Previous Lines Research Articles

Phase II of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.

e15563 Background: In chemorefractory metastatic colorectal cancer (mCRC), targeted therapy such as TAS-102 and regorafenib have shown a modest survival benefit with a median progression free survival (PFS) of only about 2 months. A phase I of FOLFIRINOX3-bevacizumab (bFOLFIRINOX 3) defined the RP2D for irinotecan and showed promising activity. The aim of this phase II trial was to evaluate the safety and efficacy of bFOLFIRINOX-3 in chemorefractory mCRC. Methods: The phase I trial defined the combination of bFOLFIRINOX-3 at the irinotecan’s RP2D of 70mg/m² day 1 and day 3. In phase II, patients > 18years and ECOG 0 or 1, with a pathological confirmed mCRC and experienced treatment failure after standard chemotherapies that include at least 5-fluorouracil, oxaliplatin and irinotecan were enrolled. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg), folinic acid (400mg/m2), 5-fluorouracil (2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (70mg/m² administered before and after infusional 5-fluorouracil). CT scan were performed every 2 months. Primary endpoint was the 2-months PFS. Secondary endpoints included objective response rate (ORR), median PFS, overall survival (OS) and toxicity. Results: Twenty-free patients were enrolled (October 2018 to December 2022). Median age was 62 y (range: 50-70y). These patients have been treated with several previous lines of chemotherapy (median = 3, range [1-6]). Median follow up was 11 months (range [3-31.3]). The 2-months PFS was 100%. Overall response rate was 17,4%. Median PFS was 7.8 months (IC95%[5.9;9.5]) and median OS was 31.3 months (IC95% [12.4;NR]). Grade 3 adverse events occured in 43.5% with mostly diarrhea (39.1%) and neutropenia (21.7%). Grade 3 diarrhea was consistently resolving after a dose reduction of chemotherapy. The most common drug-related adverse events (all grades) were fatigue (60.9%), diarrhea (73.9%), nausea (39.1%), peripheral neuropathy (47.8%), thrombopenia (82.6%) and anemia (56.5%). Conclusions: The combination of bFOLFIRINOX-3 yielded better ORR, median PFS and OS than standard of care. The regimen was well tolerated. The study met its primary endpoint and support for future randomized phase III compared to standard of care. Clinical trial information: NCT03795311 .

A self-assessment survey to identify the risk of screen failure in phase I clinical trials (SCITEP score).

e18725 Background: Screen failures (SF) in early phase clinical trial are deleterious for patients, physicians and drug companies. It is therefore crucial to identify risk factors of SF, in order to optimize drug development and maximize patient’s benefit. Self- patient reporting is a new method of clinical evaluation based on the patient's experience that can meaningfully evaluate patient’s outcome. Methods: We created a self-assessment survey comprising 15 questions extracted from the ESAS, EQ-5D and PALLIA 10 scores, which evaluate patient’s (pts) symptoms and quality of life, each item being scored from 0 to 10, for a total of 0 to 150. Patients entering a phase I clinical trial at Gustave Roussy cancer center between January 10th and October 26th 2022 were surveyed at screening (T0), and subsequently every month (T1, T2,..) until end of treatment. Results: 227 of 275 pts entering a Ph1T were assessed between January 10th and October 26th 2022. Most frequent tumor types were lung (18%), GI (16%), hematological (10%) and gynecological cancer (9.3%); 56% were female. At data cut off (December 19th 2022), 25 pts were considered SF. There was no difference observed between SF pts and pts who went on with the trial in terms of ECOG, RMH score, albumin and LDH levels, number of previous lines of treatments and of metastatic sites at baseline (Table 1). At T0, there was a significant difference in the SCITEP score between SF pts and the others (median score 41 [IQR 26-63] vs 20 [IQR 10-38], p < 0.001). Internal validity of the score was good (cronbach alpha > 0.7). With a cutoff of ≥35, sensitivity of the survey to identify pts at high risk of SF was of 66.6% and specificity of 70.5%. Regarding overall survival, pts with a score ≥35 (n = 68) at T0 were at higher risk of death (survival rate at 3 months of 53% vs 65%, p < 0.01). Conclusions: Self-assessment of risk of SF by pts entering a phase I clinical trial is feasible with the SCITEP score. A score ≥35 seemed associated with a higher risk of SF and of death at 3 months. Independent cohorts are needed to revalidate this score as a tool to better detect pts at risk of SF and thereby optimize drug development. [Table: see text]

Effectiveness of anti-B-cell maturation antigen (BCMA)-targeting therapy after selinexor treatment.

e20034 Background: Multiple myeloma (MM) remains incurable, with the disease typically becoming refractory to three main classes of standard therapies: immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (αCD38 mAbs). Treatments with novel mechanisms of action, including the XPO1 inhibitor selinexor and T-cell engaging anti-B-cell maturation antigen (αBCMA)-agents (antibody drug conjugates [ADC], bi-specific antibodies [BiS]), are increasingly used for treatment of relapsed and/or refractory MM (RRMM) after standard therapies have failed. Emerging data suggests a deleterious impact on T cell function with certain MM treatments, including alkylators and PIs, leading to inferior clinical outcomes. The influence of selinexor-based treatment on T cell function, which may alter the efficacy of αBCMA agents following selinexor treatment, is unknown. Methods: We analyzed the effectiveness of non-cellular αBCMA (NCA) therapies in pts with MM treated in 4 clinical studies (STORM [NCT02336815]; STOMP [NCT02343042]; BOSTON [NCT03110562], XPORT-MM-028 [NCT04414475]) with selinexor + dexamethasone (Xd), with or without PIs, IMiDs, or αCD38 mAbs, followed by therapy with NCA. After end of treatment with selinexor, survival follow-up data was collected every 3 months for 1 (STORM, STOMP, XPORT-MM-028) to 5 years (BOSTON). Results: Across the 4 clinical studies, 724 pts received selinexor, 404 of which had therapy post-selinexor documented. Thirty-seven pts (median age: 68, range: 40-87) received NCA therapy at any time following a selinexor regimen (Xd, n = 12; Xd + bortezomib, n = 9; Xd + pomalidomide, n = 6; Xd + daratumumab, n = 3; Xd + carfilzomib, n = 5; Xd + ixazomib, n = 2). NCAs included the ADC belantamab mafodotin (n = 28), the BiS teclistamab (n = 2), SEA-BCMA (n = 2), AMG 701 (n = 1), elranatamab (n = 1), MEDI2228 (n = 1), and investigational (n = 3; 2 had αBCMA bispecific antibodies and 1 had αBCMA BITE) (1 pt received 2 NCAs, belantamab and teclistamab). For the selinexor-based regimens, the median number of previous lines of therapy was 5 (range: 2-11) and 21 (56.8%) pts had triple-class refractory MM including 8 (21.6%) with penta-refractory MM. Median time from last dose of selinexor to NCA was 8 weeks (range: 2-117). Median time to treatment discontinuation with NCA was 4.4 months (95% CI: 2.1, NE). The median overall survival from initiation of NCA was 12.0 months (95% CI: 9.4, NE) with a median follow-up of 7.8 months. Conclusions: In this cohort of heavily-pretreated pts with MM who received a selinexor regimen prior to NCA, overall survival was in the range of 1 year, akin to historical results seen with ADCs. The 8-week median time between administration of selinexor and NCAs suggests that selinexor, with various partner agents, did not negatively impact overall survival with subsequent NCA therapy.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Central nervous system (CNS) involvement in patients with refractory or relapsed large B-cell lymphoma (LBCL) is associated with an extremely poor prognosis. Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an approved treatment for patients with refractory or relapsed (R/R) LBCL that has changed the prognosis of patients with chemoresistant LBCL. However, data regarding efficacy and safety of CART cell treatment in patients with active CNS involvement are limited since they are excluded from most of clinical trials. Methods: We retrospectively collected data from 75 patients with LBCL, treated with CART cells from January 2020 to January 2023 in Henri Mondor Hospital. We identified 13 patients with active CNS involvement at the time of CAR-T cell treatment decision: 12/13 had abnormal neurological examination, 8/11 had head and/or medullar MRI abnormalities consistent with lymphoma and 9/10 had detectable lymphoma cells in the cerebrospinal fluid. We compared the characteristics of the 13 patients with CNS involvement (CNS+) with 62 patients without evidence of active CNS disease (CNS-). Median age was 69 and 59 years, respectively (p = 0.05). CNS+ patients received a median of 2 previous lines of treatment versus 3 for CNS- patients (p = 0.34). Performance status prior to CART-cell injection was 2 or more in 9/13 (69%) and 11/62 (18%) p < 0.001, respectively. 5/13 (38%) CNS+ patients had high grade B-cell lymphomas versus 11/62 (18%) CNS- (p = 0.13). CAR-T-cell was axi-cel in 10/13 (77%) CNS+ patients versus 42/62 (68%) CNS– (p = 0.74). It is noteworthy that 7/13 (54%) CNS+ patients had pre-existing low-grade B-cell lymphomas versus 15/62 (24%) CNS- (p = 0.046). Results: The best overall response rate was identical in both groups: 12/13 (92%) in CNS+ patients versus 51/61 (92%) in CNS-, including 11/13 (85%) and 44/61(72%) complete metabolic response. As shown in the figure, median progression free survival and overall survival was 5.5 and 8.4 months, respectively in CNS+ patients versus 11.5 and 21 months in CNS- patients (not significant). Regarding safety, 13/13 (100%) CNS+ patients had a cytokine release syndrome (10 grade 1–2 and 3 grade 3) versus 54/62 (87%) CNS- (49 grade 1–2 and 5 grade 3–4) and 10/13 (77%) experienced ICANS (6 grade 1–2 and 4 grade 3–4) versus 28/62 (45%) CNS- (27 grade 1–2 and 1 grade 3–4) (p = 0.06 and 0.02 for grade 3–4). Transfer into an intensive care unit occurred in 4/13 (31%) CNS+ patients versus 9/62 (15%) CNS- (p = 022). Median time of hospitalization was 37 days for CNS+ patients versus 20 days for CNS- patients (p = 0.007). Six CNS+ patients died from which 5 died of progression and 1 of infection. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Immunotherapy Conflicts of interests pertinent to the abstract. F. Lemonnier Consultant or advisory role: BMS, Kiowa, Miltenyi Educational grants: Gilead, Janssen, Roche L. Roulin Educational grants: Kite gilead, Novartis, Bristol myers squibb

Clinical benefit of personalized treatment following high throughput sequencing in metastatic melanoma: A national retrospective study.

e21534 Background: Despite the approval of effective therapies in metastatic melanoma, durable benefit concerns only a fraction of patients and new therapeutic options are still needed. Next generation sequencing is now widely available to screen for targetable genomic alterations. Clinical impact of personalized medicine strategies in melanoma, outside classical targeting, have little been reported yet. Methods: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all metastatic melanoma patients, aged 18 and over, for whom a molecular testing has identified one, or more, actionable molecular alterations and who received molecularly matched therapy accordingly, between 2018 and 2022. We excluded patients with only BRAF, NRAS or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. Response was evaluated using RECIST 1.1 criteria. Results: We included 26 patients, median age was 63 years [24-89] and sex ratio 2.7. They had been heavily pretreated (58% have received 3 or more previous lines of treatment); 77% had 3 or more metastatic sites; 58% elevated LDH levels; and 42% and 35% had brain and liver metastasis respectively; 69 % had an ECOG PS 0 or 1. Actionable molecular alterations affected MAP kinase pathway in 12/26 cases: 10 of them received trametinib for GNA11 mutations (n = 4), MAP2K1 mutations (n = 2), CBL mutation (n = 1), NF1 loss (n = 1), FYCO1-RAF1 fusion (n = 1) and KRAS amplification (n = 1) while tipifarnib was given for an HRAS mutation and sunitinib for a CBL mutation. Cell cycle pathway was targeted in 7/26 cases with abemaciclib for a CDKN2A/B mutation, palbociclib for CDKN2A deletion, ribociclib and binimetinib for concurrent loss of CDKN2A and NRAS mutations (n = 2) and siremaldin and ribociclib for CCND1 amplification and MDM2/ CDK4 amplification (n = 2). PIK3CA pathway was targeted with alpelisib (n = 1) and with sirolimus for 1 PTEN mutation. EGFR, ALK and MET mutations were targeted using afatinib, alectinib and cabozantanib respectively. BRCA spectrum ( ATM and BRCA1) was targeted with olaparib in 2 patients in combination with dabrafenib and trametinib for one patient who had relapsed under this therapy. 11/26 patients responded to this molecularly matched strategy with 4 partial responses and 7 stable diseases including 5 ≥ 6 months stable diseases, with a median follow-up of 8 months [1-54]. Among responders, median duration of response was 6.5 months [2.5-13] and 3 are still ongoing. Responding patients had GNA11 (n = 2), MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1 (n = 2), MDM2/ CDK4 and CDKN2A/NRAS (n = 2) alterations. Conclusions: High throughput sequencing followed by matched targeted therapy is a promising approach in metastatic melanoma patients refractory to approved treatments, underlying the importance of access to molecular testing and molecular tumor boards.

Sudocetaxel zendusortide (TH1902), a novel sortilin-receptor (SORT1)-targeting peptide-drug-conjugate (PDC) in patients (pts) with advanced solid tumors: Results from part 1 (dose-escalation) of a phase 1, open-label study.

3089 Background: SORT1 is expressed in a variety of tumors when compared to most healthy tissue. TH1902 is a first-in-class PDC targeting SORT1, that consists of 2 molecules of docetaxel attached to the TH19P01 peptide via a cleavable succinyl linker. Conjugating the short peptide with various anti-cancer agents allows for targeted delivery of payloads to the tumor. Here we report results from Part 1 of a FIH, multicenter, phase 1 study, designed to explore the safety, pharmacokinetics (PK) and efficacy of TH1902 in advanced solid tumors. Methods: Part 1 used a modified rapid intrapatient dose escalation design. A starting dose of 30 mg/m2 Q3W of TH1902 was used for the study based on the available pre-clinical data of TH1902 and the known safety profile of docetaxel. Eligibility criteria included pts with advanced solid tumors (all-comers) that have relapsed or are refractory to standard anticancer treatment. Pts had no limit on previous lines of therapy, and were required to have measurable disease by RECIST, expected survival of ≥3 months, ECOG 0-1, and adequate organ function. Pts were not required to be tested for SORT1 at entry. The primary objective of the study was to characterize the safety and tolerability of TH1902. The primary objective of Part 1 was to identify the maximum tolerated dose and the recommended dose for Part 2 (dose expansion). Additional objectives included the examination of the PK of TH1902 and free docetaxel, and outcomes as related to SORT1 expression. Results: As of April 2022, 18 pts were enrolled in Part 1 and included 6 ovarian, 1 endometrial, 1 cervical, 3 prostate, 3 ER+/Her2+ BC, 3 melanoma and 1 NSCLC. Pts received an average of 8 prior regimens (range: 3-20). All pts received at least 1 dose of study drug and were evaluated after the 1st cycle for a DLT. Dose levels between 30-420 mg/m2 Q3W were studied. Following safety observations among the 6 patients enrolled at the 420 mg/m2 dose level (Gr 3 neuropathy [n=2], Gr 4 neutropenia [n=2], Gr 3 ocular [n=1] and Gr 2 skin toxicities), the dose was reduced to 300 mg/m2. At the at 300 mg/m2 cohort, seven pts received a mean of 2.9 cycles. AEs (regardless of relatedness) occurred in all 7 (100%) pts, mostly Gr 1-2. One pt had Gr 3 worsening anemia (probably related) and Gr 3 abdominal pain/fistula (unrelated). AEs of interest were all Gr 1-2, and included: ocular (keratitis/dryness)=2 pts; GI (nausea/vomiting/diarrhea)=2 pts; neuropathy=2 pts; MSK (arthralgia/myalgia/extremity pain)=2 pts. In 15 evaluable pts in Part 1 clinical benefit was observed in 10 pts: 1 PR (prostate with 53% decrease in target lesion) and 9 SD. PK and SORT1 expression analyses are ongoing. Conclusions: Although biological activity has been observed, the optimal dosing regimen of TH1902 is currently under evaluation. Clinical trial information: NCT04706962 .

SELISARC: A Spanish Sarcoma Group (GEIS) phase I/II trial of selinexor plus gemcitabine in selected sarcoma subtypes—Results of the phase I part.

11520 Background: Selinexor (KPT-330) (S), a small-molecule inhibitor of the nuclear export mediator exportin-1 (XPO-1), is able to reduce mRNA and protein expression of DNA damage repair (DDR) gene products, being synergistic with DNA damage agents as gemcitabine (G) in preclinical experiments. We hypothesized that selinexor would have a synergistic effect with gemcitabine in selected sarcoma patients (pts). Methods: Adult progressing pts, ECOG 0-1, with up to 2 previous systemic therapies for advanced disease (localized unresectable/metastatic) with centrally confirmed diagnosis of undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma (LMS), alveolar soft part sarcoma (ASPS), or osteosarcoma (OS) were eligible. S (days 1, 8, 15) and G (days 1, 8) were given in four dose levels, L1: S 60 mg + G 1,000 mg/m2 30 min, L2: S 60 mg + G 1,000 mg/m2 (10 mg/m2/min), L3: S 60 mg + G 1,200 mg/m2 (10 mg/m2/min), and L4: S 80 mg + G 1,200 mg/m2 (10 mg/m2/min). A -1 level was defined with S 60 mg + G 800 mg/m2 (30 min). A classic 3+3 design was used to determine the RP2D based on DLTs observed during the first 21-day cycle. In vitro research was performed in LMS and OS cell lines to test the synergy of the combination (MTS and flow cytometry assays). Results: Between November 2020 and June 2022, 17 pts (M/F 9/8), ECOG 0/1 (14/3), median age 50 years (22-71) were recruited. The median of previous lines was 1 (1-2). Diagnosis was: 9 LMS (52.9%), 6 OS (35.3%), 1 ASPS and 1 synovial sarcoma (SS) (5.9%). Three pts were treated in each of the first 3 levels and 8 pts in L4 (2 pts were not evaluable for DLT due to improper dosing). Only one DLT was observed in L4 (G4 thrombocytopenia) and this level was selected as RP2D. G3/4 toxicity: Neutropenia (52.9%), thrombocytopenia (41.2%), febrile neutropenia (11.8%), anemia, nausea, asthenia, vomiting, alopecia, and lipase increased (5.9% each). There were 3 RECIST PR, 7 SD, and 7 PD. Median PFS for LMS was 7 months (95% CI: 3-11). No relevant clinical activity was observed in OS. In vitro cell viability studies shown that S+G was synergistic in the majority of LMS cell lines tested (combination index of 0.789 for CP0024, 0.791 for SK-UT-1, 0.604 for AA and 1.186 for IEC005). However, our results indicated antagonism of S+G in OS cell lines, with values for the combination index of 1.67 for MG63, 1.54 for SAOS2 and 1.23 for U2OS. Apoptosis assays by flow cytometry confirmed these observations in LMS and OS cells. Conclusions: At the RP2D, S 80 mg + G 1,200 mg/m2 (10 mg/m2/min) is a feasible scheme with manageable toxicity. S+G has shown promising clinical activity for LMS, which warrants further investigation in a phase II. Preclinical studies shown the synergy and the antagonism of S+G in LMS and OS, respectively. Clinical trial information: NCT04595994 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Bispecific antibodies (BsAbs) are a promising therapeutic approach for the treatment of B-cell lymphoproliferative disorders. Limited data is available regarding the impact of COVID-19 in patients treated with BsAbs. We assessed the impact of COVID-19 infection on BsAbs treatment and evaluated the severity of COVID-19 infection and the seroconversion rate. Methods: Patients treated with BsAbs at our institution were reviewed from March 2020 to January 2023. Severity of COVID-19 infection was defined according to World Health Organization (WHO) criteria. Seroconversion rate was assessed using chemiluminescence immunoassays for the determination of antibodies against SARS-CoV2 spike glycoprotein (cutoff, 40 BAU/mL). Patients who received convalescent plasma, sotrovimab or AZD7442 (cilgavimab and tixagevimab) were excluded from the seroconversion analysis. Results: One hundred and nine patients (median age, 62 years old) were included. Most frequent diagnoses were Diffuse Large B-Cell Lymphoma (73%) and Follicular Lymphoma (18%). Median number of previous lines was 2. Ninety-four patients (86%) received an anti-CD20/CD3, 13 (12%) an anti-CD22/CD3 and 2 (2%) an anti-CD19/4-1-bb. Anti-CD20 agents in the prior 6 months had been administered alone or in combination in 61 patients (56%). Twenty-two (20%) patients had received prior CAR-T cell therapy for a median of 5 months. Eighty-six patients (79%) were vaccinated (in general with Spikevax), with an average of 3 doses. COVID-19 infection was diagnosed in 61 patients (56%); 23 (38%) presented mild COVID-19 infection, 20 (33%) moderate, 11 (18%) severe and 7 (11%) critical. Ten patients were diagnosed with a second COVID-19 episode; of these, sequencing results confirmed a reinfection in 2 patients and a persistent infection in 8 patients. Median time to first negative PCR was 34 days and 62 days for those who presented a second infection. Twenty-five patients became infected during treatment causing 84% delays and 20% discontinuations. At the time of infection, 76% of the patients had negative serology. A higher seroconversion rate was observed in the post treatment setting with BsAbs after a median of 6 months. No differences were evidenced according to recent exposure to an anti-CD20 agent (figure 1D). Patients with positive serology (24%) presented milder infection (p = 0.009). After a median follow up of 34.3 months, 32 patients died (29%), 19 due to progressive disease, 6 from COVID-19 pneumoniae (10%, 5 of which were in complete response), 5 from other infections and 2 of unknown causes. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Immunotherapy, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. A. Serna Consultant or advisory role: Pharmore Research M. Jiménez Honoraria: GSK, Sanofi A. Cabirta Honoraria: Jazz, AstraZeneca, Janssen A. Albasanz Consultant or advisory role: Gilead, GSK Honoraria: Gilead, GSK, Pfizer I. Ruiz-Camps Consultant or advisory role: GSK, AstraZeneca, BMS, MSD, Gilead, Pfizer, Janssen Honoraria: GSK, AstraZeneca, BMS, MSD, Gilead, Pfizer, Janssen T. García Consultant or advisory role: Janssen, Roche, Gilead, Celgene Research funding: Janssen, AbbVie C. Carpio Consultant or advisory role: Regeneron Pharmaceuticals, Takeda Honoraria: Gilead, Novartis, AstraZeneca, BMS S. Bobillo Consultant or advisory role: Janssen, Roche, Gilead Honoraria: Janssen, Roche, Gilead Educational grants: Gilead G. Iacoboni Consultant or advisory role: Novartis, Kite/Gilead, BMS/Celgene Honoraria: Novartis, Kite/Gilead, BMS/Celgene, AstraZeneca, Roche, AbbVie, Janssen, Miltenyi A. Marín-Niebla Consultant or advisory role: Lilly, Kite, Kiowa Kirin, Takeda, AstraZeneca, Roche, Janssen Honoraria: Lilly, Kite, Takeda, Janssen F. Bosch Consultant or advisory role: Novartis, Celgene/BMS, Roche, AstraZeneca, Takeda, Mundipharma, Gilead, AbbVie, Lilly, Beigene Honoraria: Novartis, Celgenes/BMS, Roche, AstraZeneca, Takeda, Karyospharm, Mundipharma, Gilead, AbbVie, Lilly, Beigene P. Abrisqueta Consultant or advisory role: Roche, AbbVie, BMS, AstraZeneca, Janssen, Incyte Honoraria: Roche, Abbvie, BMS, AstraZeneca, Janssen, Sandoz

Association of KMT2C loss-of-function mutations in circulating tumor DNA and prolonged response to the combination of PARPi and PI3Ki.

e13003 Background: The emergence of somatic KMT2C mutations has been associated with resistance to various treatments, including chemotherapy and endocrine therapy in patients with estrogen receptor-positive breast cancers. The impact of these mutations in patients treated with poly-ADP ribose polymerase inhibitors (PARPi) and phosphatidylinositol-3-kinase inhibitors (PI3Ki) is unknown. Methods: Circulating tumor DNA (ctDNA) was obtained from plasma and peripheral blood at different time points from 38 patients prior to treatment with the combination of the PARPi olaparib with the alpha-specific PI3Ki alpelisib (NCT01623349). CtDNA was also collected immediately before the first cycle and at the time of disease progression. CtDNA underwent deep targeted sequencing (tumor-normal pairs, 397 genes (2Mb) at 25,000x somatic and 10,000x germline) at the Broad Institute of MIT and Harvard. Variants that were exonic, non-synonymous, and predicted to lead to loss-of-function were considered mutations. Cohorts were stratified according to the presence or absence of the genomic alteration, and progression-free survival was compared with the Kaplan-Meier method and log-rank test. A Cox regression was performed using age, tumor type, germline BRCA1/2 mutation status, performance status, and number of previous lines of treatment as covariates. Results: The KMT2C gene was one of the 3 genes most frequently mutated in our cohort, affecting 5 patients (15%) after the exclusion of those with variants with non-deleterious alterations. The other 2 commonly mutated genes were TP53 (76%) and PIK3CA (15%). In the comparison of patients based on these most common mutations, we identified that patients with somatic KMT2C mutations (n=5) have longer mPFS than those that were wild type (n=28): mPFS 386 vs. 151 days, log-rank p = 0.025. Cox proportional hazards model accounting for age, tumor type, germline BRCA1/2 mutation status, performance status, and number of previous lines revealed a hazard ratio of 0.16; p = 0.007. All somatic KMT2C mutations were proximal to the SET domain critical for methyltransferase activity. Upon progression, the KMT2C-mutated clones were suppressed to below the detection level of mutation calling algorithms. Analysis of the raw files revealed that the clones were suppressed but not eliminated. Conclusions: While the emergence of KMT2C has been reported to be associated with cancer progression and resistance to different therapies, patients with deleterious KMT2C mutations in the ctDNA may benefit from therapy with PARPi and PI3Ki.

Immunohistochemical expression of ER and p53 as predictive biomarkers of immunotherapy in endometrial cancer.

e17626 Background: Immune Checkpoint Inhibitors (ICIs), either as monotherapy or in combination with tyrosine kinase inhibitors (TKIs), were recently incorporated into the therapeutic guidelines for recurrent/metastatic endometrial cancer (EC). Microsatellite Instability (MSI) is the only biomarker to guide treatment. We evaluated the predictive significance of Estrogen Receptor (ER) and p53 expression. Methods: Medical charts of EC patients that received ICIs in our institution for advanced/metastatic disease were retrospectively reviewed. TP53 and ER expression were determined by immunohistochemistry. Survival analysis was performed using IBM SPSS statistics v.25. Results: Thirty-two patients were included in our analysis. The median age was 63.1 years (25th-75th percentile: 57.6 – 69.6). 62.5% of the patients had endometrioid histology, 21.9% serous histology and 15.6% of them displayed other histology. 46.9% of the patients had grade 1-2 tumors and 53.1% grade 3 tumors. 21.9% of them were diagnosed with stage 1-2 disease, while 78.1% presented with stage 3 disease. 62.5% received 0-1 prior lines of treatment and 37.5% of them received more than 2 prior lines. Molecular characteristics are presented in the table. All MSI-High patients received anti-PD1 monotherapy with a median PFS of 11.9 months (95% CI:2.3-21.5). Microsatellite Stable (MSS) patients received pembrolizumab-lenvatinib combination with median PFS 7.54 months (95% CI:2.6-11.5). ER positivity was associated with significant PFS benefit in both the ICI monotherapy group (11.9 vs. 0.63 months, p=0.061) and the group that received ICI/TKI combination (11.3 vs. 1.75 months, p=0.001). Analogous benefit was noted in the Overall Survival post start of IO or IO/TKI treatment (9.8 vs 0.6 months in MSI-high patients and 20.6 vs 5.9 months in MSS patients). ER-positivity remained an independent predictive factor favoring PFS in the Multivariate Cox regression analysis when adjusting for immunotherapy type, histology, and previous lines of therapy (HR=0.216, p=0.013). Conclusions: ER expression proved to be an independent prognostic factor regarding PFS in our cohort of patients. Further studies are needed to investigate the role of ER as a predictive biomarker for immunotherapy in EC. [Table: see text]

Molecular characterization of resistance to immune checkpoint inhibitor and chemotherapy treatment in advanced non-small cell lung cancer.

9034 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a leading cause of cancer death. Standard of care (SOC) treatment for advanced NSCLC patients include immune checkpoint inhibitors (ICI) and/or chemotherapy (CT). However, the majority of patients do not respond to SOC therapy. Mechanisms of resistance and how they differ across treatments are not fully understood. We characterized molecular markers of resistance for advanced NSCLC patients with ICI monotherapy, CT, or combination ICI-CT. Methods: Advanced stage III or IV NSCLC patients with adenocarcinoma histology who received at least 21 days of ICI monotherapy, CT, or combination ICI-CT were identified from a de-identified, multimodal real-world database from Tempus Labs, Inc. All patients had a tissue biopsy taken within 100 days prior to the specified therapy start and all samples underwent next generation sequencing with the Tempus xT assays (DNA-seq of 596-648 genes at 500x coverage and whole transcriptome RNA-seq). Resistance to therapy was defined as having time to next treatment &lt; 90 days, or disease progression or death within 120 days of therapy initiation. We characterized the clinical and molecular characteristics of patients and compared differential expression of genes by resistance status for each cohort. Results: A total of 365 patients were included in the study (ICI = 121, CT = 122, ICI-CT = 122). Across cohorts, 30% of patients were identified as having resistance to treatment (ICI = 35%, CT = 23%, ICI-CT = 32%). 53% of patients were &gt; 65 years (median [range] = 67 [25- 88]), and 53% were males. Most patients were white (63%) and had a history of tobacco use (85% current or former smoker). At the time of biopsy, most patients were diagnosed with metastatic NSCLC (Stage IV = 73%) and had received no previous lines of therapy (92%). The alteration frequencies of known NSCLC oncogenic driver mutations including TP53 (65%), KRAS (42%), STK11 (14%), KEAP1 (11%), and EGFR (9%) were broadly consistent with previous characterizations of NSCLC. Validated biomarkers of response to ICI treatment such as Tumor Mutation Burden, IFN-γ signaling, PD-1, and PD-L1 expression were negatively associated with resistance to ICI treatment. Across the ICI, ICI-CT, and CT cohorts, 253, 153, and 178 genes, respectively, were significantly upregulated (FDR &lt; 0.05, LogFC &gt; 1) in patients with resistance to treatment. Of the 550 distinct genes correlated to resistance across treatments, 95% were unique to each cohort, and only 32 genes (5%) were shared across more than one treatment cohort. Conclusions: Distinct molecular characteristics were associated with resistance to ICI and/or CT treatment. This suggests that mechanisms of resistance to ICI monotherapy, ICI-CT, or CT could be separate and unique. Further research can provide valuable insights for novel therapies or combinations.

Outcomes following brexucabtagene autoleucel administered as an FDA-approved therapy for adults with relapsed/refractory B-ALL.

7001 Background: In October 2021, brexucabtagene autoleucel (brexu-cel) became the first CAR-T cell therapy to receive FDA approval for adults (≥18 yrs) with relapsed/refractory (r/r) B-ALL. Approval was based on Phase II results of ZUMA-3, a single-arm, open-label, multicenter trial which reported on 55 treated patients with CR/CRi achieved in 71%; cytokine release syndrome (CRS) and neurologic toxicities occurred in 89% (grade 3-4, 24%) and 60% (grade 3-4, 25%), respectively. Here, we report outcomes of 76 adults with r/r B-ALL treated with post-approval brexu-cel at 13 U.S. centers. Methods: Retrospective data were collected across centers participating in a real-world outcomes collaborative of CAR-T in ALL (ROCCA). Descriptive statistics, Kaplan-Meier methodologies and cumulative incidence functions were used to summarize outcomes. Results: Among 76 patients infused, median age was 44 yrs (range, 18-81); 54% were male, 57% were non-Hispanic White (25% Hispanic), and 71% had Ph-neg disease. Median number of previous lines of therapy was 3.5 (range, 1-9) including blinatumomab in 53% and inotuzumab in 37%; 46% had relapsed post-transplant. Prior to apheresis, 69% of patients had active disease ( &gt; 5% marrow blasts or presence of extramedullary disease), including 8 patients with CNS3 disease, 19% had detectable measurable residual disease (MRD) only, and 12% were MRD-neg. Median time from apheresis to infusion was 31 days. Lymphodepletion was predominantly with flu/cy (88%); 5 received cy/cladribine, and one patient each received single agent cy, single agent cladribine, and single agent bendamustine. Among 65 patients at least 28 days post-CAR-T with response assessed, 90.8% achieved CR/CRi, of whom 83% were MRD-neg, including CNS disease clearance in 7/8 CNS3 patients. CRS and ICANS (ASTCT criteria) occurred in 81.6% (grade 3-4, 6.6%) and 59% (grade 3-4, 38.6%), respectively. Median follow-up for survivors was 196.5 days (IQR 135.5-284.5). At last follow-up, 21 patients progressed/relapsed and 13 had died (7 of B-ALL; 6 of neurotoxicity/infection). Cumulative incidence of relapse and death in remission at 180 days were 31.5% (95% CI: 19.7%-44.1%) and 8.9% (95% CI: 3.5%-17.5%), respectively, while six-month PFS and OS were 58.8% (95% CI: 44.6%-70.5%) and 86.7% (95% CI: 75.8%-92.9%), respectively. Eleven patients underwent allogeneic transplant in CR/CRi after brexu-cel; all of whom remain in remission at last follow-up. Conclusions: These data are the first to demonstrate post-approval efficacy and toxicity rates of brexu-cel in adults with r/r B-ALL. Unlike the ZUMA-3 population, 31% of patients infused in this real-world cohort lacked morphologically detectable disease and 8 had CNS3 prior to apheresis. Our data confirm high response rates associated with brexu-cel in adult ALL, but also highlight the need for interventions to reduce associated toxicities.

Real-life experience of trastuzumab deruxtecan (T-DXd) in patients with heavily pretreated HER2 positive advanced breast cancer: A retrospective single institution study.

e13035 Background: T-DXd is a HER2 antibody–drug conjugate. It improves patient outcomes and is FDA approved for the treatment of patients with Her-2 positive and Her-2 low metastatic breast cancer. However, the impact of T-DXd use in real life compared with the findings reported in clinical trials with strict inclusion criteria has rarely been assessed. We performed a real-world study to evaluate the outcomes of patients with advanced HER2+ and HER2-low expression breast cancer. Methods: We conducted a retrospective single institution study and collected the clinical and pathologic data of patients with metastatic breast cancer who were treated with T-DXd from 2019 to 2022. The primary end point, time to treatment failure (TTF) was defined as the interval from T-DXd initiation to discontinuation. We compared the TTF of T-DXd with previous lines of treatment and also report its safety and tolerability. Results: Thirty-one patients were included in this study, seventeen with HER2-low expression and fourteen with HER2 positive. Patients had received a mean of three prior lines of therapy (ranging from 1 to 13). 32.2% of patients had ≥ 5 lines of therapy prior to T-DXd. TTF was 104 days, 95% CI [58,162] in T-DXd compared with 151 days, 95% CI [119,217] in the previous line of therapy. 2 patients (6.4%) had treatment discontinuation due to adverse events (AEs) (1 patient due to grade 3 fatigue and 1 patient due to concern for ILD). 3 patients (9.6%) had treatment delay or dose reduction due to AEs. A total of 67.7% of patients (21/31) developed AEs on T-DXd. 4 (12.9%) had grade 3 or 4 AEs. Fatigue was the most common AE followed by nausea/vomiting and thrombocytopenia. A total of 17 patients had T-DXd discontinued-15 patients discontinued due to progression or death, 2 discontinued due to AEs. 9 out of 31 patients had brain metastasis. Amongst patients with brain metastases, 7 showed stable disease while on T-DXd (1 had previously progressed on tucatinib, trastuzumab, and capecitabine). In the subgroup analysis, in patients with HER2-low expression, TTF was 98 days 95% CI [41-153] with T-DXd compared with 192 days, 95% CI [84,363] in the previous line of therapy. 2 out of 14 patients developed grade 3 or 4 AEs. Fatigue was the most common AE. In HER2+ subgroups, TTF was 126 days, 95% CI [58,353] in T-DXd vs 125 days, 95% CI [106,217] in the previous line of therapy. 2 out of 17 patients developed grade 3 or 4 AEs. Conclusions: To the best of our knowledge this is the first real life retrospective study evaluating the efficacy and tolerability of T-DXd. Overall, T-DXd had acceptable efficacy and tolerable toxicity in heavily pretreated patients. T-DXd showed a good response rate in patients with active brain metastasis. Our findings are consistent with published data on T-Dxd but is limited by virtue of retrospective series.

Randomized phase 2 study of gemcitabine with or without ATR inhibitor berzosertib in platinum-resistant ovarian cancer: Final overall survival (OS) and biomarker analyses.

5512 Background: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (HR = 0.57, one-sided log-rank p = 0.044, which met the one-sided significance level of 0.1 used for sample size calculation). Final overall survival (OS) and corresponding biomarker analyses are reported here. Methods: Patients (pts) with platinum-resistant high-grade serous ovarian cancer and unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting, were randomized 1:1 to gemcitabine/berzosertib versus gemcitabine alone. Randomization was stratified based on platinum free interval (PFI), PFI≤3 months versus &gt; 3 months. Crossover from gemcitabine to gemcitabine/berzosertib was allowed upon disease progression by RECIST 1.1. OS was a secondary endpoint while preplanned exploratory correlative studies included assessment of DNA repair pathways and replication stress (RS) alterations by targeted gene sequencing and/or immunohistochemistry (IHC). Results: Seventy pts were randomly assigned to treatment with gemcitabine/berzosertib (34 pts) or gemcitabine alone (36 pts); 15 pts crossed over from gemcitabine to gemcitabine/berzosertib. At the final OS analysis (92.9% maturity), median follow-up was 53.2 weeks in the gemcitabine/berzosertib and 43 weeks in the gemcitabine alone groups. Median OS in the intent-to-treat (ITT) population was 59.4 weeks in the gemcitabine/berzosertib group versus 43.0 weeks in the gemcitabine alone group (HR 0.79, 90% CI 0.52-1.2, one-sided p = 0.18). However, when patients who crossed over to gemcitabine/berzosertib were excluded from analysis, a significant OS benefit was observed with gemcitabine/berzosertib (HR 0.60, 90%CI 0.37−0.97); HR was 0.26 (90% CI 0.1−0.7) in pts with PFI≤3 months and 0.89 (90%CI 0.50−1.59) in pts with PFI &gt; 3 months. Furthermore, significant OS benefit was observed in pts with RS-low tumors (HR 0.39, 90%CI 0.17−0.91, defined as tumors harboring no genomic RS alterations related to loss of RB pathway regulation and/or oncogene-induced RS) but not in pts with RS-high tumors (HR 0.74, 90%CI 0.35−1.56). Additional targeted gene sequencing and IHC analyses as well as analyses adjusting for patient crossover will be reported at the meeting. Conclusions: In the ITT population, gemcitabine/berzosertib did not significantly improve OS versus gemcitabine alone. Pts with PFI≤3 months and pts with RS-low tumors may derive a survival advantage from addition of berzosertib to gemcitabine in the platinum-resistant setting. Clinical trial information: NCT02595892 .

PEMBROCABOSARC: Combination of pembrolizumab and cabozantinib in patients with advanced sarcomas.

TPS11586 Background: Despite optimal treatment, up to 40% of patients with sarcomas will develop locoregional and/or distant relapse and median survival in this setting is less than two years. There are very few options in the treatment of undifferentiated pleomorphic sarcomas whereas there is no specific treatment regimen established for recurrent osteosarcoma (OSS) and Ewing sarcoma (ES). Innovative strategies are therefore urgently needed in these settings. In preclinical studies, while immune checkpoint inhibitors were insufficient in controlling tumour growth, combining them with M2 macrophage or angiogenesis targeting resulted in superior tumour control (Mao et al, Clin Cancer Res 2016; Zhu et al, Cancer Res 2014). Combining both antiangiogenic and MET inhibition properties, cabozantinib has shown both preclinical and clinical activity, notably in osteosarcoma and Ewing sarcoma (Italiano et al. ESMO 2018). Interestingly, cabozantinib has also recently been shown to trigger an innate immune response in a preclinical model (Patnaik et al, Cancer Discov 2017). Altogether, these findings pave the way for studies assessing the impact of targeting angiogenesis, MET and immune response in soft-tissue and bone sarcomas. Methods: PEMBROCABOSARC (NCT05182164) is a multi-stratum, three single-arm phase 2, multicenter, open-label study investigating pembrolizumab combined with cabozantinib in patients with advanced selected sarcomas: undifferentiated pleomorphic sarcoma (stratum 1), osteosarcoma (stratum 2), Ewing sarcoma (stratum 3). Strata 1 and 2 will enroll ~32 patients and stratum 3 ~55 patients, respectively. Each stratum phase II will be conducted using a Simon's optimal two-stage design. Eligible and consented patients must be ECOG PS 0–1, have measurable and progressive disease according to RECIST 1.1 and have received less than 3 previous lines of systemic therapy for advanced disease and consent also to baseline and per treatment biopsies. Cabozantinib will be administered orally, once daily at a fixed dose of 40 mg, continuously. Pembrolizumab will be administered by intravenous infusion every 3 weeks on Day 1 of each cycle, at a fixed dose of 200 mg. Both treatments will start on Day 1 (of cycle 1). The primary endpoint is 6-months non progression rate as per RECIST 1.1. Secondary endpoints include adverse events (AEs)/serious AEs, best overall response, and progression-free survival. Pharmacodynamic and other biomarkers will be explored on blood and tumor tissue. The first patient received study drug on May, 31, 2022; 8 of planned 119 patients have been enrolled and 5 sites across France among the planned 10, are currently enrolling patients. Clinical trial information: NCT05182164 .

Serum soluble MAdCAM-1: A new biomarker for cancer immunotherapy.

4548 Background: Antibiotics (ATB) deviate the gut taxonomic microbiota composition and have a deleterious impact on survival in ICI-treated pts. ATB downregulate the ileal mucosal addressin cell adhesion molecule-1 (MAdCAM-1), leading to the recirculation of immunosuppressive enterotropic T cells into the tumor and ICI resistance. Here, we aimed to assess the prognostic impact of MAdCAM-1 in ICI-treated mRCC pts. Methods: The GETUG-AFU 26 NIVOREN phase II trial (NCT 0301335) is a multicentric study that assessed the activity and safety of Nivolumab in pts with clear cell mRCC after anti-angiogenic therapy. We measured serum soluble MAdCAM-1 (sMAdCAM-1) levels (correlating ileal MAdCAM-1 transcripts) using Human Luminex Discovery Assay in the available plasma. Progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) were assessed using sMAdCAM-1 median as a cut off value (high if &gt;median and low if &lt;median). Multivariate Cox analysis adjusted for established risk factors: ATB, gender, age, international Metastatic RCC Database Consortium (IMDC) score, number of previous lines, hypoalbuminemia, and brain, bone and liver metastasis. Two independent cohorts of metastatic lung and bladder cancer patients validated the data. Results: Overall, 212 pts were included. Median age was 64 years (22-87), and pts were mostly male (82%). ATB users had lower levels of sMadCAM-1. Low sMadCAM-1 pts had diminished OS compared to high sMadCAM-1 pts [HR 2.97 (95%CI 1.99-4.44), p&lt;.0001]: 13.3 (95%CI 9.8-14.9; 72/106) versus 25.3 (95%CI 24.1-NR; 36/106) months. Also, low sMadCAM-1 pts had diminished PFS [HR 1.92 (1.43-2.57), p&lt;.0001]: 2.6 (95%CI 2.4-2.8; 99/106) versus 5.2 (95%CI 4.6-5.7; 86/106) months. Interestingly, sMAdCAM-1 was independently associated with OS [HR 2.40 (1.52-3.80), p=0.0002] and PFS [HR 1.55 (1.13-2.13), p=0.0071] in multivariate analysis. Low sMadCAM-1 pts had lower CBR (37% versus 63%, p=0.0004). Serum sMAdCAM-1 also predicted OS in 381 ICI-treated patients with lung and bladder cancer. Conclusions: Low sMAdCAM-1 is associated with ATB intake, ATB-independent gut dysbiosis and worse outcomes, in ICI-treated pts with metastatic lung, bladder and RCC cancer. ELISA determination of sMAdCAM-1 might guide the selection of patients amenable to microbiota-centered interventions, such as Akkermansia sp., and fecal microbiota transplantation. Clinical trial information: NCT0301335 .

Venetoclax-based salvage therapy for adult patients with relapsed/refractory acute lymphoblastic leukemia.

Dysregulation of BCL-2 family members has been reported in acute lymphocytic leukemia (ALL), with various BH3-dependencies of the leukemic clone. We conducted a multicenter retrospective cohort of patients with relapsed/refractory B or T ALL, with ven-chemotherapy or ven-navitoclax combinations, to assess efficacy and safety. Seventeen patients were included in the analysis, median age was 32 years, with 6 B-ALL and 11 T-ALL patients. Nine patients received venetoclax combined with chemotherapy, and 13 patients received venetoclax in combination with navitoclax, vincristine and asparaginase, of which 5 were already exposed to venetoclax in previous lines. ORR was 55% and 46% among the ven-chemotherapy and the ven-navitoclax-chemotherapy, respectively. Most of the responders proceeded to an allogenic bone marrow transplant in both cohorts. The most common adverse effects of the ven-navitoclax combination were infectious complications and hepatotoxicity. Our data demonstrated the possible efficacy of ven-chemotherapy and ven-navitoclax in r/r ALL with moderate toxicity.

Value of chemotherapy post immunotherapy in stage IV non-small cell lung cancer (NSCLC)

Lung cancer is the number one cause of mortality among all types of cancer worldwide. Its treatment landscape has shifted from the classic chemotherapy alone to newer regimens based on the discovery of new immunotherapy and targeted therapy drugs. However, chemotherapy is still an option for treatment of advanced non-small cell lung cancer (NSCLC) after progression on immunotherapy alone or in combination with first-line chemotherapy. This is a retrospective study based on chart review of patients diagnosed with advanced NSCLC cases who received Docetaxel as second or third line after being treated by immunotherapy and/or chemotherapy in previous lines. The data was collected from the medical records of physicians' clinics in three different hospital centers in Lebanon over the period of 5 years from July 2015 until December 2020. February 2021 was data analysis cut off time. The main aim was to assess the role of Docetaxel post-chemoimmunotherapy for patients with diagnosed NSCLC. A total of 21 patients were included in this study. The majority of our patients were males (81%). As for histologic type, most patients had non-squamous lung cancer (67%) as compared to 33% who had squamous lung cancer. Overall, our study reported a 24% response rate to Docetaxel including stable disease and partial response and a median progression free survival (PFS) of 3 months. The mean time interval elapsed from diagnosis to the initiation of Docetaxel was 11.5 months. New therapeutic options should be validated for the treatment of NSCLC in the second and subsequent lines of therapy considering the poor prognosis of this disease. The chemotherapy in second and third line may keep an important role in the treatment after progression on newer agents, but it needs more evidence in prospective studies including a larger number of patients.

The critical isthmus of left atrial anterior wall flutter is mostly circumscribed into a small area immediately behind the aortic root. Implications for catheter ablation

Abstract Funding Acknowledgements Type of funding sources: None. Background Left atrial flutters (LAFL) are typically observed in patients with previous ablation lines or surgery in the left atrium (LA). Less frequently, scar-related left atrial anterior wall (LAAW) flutters may occur. Although the presence of low-voltage areas (LVAs, a surrogate of scar) in the LA is considered an arrhythmogenic substrate and a marker of atrial cardiomyopathy, the pathophysiologic factors responsible for its formation remain unclear. We hypothesized that compression of the LAAW by the aortic root could be responsible of LVAs found in the LAAW, and therefore, be the substrate for the development of LAAW flutter. Purpose We aimed to describe: 1) the relationship between the aortic root and the presence of LVAs in the LAAW, which is the substrate for reentry; and 2) the clinical and electrophysiological characteristics of LAAW atrial flutter. Methods Consecutive patients referred for LAFL ablation between April 2019 and September 2022 in a single center were retrospectively collected. Among 55 patients with LAFL, 10 (18%) demonstrated a macroreentrant circuit with a critical isthmus identified in the LAAW, in the absence of previous ablation lines or surgery, and were included in the analysis. Previous pulmonary vein isolation (PVI) was not an exclusion criterion. All patients underwent a multidetector computerized tomography (MDCT) prior to the procedure and the images were analyzed using ADAS 3DTM imaging platform. Activation mapping was performed in all patients using a multielectrode mapping catheter and CARTO 3 navigation system. Results 9 of 10 patients were male (mean age 74,3 ± 6,3 years). LA enlargement was present in all patients (48,3 ± 4,7 mm) and the mean aortic root diameter was 34,8 ± 3,4 mm. The mean LAAW flutter cycle length was 293,4 ± 68,3 ms. In 9 of the patients (90%), the LAAW flutter critical isthmus was just behind the aortic root, separated by &amp;lt; 1 mm according to the LA-aortic root fingerprinted isodistance map (mean fingerprinted isodistance area was 5,8 ± 2,5 cm2). The remaining patient had the critical isthmus just below the aortic root, between the area in contact with the latter and the mitral annulus. Furthermore, in all cases, the critical isthmus was immersed in LVAs. All but 1 LAAW flutter terminated during radiofrequency (RF) energy applications and rendered it non-inducible. After a median follow-up of 13,6 months (IQ range 5,3-21,6), 7 patients (70%) remained without recurrences. Conclusion In patients with LAAW atrial flutter, the presence of LVAs and the critical isthmus of the tachycardia are mostly circumscribed into small areas immediately behind the aortic root. Knowledge of this close relationship and the use of the isodistance map could be useful when mapping and ablating LAAW flutter, helping to straightforward the ablation procedure.

Epicardial ablation of left atrial flutter

Abstract Funding Acknowledgements Type of funding sources: None. Background Left atrial flutter (LAFL) may have epicardial components not accessible to endocardial ablation by radiofrequency (RF) application. Subxiphoid access to the pericardial space has been reported in isolated cases. Purpose to prospectively evaluate the efficacy and safety of subxiphoid access to the pericardial space to map and ablate LAFL refractory to endocardial RF application. Methods Patients with LAFL confirmed by activation and entrainment mapping and refractory to endocardial RF application were consecutively enrolled. An epicardial component of the tachycardia circuit was suspected when parts of the AFL activation, channels of slow conduction or conduction gaps on previous ablation lines intersecting the AFL circuit were not found. Pericardial access was obtained by subxiphoid puncture performed conventionally or facilitated by saline infusion or CO2 insufflation into the pericardial space. Following pericardial access, epicardial mapping and ablation was performed with a conventional RF irrigated tip ablation catheter. All procedures were performed under oral anticoagulation and during following heparin infusion for 350 sec activation clotting time target. Results 15 patients with 18 LAFL were included (61.0 ± 8.8 years, 80% male). 14 patients have had a previous atrial fibrillation (AF) ablation. Epicardial ablation was attempted after a previous LAFL endocardial ablation procedure in 6 patients and during the same endocardial ablation procedure in the last 9 patients. Pericardial access was not achieved in 1 patient due to pericardial adhesions (after prior cardiac surgery). Ablation was successfully performed in 11 patients (73.33%) and failed in 4 patients with perimitral AFL (1 patient also had a peri-left appendage AFL). The successful ablation site was found in the transverse sinus of Theile over the Bachmann bundle in 14 patients with perimitral, septal and anterior-wall LAFL and in the oblique sinus in a posterior-wall LAFL. No patient presented relevant complications except for 2 patients who presented hemopericardium and 1 with delayed cardiac tamponade following accidental RV puncture and who required pericardiocentesis. No patient presented AFL recurrences at 19.8 months (range 6-34 months) follow-up except for 2 patients in whom ablation failed or pericardial access was not achieved. Conclusions Epicardial ablation of LAFL refractory to endocardial ablation is successful in most patients following successful pericardial access. This approach appears associated with low risk of significant complications.