were 35% and 65%, respectively. Patients reaching a CR upon nivolumab had a significantly longer PFS than those reaching a PR (median = not reached vs 10.1 months).In our cohort, 17 patients underwent consolidation with allogenic stem cells transplantation (alloHSCT) after nivolumab therapy (Figure 1). At the time of transplantation, 8 patients were in CR, 5 in partial response (PR) and 4 had progressed of whom 3 received a salvage therapy before alloHSCT. Interestingly, 6 out of 7 patients who were not in CR at the time of transplantation (5 PR and 1 progressive disease) converted into a CR after alloHSCT. At the time of analysis, 14 patients were alive and 13 remained disease-free after a median follow-up of 30.4 months. One-year OS and PFS from alloHSCT were 82% and 76%, respectively. Among responding patients (i.e. in CR or PR) after nivolumab monotherapy, those who underwent subsequent alloHSCT (N=13) had a better outcome than those who were not consolidated with alloHSCT (N=35) (Figure 2). In the transplanted group, none of the patients relapsed whereas in the non-transplanted group 60% of the patients relapsed (p<0.001). In the transplanted group, all patients experienced graft-versus-host disease (GVHD), acute (N=14) and/or chronic (N=7) GVHD, including 7 patients with grade III-IV GVHD. At the time of analysis, GVHD had resolved in 9 out of 13 patients. Two patients experienced non-infectious febrile syndrome which resolved with corticosteroids and one patient experienced a sinusoidal obstructive syndrome. Two patients died, one from steroid-refractory GVHD and encephalitis, one from unexplained hemoptysis after experienced steroid-refractory GVHD.Conclusions: Although patients who achieve a CR upon anti-PD1 therapy may experience prolonged remissions, most R/R HL patients treated with anti-PD1 antibody eventually progress or relapse. Our study demonstrates unprecedented disease-free survival in patients undergoing consolidation with alloHSCT after anti-PD1 therapy. Interestingly, alloHSCT post anti-PD1 can convert incomplete responses into CR in most cases. Despite expected toxicities, alloHSCT after anti-PD1 therapy appears manageable and safe in most patients. Our results suggest that consolidation with alloHSCT may represent a good option in patients treated with anti-PD1, notably in patients who are unable to achieve a CR. [Display omitted] DisclosuresHerbaux:Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Stamatoullas:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Consultancy. Brice:bristol myers squibb: Consultancy, Honoraria. Houot:bristol myers squibb: Consultancy, Honoraria.

Non-Interventional Retrospective Multicenter Study Evaluating Real Word Idelalisib Use in Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin Lymphoma Patients Enrolled in the French Early Access Program

INTRODUCTIONIdelalisib (IDELA), the first-in-class PI3K-delta inhibitor, is indicated in Europe in combination with rituximab (R) or ofatumumab for the treatment (tt) of adult patients (pts) with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, or as first-line tt of pts with 17p deletion (del(17p)) or TP53 mutation (TP53m), not eligibles for any other therapies and as monotherapy for pts with follicular lymphoma (FL) refractory to two prior lines of tt. IDELA has significant clinical activity with a manageable safety profile. However, there is a paucity of real word data regarding its effectiveness and safety. The REALIST study was initiated to better describe pts who started IDELA treatment during the French Early Access Program (EAP).AIMSThe aim of this retrospective multicenter study was to describe efficacy, adverse events (AEs), serious AEs (SAEs), AEs of special interest (AESIs, defined as diarrhea/colitis, pneumonitis, liver enzyme elevation, neutropenia, infection, and rash) and IDELA use in adult pts previously enrolled in the French EAP for CLL or iNHL.METHODSAll Investigators who enrolled at least one pt in the EAP were contacted by email inviting them to participate in this study. Only pts who initiated IDELA tt between June and October 2014 have been included in this study. For each pt, 12 months (m) follow up data were collected via an electronic Case Report Form and monitored by the Lymphoma Academic Research Organization (LYSARC). The Primary endpoint was the overall response rate (ORR) at 6 m and its 95% confidence interval (95% CI). Statistical analysis was descriptive.RESULTSSeventy-five pts were included, 41 in CLL group (39 in third-line or late and 2 in first-line with del(17p)/TP53m unsuitable for chemo-immunotherapy (CIT)) and 34 in iNHL group, all refractory after two prior lines of tt. Table 1 lists key pt characteristics at the time of initiation of IDELA. In CLL/iNHL groups respectively, median IDELA tt duration was 25.1 weeks/18.9 weeks, ORR, was 82.8%/56.5% at 6 m (data reported in 29 pts/23 pts) and 100%/57.1% at 12 m (data reported in 12 pts/14 pts), median PFS was not reached (NR)/ 6.7 m, median time to next tt (TTNT) defined as the time between the date of the last IDELA intake and the start of next tt after progression of disease (PD) was NR/11.6 m, median OS was NR in both groups and OS estimate at M12 was 69.9%/67.6%. Additional efficacy data are presented in Table 2, Fig 1 and Fig 2. In CLL/iNHL groups respectively, at least one AE was reported during the study in 35 pts (85.4%)/26 pts (76.5%), most frequently reported AEs by SOC/PT were: infections and infestations 61.0%/50.0% (pneumocystis jirovecii pneumonia (PJP) 2.4%/5.9%), gastrointestinal disorders 56.1%/35.3% (diarrhea 41.5%/29.4%), blood and lymphatic system disorders 41.5%/41.2% (neutropenia 17.1%/23.5%) and investigation 43.9%/47.1% (hepatic enzyme increase 19.5%/14.7%). 24 pts (58.5%)/15 pts (44.1%) discontinued temporary IDELA, 6 pts (14.6%)/8 pts (23.5%) discontinued permanently for AE, 38 pts (92.7%)/25 pts (73.5%) had at least one AESI, 10 pts (24.4%)/11 pts (32.4%) had at least one serious AESI, 3 pts (7.3%)/6 pts (17.6%) permanently discontinued IDELA for AESI and deaths were reported during the study in 13 pts (31.7%)/11 pts (32.4%), mainly due to PD (46.2%/72.7%).CONCLUSIONThe results of this non-Interventional study of heavily pretreated CLL and iNHL population treated by IDELA monotherapy or in combination with rituximab indicate that IDELA is an effective treatment in routine clinical practice with an acceptable safety profile. ORR at 6 months was 83% in CLL full analysis set and 79% in del(17p)/TP53m sub-group and 55% in FL sub group. These results mirror those of clinical trials. No unexpected IDELA safety information was identified in this study and the pattern of AEs corresponds to that reported in previous clinical studies and might be improved by specific management of AESI including PJP prophylaxis to be administered to all patients throughout IDELA treatment. DisclosuresYsebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Feugier:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salles:Novartis: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Sylvain:Gilead: Other: scientific advisor board. Glorian Kergaravat:Gilead Sciences: Employment. Simpson:Gilead Sciences: Employment. Ramroth:Gilead Sciences: Employment. Abdelhadi:Gilead Sciences: Employment. Haioun:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Troussard:Gilead: Other: scientific advisory board.

Real-life efficacy of osimertinib in pretreated patients with advanced non-small cell lung cancer harboring EGFR T790M mutation

Objectives The efficacy of osimertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR T790 M resistance mutation was demonstrated in clinical trials. However, data on efficacy of osimertinib in real world remain rare.Materials and methods This retrospective multicentric study analyzed T790M-positive advanced NSCLC patients enrolled in French early access program for osimertinib. Patients were pretreated with first- or second-generation EGFR tyrosine-kinase inhibitor and for a majority with chemotherapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation.Results 205 patients (mean age, 69.5 years; female, 68.8%; adenocarcinoma, 97.5%, never-smokers, 71.5%) were analyzed. Osimertinib was used in second and third line in 18.0% and 82.0% of patients, respectively. Median PFS was 12.4 (95% CI, 10.1–15.1) months. In patients with and without cerebral metastasis, PFS was 9.7 (7.7–13.5) and 15.1 (12.0–17.1) months (p = 0.21), respectively. PFS in second and third line or more was 12.6 (6.7–17.5) and 12.4 (9.7–15.3) months, respectively. Median PFS in patients with EGFR exon 19 deletion and exon 21 mutation was 13.5 (10.1–16.0) and 9.7 (7.4–13.2) months, respectively (p = 0.049). Median OS since osimertinib initiation was 20.5 (16.9–24.3) months: 23.1 (18.6–27.8) and 18.0 (12.2–22.2) months in patients without and with cerebral metastasis (p = 0.11); 17.5 (11.6–27.8) and 21.7 (17.3–24.3) months as second or third line of treatment or more (p = 0.46), respectively. Median OS in patients with EGFR exon 19 deletion and exon 21 mutation was 23.1 (18.6–25.7) and 15.3 (11.6–21.7) months, respectively (p = 0.03).Osimertinib dosage was modified in 8.0% of patients and definitively discontinued for adverse events in 5.9%. Fifty patients benefited from rebiopsy (persistence of T790 M mutation, 44.7%; C797S mutation, 21.1%; cMET amplification, 8.0%).Conclusion In pretreated patients with T790M-mutated advanced NSCLC, the efficacy of osimertinib appears similar in real-world setting to that of clinical trials.

P1.13-09 Efficacy and Tolerance of Osimertinib in Real Word Setting: Results of the French Early Access Program (EXPLORE T790M GFPC Study)

P1.13-09 Efficacy and Tolerance of Osimertinib in Real Word Setting: Results of the French Early Access Program (EXPLORE T790M GFPC Study)

Impact of simultaneous radiotherapy in melanoma patients treated with pembrolizumab in the French early access program.

9555 Background: Information on the use of radiotherapy in anti-PD-1 monoclonal antibody-treated melanoma pts is limited although some data support a synergistic effect. Methods: We investigated the influence of simultaneous radiotherapy in a multicenter ambispective cohort of advanced melanoma patients initiating pembrolizumab between May 2014-sept 2015 (CCTIRS, #15.640). Palliative or curative intent of radiotherapy was recorded. Overall (OS) and progression-free (PFS) survivals were analyzed using Kaplan-Meier survival analysis and Log rank tests were used to compare curves. Results: 663 pts (151 pts with brain metastases) were included in 40 French centers, with 125 pts (19%) receiving simultaneous radiotherapy (43 pts with ≥1 brain metastasis, 82 without). No significant difference in baseline LDH level, ECOG performance status, N of metastatic sites, previous treatment lines or post-progression therapies was observed between pts who did or did not receive radiation. As compared to pts without brain metastases, radiotherapy was performed in brain metastases pts closer to initiation of pembrolizumab (median 1.1 m vs 3.7 m, p = 0.009) and more frequently with a curative intent (72% vs 37%, p < 0.001). Globally, OS was longer in radiated vs non-radiated pts (median 18.9 m vs 12.5 m, HR:0.78, 95%CI: 0.57-0.96). This benefit was mainly driven by the pts with brain metastases (OS: median 26.0 m vs 6.0 m, HR:0.35, 95%CI:0.22-0.56, p < 0.001)(PFS: 6.4 m vs 2.5 m, HR:0.54, 95%CI:0.36-0.81, p < 0.002). No significant difference was seen for OS in radiated pts without brain metastasis, who were mainly radiated later and for palliative reasons and had shorter PFS (2.8 vs 3.4 m, HR 1.32, P < 0.03). Conclusions: Simultaneous radiotherapy may enhance efficacy of anti-PD1 therapy, particularly when initiated early and in brain metastases pts. Controlled studies are needed. Clinical trial information: 15.640.