Number Of Previous Treatment Lines Research Articles

Efficacy and safety of ruxolitinib in the treatment of chronic graft-versus-host disease: a retrospective analysis

Steroid-refractory chronic graft-versus-host disease (cGvHD) is associated with significant morbidity and mortality, with ruxolitinib being the first drug approved for its treatment. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of cGvHD at our center between 07/2015 and 12/2022 and identified 48 patients receiving ruxolitinib as second (18/48) or advanced (30/48) treatment line. Ruxolitinib was started on median day 340 (range 119–595) after cGvHD onset; median duration of administration was 176 (range, 79–294) days with 16/48 patients continuing treatment at last follow-up. National Institutes of Health organ grading and the intensity of immunosuppression were assessed at the start of ruxolitinib treatment and repeated after 1, 3, 6, and 12 months. Response assessment was terminated at the start of any additional new immunosuppressant treatment. The median time of follow-up was 582 (range, 104–1161) days. At the primary analysis after six months on ruxolitinib treatment, the overall response rate was 33%, and failure-free survival was 58%. Infectious adverse events ≥ CTCAE grade III were observed in 10/48 patients. The response rate was not associated with the severity of cGvHD, number of previous treatment lines, or number of additional agents combined with ruxolitinib applying a univariate regression model. At the time of the 12-month follow-up, four patients experienced recurrence of the underlying malignancy and two patients had experienced non-relapse-related mortality. Overall, ruxolitinib was relatively well-tolerated and showed outcomes comparable to the REACH3 trial in a heavily pretreated patient population.

Efficacy and safety of fruquintinib across different subgroups of patients with previously treated metastatic colorectal cancer: A meta-analysis.

e15589 Background: Most patients with mCRC eventually develop disease progression or intolerance to first- and second-line therapy. Fruquintinib, a selective oral tyrosine kinase inhibitor of VEGFRs 1, 2, and 3, has emerged as a novel treatment option for refractory mCRC. We conducted a meta-analysis to assess the safety and efficacy of Fruquintinib for the treatment of refractory mCRC compared to placebo in specific patient subgroups of interest. Methods: We systematically searched PubMed, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) reporting Fruquintinib efficacy. The data extraction followed PRISMA guidelines and our protocol was registered in PROSPERO (CRD42023477783). Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. The likelihood of Fruquintinib being associated with adverse events (AEs) was expressed by odds ratios (ORs). Results: Of the 1138 studies yielded by the search, three were included, totaling 1178 patients, of whom 786 (67%) received Fruquintinib. This meta-analysis of three randomized trials assessed the clinical outcomes of Fruquintinib in the intervention group compared with placebo in refractory mCRC. Pooled results from all three studies suggested the superiority of Fruquintinib in PFS (HR: 0.29 [0.25, 0.34], 95% CI, I² = 10%, p < 0.01) and OS (HR: 0.66 [0.57, 0.76], 95% CI, p < 0.01). Notably, subgroup analysis showed that Fruquintinib was associated with improved PFS in patients with prior use of VEGF inhibitors (HR: 0.32 [0.27, 0.38], 95% CI, p < 0.01) and those with more than three prior lines of treatment (HR: 0.37 [0.25, 0.53], 95% CI, p < 0.01), RAS wild-type status (HR: 0.25 [0.13, 0.35], 95% CI, p < 0.01), or RAS mutated (HR: 0.33 [0.28, 0.40], 95% CI, p < 0.01). In the safety analysis, fruquintinib and placebo showed no significant differences in serious AEs; nonetheless, the VEGFR inhibitor was associated with more frequent grade ≥ 3 AEs (OR: 3.13 [1.15, 8.53], 95% CI, p = 0.03). Conclusions: This meta-analysis supports the efficacy of Fruquintinib for refractory mCRC regardless of previous use of VEGF inhibitors, the number of previous treatment lines, and gene RAS mutational status, without a significant increase in serious adverse events. [Table: see text]

Apheresis for Production of Chimeric Antigen Receptor (CAR) T Cells in Patients with Multiple Myeloma - Clinical Factors, Cell Composition and T Cell Senescence

Chimeric antigen receptor (CAR) T cells have been proven as a highly promising immunotherapy for patients with multiple myeloma (MM). Apheresis of autologous CD3+ lymphocytes is the first pivotal step in the production process of chimeric antigen receptor (CAR) T cells. Repetitive activation of T lymphocytes can affect the qualitative properties, i.e. the fitness of CD3 cells leading to progressive loss of expression of the costimulatory receptors CD27 and CD28. CD3+27-28- cells are non-proliferating memory, senescent cells. In that regard, the factors influencing the manufacturing process of CAR T cells in patients with MM have not been sufficiently explored. We performed a retrospective analysis of clinical parameters influencing both collection of autologous lymphocytes and the subsequent manufacturing of idecabtagene-vicleucel with a special focus on T cell senescence, defined as loss of CD27 and CD28. Furthermore, we focused on cell-compositions of collections resulting in out of specification (OOS) events during CAR T cell manufacturing. Between January 2022 and January 2023, 36 lymphocyte collections of 32 patients with relapsed/refractory (r/r) MM were performed for subsequent CAR T cell therapy with idecabtagene-vicleucel. All collections were forwarded for further manufacturing without prior cryokonservation. 9 (25%) collections resulted in OOS; 7/9 resulting in insufficient proliferation or expansion of T cells, while 2/9 showed a microbial contamination during the manufacturing process after viral transduction for CAR generation. At apheresis, the patients were a median 63 (range 39-75) years old, 12 (38%) were female with median body weight 79 kg (49-103). The patients had a median of 7 previous treatment lines (range 3-13) and 15/36 collections were performed at partial remission or better. 8/36 collection had prior exposition to bispecific antibodies whereas in 13/36 collections the unspecific positivity for cytomegalovirus (CMV) in polymerase chain reaction (PCR) was detected. The collections were performed on a Spectra Optia cell-separator by processing median 3x total blood volume. CD3+ cells in peripheral blood (pB) were median 513.9 /µl (range 70.6-3616.0). The collections showed a median CD3+ yield with 29.8 x10 8 (range 4.9-171.6), with CD3+4+ and CD3+8+ yields 10.6 x10 8 (range 1-663.4) and 16.3 x10 8 (range 3.2-121.2) respectively, resulting in median CD4:CD8 ratio of 0.6 (range 0.1-2.6). The median yields for CD3+27+28+ and CD3+27-28- cells were 14.8 (range 2.3-88.8) x10 8 and 2.1 (range 0.1-59.8) x10 8 respectively. Noteworthy, OOS events were more common in patients with detectable cytomegalovirus replication at apheresis ( P=0.037) with a trend for prior exposition to bispecific antibodies ( P=0.086). In contrast, the collections with OOS did not differ regarding patients' age ( P=0.498), sex ( P=0.442), body weight ( P=0.364), number of previous treatment lines ( P=0.185) or remission status at apheresis ( P=0.443). In OOS collections, CD3+ cells in pB were significantly higher with median 991 /µl (range 558-2968) compared to 448.9 /µl (70.6-3616.0) ( P=0.002) and showed a trend for higher CD3+ yields with 38.9 x10 8 (range 23.9-62.2) and 28.2 x10 8 (range 4.9-171.6) respectively ( P=0.096). Interestingly, OOS products also had higher median yields of CD3+CD8+ cells with 28.1 x10 8 (range 12.2-52.3) compared to 15.3 x10 8 (range 3.2-121.2), ( P=0.046) and showed a trend for lower median CD3+CD4+ yields with 9.1 x10 8 (range 3.8-11.9) compared to 11.4 x10 8 (range 1.6-63.4), ( P=0.071). Median CD3+27+28+ yields in OOS and successful manufacturings were 9.7 x10 8 (4.7-26.0) and 17.0 x10 8(range 2.4-88.8) respectively ( P=0.030). OOS events yielded with higher median CD3+27-28- with 17.8 x10 8(range 0.2-46.1) compared to 1.4 x10 8 (0.1-59.8), ( P=0.031). We observed a negative prognostic role of CMV replication as well as of senescence of T lymphocytes on the manufacturing process. In contrast, a successful manufacturing was not influenced by patient age, sex, remission status at apheresis or number of previous treatment lines. Further analyses are required to determine measures appropriate for further optimization of autologous lymphocyte collections and improvement of collection outcomes in patients with MM.

BTK Inhibitors and Chidamide-Combined Therapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background: Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) shows poor clinical outcomes, particularly in patients ineligible for stem cell transplantation or who failed induction therapy or salvage therapy. Monotherapy Bruton tyrosine kinase inhibitors (BTKi) have established modest antitumor effect in R/R DLBCL by targeting B-cell receptor signaling, with median progression-free survival (PFS) and overall survival (OS) of 1.64-2.8 months and 6.4-8.4 months, respectively. Chidamide is a selective oral histone deacetylase inhibitors (HDACi) that shows promising treatment for DLBCL and may overcome BTKi resistance. So, we evaluated the efficacy and safety of BTKis and chidamide-combined therapy in R/R DLBCL. Methods: This retrospective study consists of 11 R/R DLBCL who received combination therapy of chidamide and BTK inhibitors between September 2021 and July 2023. Chidamide was orally administered at a dose of 20 mg twice a week, while the BTK inhibitor was administered daily. Patient clinical characteristics were collected upon patient enrollment. Efficacy outcomes included overall response rate (ORR), PFS and OS, whereas safety outcomes included incidence of adverse events. Results: 11 R/R DLBCL patients were enrolled. Median age was 61 years (range, 56-73), and 81.82% of the patients had non-germinal center B-cell-like (non-GCB) DLBCL, one had GCB DLBCL, one had transformed DLBCL. The median number of previous treatment lines was 3 (range, 3-8). 10 patients (90.91%) received treatment with BTK inhibitors before. Four patients（36.36%）failed to chimeric antigen receptor T-cell/NK-cell(CAR-T/CAR-NK) therapy. The best ORR was 81.82%, with 9 patients acquired objective disease remission after 1-2 cycles. Among them, 3 patients (27.27%) achieved complete response, and6 patients (54.55%) achieved partial remission. With a median follow-up of 5 months, the median PFS was 6.0 months (95%CI 3.14-8.86) and median OS was not yet reached. In terms of adverse events, the most common hematologic toxicities observed were grade ≥3 neutropenia (36.36%, 4/11) and grade ≥3 thrombocytopenia (36.36%, 4/11). Two patients (18.18%) had pneumonia, and one patient (9.09%) had herpes zosters. Due to the positive real-world outcomes observed in the retrospective study, prospective clinical studies of chidamide in combination with BTK inhibitors for the treatment of R/R DLBCL are underway (ChiCTR2300073233). Conclusion: This real-world study revealed promising results. Despite the majority of patients had been treated with BTK inhibitors and experienced relapse and resistance, the addition of chidamide brought patients back into remission, suggesting that chidamide can enhance the efficacy of BTK inhibitors and overcome acquired resistance. Notably, chidamide combined with BTK inhibitors showed high efficacy and manageable tolerability, making it a promising treatment option for patients with R/R DLBCL. Keywords: BTK inhibitors, Chidamide, R/R DLBCL, efficacy and safety

Improved Outcome of Relapsed/Refractory B-Cell Lymphomas Treated in Phase I Trials with T-Cell Engaging Bispecific Antibodies: A Single Center Experience

Background. Phase I trials usually enroll patients (pts) refractory to standard treatments in order to evaluate the toxicity, pharmacokinetic and preliminary efficacy of new therapeutic agents. However, in the last decade, the emergence of targeted and immune therapies has rapidly expanded the scope and eligibility of phase I trials which currently include also the efficacy assessment. This is particularly evident in B-cell non-Hodgkin lymphomas (NHL), were several treatments proved substantial efficacy in the relapsed/refractory (R/R) setting. Specifically, T-cell based immunotherapy i.e. CART cells and T-cell engaging bispecific antibodies (BSA) showed practice changing results. Aim of this study was to compare the outcome of pts enrolled in phase I trials treated with BSA-based treatment versus all the other treatment modality, with the exclusion of CART cells therapy. Methods. A total of 93 R/R B-NHL pts were enrolled and treated in 11 phase I trials from September 2016 to May 2022 at ASST Papa Giovanni XXIII Hospital of Bergamo, Italy. Investigational treatments included BSA, antibody-drug conjugate, small molecules and immunomodulatory agents, both as single agent or in combination. Clinical characteristics and outcome of patients treated with BSA-based treatment (BSA group) were compared to those of patients treated with the other classes of drug (other group). To assess clinical efficacy, the PFS of the line of treatment prior to enrollment in the phase I trial was compared to the PFS achieved after enrollment. Results. Pts population included 49 pts receiving BSA-based treatment (DLBCL=32, MCL=2, FL=12, MZL=2) and 44 pts other classes of drug (DLBCL=35, MCL=1, FL=8). Median age was 63 years-old (range 19-83) for BSA group and 61 (range 32-79) for the other group. At enrollment, most of the pts were in advanced stage (75% for BSA group and 71% for other group). In the BSA group, the median number of previous treatment lines were 4 (range 2-7) including autologous SCT (28%) and CAR-T cells (4%). In the other group median previous treatment lines were 4 (range 2-9) including autologous SCT (20%) and CAR-T cells (11%). The 2-year PFS in the BSA group was 14% and 9% with the last line of treatment (i.e. prior enrollment) and 53% and 17% after the investigational treatment in the BSA and other groups, respectively (Figure 1). We further analyzed predictor of response and PFS in the BSA group. By univariate analysis, primary or secondary refractory status (P<0.001) were correlated with clinical response. Refractory status (P=0.02), high Ki67 (P=0.016), elevated ferritin (P=0.012), ECOG >1 (P=0.004) and aggressive NHL histology (P=0.026) were correlated with poor PFS. Of note, clinical indices e.g. IPI or FLIPI, did not correlated with clinical outcome. Conclusion. The use of BSA-based treatment markedly improved the outcome of patients with R/R B-cell NHL enrolled in phase I trials, with substantial response rates and durable disease control not commonly seen with other classes of drug.

BIOM-13. ASSOCIATION OF HAND-FOOT SKIN REACTIONS WITH SURVIVAL IN RECURRENT GLIOBLASTOMA PATIENTS TREATED WITH REGORAFENIB

Abstract INTRODUCTION The phase 2 REGOMA trial suggested a survival benefit of the multikinase inhibitor regorafenib for treating patients with glioblastoma at first recurrence. Hand-foot skin reactions (HFSR) following multikinase inhibitor therapy have been reported to predict prolonged overall survival (OS) in patients with solid tumors. The predictive value of HFSR in patients with recurrent glioblastoma undergoing regorafenib therapy remains to be investigated. METHODS Fifty-seven patients (age range, 35-77 years) with recurrent IDH-wildtype glioblastomas were retrospectively identified from five centers in Germany and Switzerland. Regorafenib was administered at 160 mg/d for the first three weeks of each 4-week cycle, with individual dose adjustments according to toxicity. Patients were stratified into two groups based on the occurrence of HFSR following regorafenib. Group differences were investigated using the Mann-Whitney rank-sum and Fisher's exact tests. Kaplan-Meier analysis was used for univariate analyses, and the Cox proportional hazards regression model for multivariate analyses. RESULTS Patients received a median of two regorafenib cycles (range, 1-14 cycles). Median follow-up after recurrence was 7.0 months (range, 0.6-35.9 months). The median number of previous treatment lines was 2 (range, 1-6 lines). At the time of data analysis, 47 patients (82%) had died. HFSR were observed in 14 out of 57 patients (25%) and associated with a significantly longer OS (10.6 vs. 6.0 months; P = 0.040). No significant group differences (HFSR compared to no HFSR) were observed regarding age, the extent of resection, MGMT promoter methylation, Karnofsky performance status, or the number of completed regorafenib cycles (all P > 0.05). Cox proportional hazards regression analysis confirmed that HFSR were associated with longer OS (P = 0.039; HR, 0.438), independent of age, Karnofsky performance status, and the number of previous treatment lines (all P > 0.05). CONCLUSION Our data suggest that the occurrence of HFSR following regorafenib is associated with longer OS in recurrent glioblastoma patients.

Efficacy and Safety Analysis of Combination Therapy Based on Liposomal Mitoxantrone (Lipo-MIT) in Relapsed/Refractory NK/T-Cell Lymphoma

Background: Currently, there is no standard treatment for relapsed/refractory NK/T-cell lymphoma (NKTCL), which is characterized by highly aggressive and poor prognosis. New drugs are urgently needed to improve the therapeutic effect. Liposomal mitoxantrone (Lipo-MIT) is approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma patients who have received at least one line standard therapy previously. Phase II study data showed that the objective response rate (ORR) of patients after monotherapy was 41.7% and the complete response rate (CR) was 23.1%. Progression-free survival (PFS) was 8.5 months. Lipo-MIT showed excellent anti-tumor effect in patients with NKTCL subtype, with an ORR of 42.9%, which broke the limitation of natural resistance of NKTCL to anthracyclines. To further improve the efficacy, we tried a combination therapy based on Lipo-MIT in patients with relapsed/refractory NKTCL. Herein we will report its efficacy and safety. Methods: Nine patients with relapsed/refractory NKTCL were enrolled in this study, all of whom had previously received pegaspargase-based combination chemotherapy. The salvage treatment was a combination regimen based on Lipo-MIT. The efficacy was evaluated after every 2 cycles using PET-CT or MRI scan, and hematological and non-hematological adverse events were collected after treatment. Progression-free survival (PFS) was defined as the time from initiation of Lipo-MIT to disease progression, recurrence, death, or last follow-up. Overall survival time (OS) was defined as the time from initiation of Lipo-MIT to death from all causes or the last follow-up. Results: The median age of the nine patients was 53 years old (17-67 years old), and the male-female ratio was 7:2. Eight patients had stage IV NKTCL, one was stage II NKTCL, and all patients had an NRI score of ≥3. The median number of previous treatment lines was 2 (1-4). Three patients had recurrent NKTCL, and six patients had refractory disease to previous treatments, among whom two patients had concurrent hemophagocytic syndrome. The salvage treatment regimens were as follows: Lipo-MIT + pegaspargase + dexamethasone (N=3); Lipo-MIT + pegaspargase + dexamethasone +PD1 monoclonal antibody (N=2); Lipo-MIT +PD1 monoclonal antibody + dexamethasone (N=2); Lipo-MIT + etoposide + pegaspargase + dexamethasone (N=2). Efficacy was evaluable in all patients and the median number of treatment cycles was 3 (2-6). The best response rates were as follows: complete response in 3 (33.3%) patients, partial response in 4 (44.4%) patients, stable disease in 1 (11.1%) patient, and progressive disease in 1 (11.1%) patient. At a median follow-up of 4 months (2-13 months), 6 patients died, including 5 from disease progression and 1 from pegaspargase -associated acute pancreatitis, with a median PFS of 5 months and a median OS of 7 months. One patient underwent allogeneic hematopoietic stem cell transplantation after achieving a complete response and has been disease-free for more than 13 months now. The main adverse reactions of Lipo-MIT combination regimen were grade 3 or more bone marrow suppression (N=7), skin cyanosis (N=4), liver insufficiency (N=4), coagulation dysfunction (N=4), acute pancreatitis (N=1). The median recovery time from myelosuppression was 17 days (6-35 days). There was no correlation between skin cyanosis and efficacy. Conclusion: Combination therapy based on Lipo-MIT has a high remission rate for relapsed/refractory NKTCL, but the duration of remission needs to be further extended, and subsequent allogeneic hematopoietic stem cell transplantation may prolong survival. Lipo-MIT has obvious myelosuppression toxicity, and active supportive therapy should be given when combined with other cytotoxic drugs. In the future, it is worthwhile to conduct prospective clinical trials to explore the optimal combination therapy based on Lipo-MIT in relapsed/refractory NKTCL.

Efficacy and safety of zimberelimab (GLS-010) monotherapy in patients with recurrent or metastatic cervical cancer: a multicenter, single-arm, phase II study

ObjectiveThere is an unmet need to improve clinical outcomes for patients with recurrent/metastatic cervical cancer. Checkpoint inhibitors represent a promising treatment strategy. We evaluated the safety and anti-tumor activity of...

Clinical experience of using brentuximab-vedotin as therapy in relapsed/refractory Hodgkin's lymphoma at Hospital Guillermo Grant Benavente, Concepción, Chile

Hodgkin's lymphoma is a B-cell neoplasm with a good prognosis but a poor response to chemotherapy in refractory or relapsed cases. Brentuximab-vedotin is an anti-CD30 monoclonal antibody approved for use in these cases. This study aims to describe the clinical experience of patients treated with brentuximab-vedotin through expanded access modality. A retrospective study on clinical information of patients diagnosed with refractory or relapsed Hodgkin's lymphoma treated with brentuximab-vedotin at the Regional Hospital of Concepción in the period 2015-2021. 7 patients were identified, 5/7 male, with a median age of 35 years (21-50). Five cases were mixed cellularity, and two were nodular sclerosis. Four were in stage II, 1/7 in stage III, and 3/7 in stage IV. The median number of previous treatment lines was 4 (3-5), and the relapse was post-transplantation in two cases. In 6/7 cases, brentuximab-vedotin was used as induction, and in one case, it was used as post-autologous bone marrow transplant maintenance. The administration was outpatient via a peripheral route with a median dose of 150 mg and ten cycles. In one case, dose adjustment was required due to toxicity. Three out of 6 patients achieved complete remission and underwent autologous stem cell transplantation. brentuximab-vedotin is an outpatient medication with low toxicity that can optimize the treatment of patients with relapsed-refractory Hodgkin's lymphoma.

Reimbursement in the Context of Precision Oncology Approaches in Metastatic Breast Cancer: Challenges and Experiences

Background: Precision oncology programs using next-generation sequencing to detect predictive biomarkers are extending therapeutic options for patients with metastatic breast cancer (mBC). Regularly, based on the recommendations of the interdisciplinary molecular tumor board (iMTB), an inclusion in a clinical trial is not possible. In this case, the German health insurance system allows for the application of reimbursement for an off-label drug use. Here, we describe the current challenges and our experience with reimbursement of molecular therapies in mBC. Methods: A total of 100 applications for reimbursement of off-label therapies recommended by an iMTB were filed for patients with mBC, of which 89 were evaluable for this analysis. The approval rate was correlated with the molecular level of evidence of the respective therapy according to the National Center for Tumor Diseases (NCT) and European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) classification as well as with pretreatment therapy lines. Findings: Overall, 53.9% (48/89) of reimbursement applications were approved. Applications for therapies based on level of evidence m1 (NCT classification), tier I and II (ESCAT classification) had a significantly and clinically relevant increased chance of reimbursement, while a greater number of previous treatment lines had no significantly increased chance of approval, though a trend of approval toward higher treatment lines was detectable. Interpretation: Currently, the German jurisdiction seems to aggravate the clinical implementation of clinically urgently needed molecular therapies.

JS09.6.A ASSESSMENT OF RESPONSE TO REGORAFENIB IN RECURRENT GLIOMA PATIENTS USING FET PET AND MRI INCLUDING ADC VALUES

Abstract BACKGROUND The phase 2 REGOMA trial suggested that glioblastoma patients treated with the multikinase inhibitor regorafenib at first progression have significantly longer overall survival than patients treated with lomustine. Here, we evaluated the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and MRI for the evaluation of response to regorafenib in recurrent glioma patients. MATERIAL AND METHODS Twenty patients (age range, 30-72 years) with CNS WHO grade 3 or 4 gliomas (glioblastoma, 85%) at recurrence were treated according to the REGOMA trial with regorafenib at 160 mg/d for the first three weeks of each 4-week cycle, with individual dose adjustment according to toxicity. FET PET and MRI were performed at baseline and follow-up after the second cycle. Static FET PET parameters comprised tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Parameters derived from dynamic FET PET acquisition were time-to-peak and slope. MRI response assessment was based on RANO criteria. Additionally, mean and minimum apparent diffusion coefficients (ADC) were obtained from diffusion-weighted MRI. FET PET parameters and ADC thresholds were defined using ROC analyses to predict an overall survival of ≥ 6 months. The predictive values of FET PET parameters, ADC values, and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. RESULTS Patients received a median of three regorafenib cycles (range, 2-10 cycles). After treatment initiation, the median follow-up was 8.6 months (range, 3.2-27.3 months). The median number of previous treatment lines was two (range, 1-4 lines). At the time of data analysis, 17 patients (85%) had died. After two cycles of regorafenib, a regorafenib-induced reduction of mean TBR values by ≥ 10% predicted a longer overall survival (9.9 vs. 5.3 months; P=0.023). Interestingly, absolute mean TBR values ≤ 2.0 at follow-up were prognostic and associated with longer OS (10.6 vs. 4.5 months; P=0.007). In contrast, MTV, dynamic PET parameters, RANO criteria, and ADC values were not predictive for response or prognostic (all P>0.05). Multivariate survival analyses revealed that relative mean TBR changes were most potent in predicting response to regorafenib (P=0.038; HR, 0.246) and absolute mean TBR values for prognostication (P<0.001; HR, 0.005). CONCLUSION Data suggest that FET PET parameters are clinically valuable for identifying responders to regorafenib early after treatment initiation and helpful for prognostication. MRI parameters, including ADC values, do not appear to add valuable information in this context.

Artificial intelligence–based biomarkers of response to immunotherapy in patients with non–small-cell lung cancer considering previous lines of treatment.

e14652 Background: Lung cancer is one of the most prevalent types of cancer worldwide: 250,000 new cases are diagnosed yearly in the US, amongst which 80% are non-small cell lung cancers (NSCLC). The optimal biomarker to select patients diagnosed with advanced disease and benefiting the most from immunotherapy is still to be identified. Herein, we used KEM (Knowledge Extraction and Management) explainable Artificial Intelligence (xAI) as a tool that systematically extracts and evaluates all association rules between all variables in a database, thus enabling the identification of subgroups of patients with advanced NSCLC treated with immunotherapy with higher chances of overall survival in the NIVOBIO cohort (Foy et al. Eur J Cancer 2023). We aimed to identify biomarkers linked to optimum response to immunotherapy considering previous lines of therapies. Methods: Data was retrieved from GEO warehouse (GSE161537) and aggregated into a consolidated database totaling 82 patients and 2,568 variables. A two-step analysis plan was then performed. First step relied on KEM xAI: rules between gene expression, number of previous treatment lines and survival were explored: 51,306 rules were generated. 19 rules involving 3 genes were retained using metrics such as Support (number of examples), Confidence (conditional probability) and Lift (relative probability) and focusing on genes with a consistent signal across rules. Second, Cox proportional hazards models were generated using these genes to test the interaction between their expression and the number of previous treatment lines the patient had undergone. Genes with a significant log-rank and interaction p-value were retained. Results: Our analysis identified 2 genes that were significantly associated with overall survival and previous lines of treatment: SOS2 (p < 0.001) and LIFR (p = 0.020) high expression was associated with improved survival among patients with at least two previous treatment lines, whereas it was associated with poor survival for other patients. Consistently, low expression values of these genes were associated with poor survival in patients with less than two previous treatment lines. SOS2 and LIFR gene expression was identified as having a significant interaction with the number of previous treatment lines in the Cox model with a hazard ratio of 0.08 and 0.39 respectively. Conclusions: Our analysis enabled the identification of biomarkers not obviously related to the immune microenvironment and associated with an improved or poor survival depending on when immunotherapy was administered. These findings are laying promising foundations for the development of dynamic biomarkers and their potential translation into therapeutic recommendations after further validation.

Anti-PD1 plus BRAF/MEK inhibitors (triplet therapy) after failure of standard therapy in patients (pts) with advanced melanoma.

9528 Background: Preclinical models support the combination of immune checkpoint inhibitors (ICI) with targeted therapy (TT), suggesting a synergistic effect; however, clinical trials evaluating the efficacy of triplet combination in first-line setting showed limited advantage compared to TT only. Early data from the phase II TRIDeNT (NCT02910700) study showed promising clinical activity in anti-PD1 refractory pts. We sought to evaluate the efficacy of combined TT plus anti-PD1 after the failure of standard therapy in pts with advanced melanoma. Methods: This retrospective, multicenter study included pts with advanced melanoma who were treated with a BRAF inhibitor and a MEK inhibitor in combination with a PD1 inhibitor after failure of a minimum of one standard therapy in seven major melanoma centers between February 2016 and July 2022. Demographics, disease characteristics, therapy details, and outcome data were evaluated. Results: 59 pts were identified; med age was 48 yrs (range, 24-80), 32 pts (54.2%) were males, 20 pts (33.9%) had ECOG PS 1, 46 pts (78%) had 3 or more metastatic sites, 40 pts (67.8%) had brain metastases, and 25 (42.2%) had LDH levels above the upper limit of normal before initiation of triple therapy. Median follow-up time was 16.2 months (IQR, 6.02-20.81). Median number of previous treatment lines was 2 (range, 1-6); 40 pts (67.8%) were pretreated with at least one line of ICI and TT in any sequence. Of 55 pts who received ICI (n = 41 CTLA4 plus PD1; n = 9 PD1 mono; n = 2 CTLA4 mono; n = 3 PD1-based therapy) prior to triplet therapy, 44 pts (80%) were primary resistant (progressive disease (PD); stable disease (SD) for < 6 months), and 11 pts (20%) secondary resistant (complete response (CR), partial response (PR), SD for > 6 months) to the ICI therapy. Treatment with triplet therapy resulted in an overall response rate (ORR) of 44.1% (n = 26) and a disease control rate (DCR) of 55.9% (n = 33) with a median duration of response of 13.7 months (range, 5.4-33.2). Median PFS for the entire cohort was 6 months (95% CI, 3.88-8.08), with a 12-month PFS of 29.4% (95% CI, 17.8-42.1) and a 24-month PFS of 20.2% (95% CI, 11.0-32.8). Median OS was 15.7 months (95% CI, 8.1-23.3 months), with a 12-month OS of 52.7% (95% CI, 39.1-65.7) and a 24-month OS of 43.2% (95% CI, 29.6-55.9). Pts with extracerebral PD prior to triplet therapy (40.7%, n = 24) showed an ORR of 50%, pts with intracerebral PD (32.2%, n = 19) of 47.4%, and pts with global PD (27.1%, N = 16) of 31.3%. Treatment-related adverse events (TRAE) of grade ≥3 occurred in 17 of 59 pts (28.8%), of which cytokine release syndrome (n = 7) and hepatitis (n = 3) were the most common. In 16.9% (n = 10) of pts, TRAEs led to treatment discontinuation. Conclusions: Triple therapy has shown promising efficacy in heavily pretreated pts with advanced melanoma and may represent a treatment option after failure of standard therapy with ICI and TT.

First in class TLR7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiation therapy in patients with advanced pancreatic adenocarcinoma: Results from the AGADIR study.

4153 Background: Pancreatic adenocarcinoma is refractory to immune checkpoint inhibitors such as PD1/PDL1 antagonists. Investigating alternative immunotherapeutic approaches is a crucial need for this devastating disease. The potent immunostimulatory effects of Toll-like receptor (TLRs) have spurred efforts aimed at the development of TLR agonists as new immune-oncology agents. Radiation therapy combined with TLRs agonists has been shown to enhance antitumor immunity in the preclinical setting. Methods: AGADIR is a multi-cohort, phase 2, multicenter, open-label study investigating the novel TLR 7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiotherapy (SBRT) in patients with advanced cancers. Cohort A enrolled patients with advanced pancreatic adenocarcinoma. BDB001 was administered IV at the dose of 0.75 mg/m² on days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 on day 1 every 3 weeks. Atezolizumab was given at the dose of 1200 mg every 3 weeks. SBRT of at least one metastatic lesion was started at least one week after the first administration of atezolizumab and at the latest before the Cycle 2 Day 1. The primary endpoint is disease control rate defined as the proportion of participants with complete response, partial response or stable disease, as per adapted RECIST v1.1, observed within 24 weeks of treatment onset. Secondary endpoints include objective response, progression-free survival, overall survival and safety. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 32 pts were enrolled in 3 centers (14 male, 18 female). Median age was 64 years (range 38 – 78). Median number of previous treatment lines was 1 (range 1 – 5). The most common treatment related adverse events were grade 1/2 asthenia, chills and fever. No death was related to the treatment. Among the 21 patients for whom central review was performed at the time of this writing, best tumor response was confirmed partial response, stable disease and progressive disease in 2 (9.5%), 6 (28.5%) and 13 (62.0%) patients respectively. The disease control rate was 38.0% (95%CI 18.1-61.5). Conclusions: The AGADIR study met its first endpoint for disease control rate in patients with advanced pancreatic cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03915678 .

Safety and efficacy of trifluridine/tipiracil plus bevacizumab in RAS mutated patients with metastatic colorectal cancer.

e15605 Background: Trifluridine-tipiracil (FTD/TPI) plus bevacizumab has shown efficacy inrefractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in Ras mutated population, is limited. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to KRAS status. Methods: Eligible patients were mCRC refractory or intolerant to all standard therapies including fluoropyrimidines, irinotecan and oxaliplatin. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), PFS, and safety data were collected and analyzed. Results: Forty-two patients were enrolled. Median age was 67 years (range 41–79 years), 44% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, 85% were KRAS and 15% NRAS mutant, and 75% underwent primary tumor resection; 68% of patients had liver metastases, 49% had lung metastases, and 18% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range1–3), and 85% of patients received at least one previous anti-angiogenic agent. DCR was 57.1% (90% CI, 44.6 %-69.3%, P = 0.0690), respectively. The median progression-free survival (PFS) was 4.6 months. The most common grade 3 or higher adverse event was neutropenia (54%), and anemia (16%); 32% of patients required either dose delays or dose reductions due to toxicity. No treatment-related deaths occurred. Conclusions: FTD/TPI is an important therapeutic resource in refractory RAS mutated metastatic colorectal cancer that combines manageability and safety.

Targeting EZH2 to overcome the resistance to immunotherapy in microsatellite stable colorectal cancer: Results from the CAIRE study.

3599 Background: Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. Targeting EZH2 can enhance anti-tumor immunity by reshaping the tumor microenvironment (TME). The CAIRE study is first study investigating the impact of EZH2 inhibition in combination with immune checkpoint inhibitor in solid tumors. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of tazemetostat (800 mg BID) combined with durvalumab (1120 mg every 3 weeks) in patients with advanced microsatellite stable colorectal cancer. The primary endpoint was the disease control rate within 24 weeks after treatment onset defined as the proportion of patients with at least a tumor assessment showing connfirmed or unconfirmed complete response, confirmed or unconfirmed partial response or stable disease based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 47 pts were enrolled at Institut Bergonié (Bordeaux, Centre). Median age was 67.7 (range 39.6 – 84.0). Median number of previous treatment lines was 4: (range 1 – 6). The most common treatment related adverse events were grade 1/2 asthenia, nausea. No death was related to the treatment. Among the 34 pts for whom blinded central review of imaging was available for at least one imaging tumor assessment, best tumor response was confirmed partial response, stable disease and progressive disease in 1 (2.9%), 11 (32.3%) and 22 (64.7%) patients respectively. The disease control rate was 35.3% (95%CI 19.7 – 53.5). Conclusions: The CAIRE study met its first endpoint for disease control rate in patients with advanced colorectal cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT04705818 .

77P BRCA mutations may induce immune-resistance in breast cancer patients treated with IO-only approach: A retrospective analysis

Immunotherapy (IO) has been recently introduced in triple-negative breast cancer (TNBC) therapeutic algorithm, however no predictive biomarkers beyond PDL-1 expression demonstrated utility in clinical practice. BRCA mutations account for 15-20% of TNBC, with a positive association with platinum response and an inflammatory background on tumor tissue. Preclinical evidences demonstrated a lack of T-cell activation in BRCA-mutant (BRCAm) tumors due to an HLA machinery defects, but no subgroup effects were observed in IO pivotal trials evaluating chemotherapy-IO combinations. We retrospectively evaluated the effect of germline BRCA mutations in consecutive BC patients underwent any-line IO-only treatment in phase I/II trials at Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. Only mutations evaluated as pathogenic after genetic counselling were considered. IO treatment included PD(L)1, LAG3 and ICOS inhibitors, single agents or in combination. Statistical analysis were performed with RStudio software v2022.07.0. Of 39 pts treated with IO from June 2016 to September 2022, 22 had available germline BRCA status. 4 pts exhibited mutations in BRCA1 gene, 1 in BRCA2. All pts had triple-negative histology, except one (HR+). Median number of previous treatment lines for metastatic disease was 2 (1-8), without significant difference among BRCA groups (p=0.872). None of the other clinical features evaluated significantly differ among BRCA groups. 18 (81.8%) patients received platinum compound as therapy for metastatic disease, while 4 (18.2) received a PARP inhibitor. BRCAm pts demonstrated a significantly shorted PFS compared to wild-type (1.7 vs 3.6 months; HR 4.12, CI 95% 1.32-12.89, p=0.015), whereas a non-significant trend toward a worse OS was observed in BRCAm pts (77.1 vs 42.0 months; HR 2.31, CI 95% 0.65-8.24, p=0.199). A numerically higher primary resistance rate was also observed in BRCAm pts (80% vs 50%). In our small retrospective cohort, the presence of a pathogenic mutation in BRCA1/2 genes resulted in reduced benefit to IO-alone approach. If confirmed in a wider and prospective cohort, these results could guide the decision on first-line treatment of BRCAm TNBC.

CINOVA: a phase II study of CPC634 (nanoparticulate docetaxel) in patients with platinum resistant recurrent ovarian cancer

ObjectiveRecurrent platinum-resistant ovarian cancer has a poor prognosis with limited therapeutic options. Sub‐therapeutic intra-tumoral drug concentrations may add to therapy resistance. CPC634 (docetaxel entrapped in CriPec nanoparticles) was designed to...

Real-life experiences with CAR T-cell therapy with idecabtagene vicleucel (ide-cel) for triple-class exposed relapsed/refractory multiple myeloma patients

BackgroundChimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM), leading to unprecedented responses in this patient population. Idecabtagene vicleucel (ide-cel) has been recently approved for treatment of triple-class exposed RRMM. We report real-life experiences with the commercial use of ide-cel in RRMM patients.MethodsWe performed a retrospective analysis of the first 16 triple-class exposed RRMM patients treated with ide-cel at a single academic center. We assessed toxicities, response to treatment, CAR T expansion and soluble BCMA (sBCMA) levels.ResultsWe identified 16 consecutive RRMM patients treated with ide-cel between 06–10/2022. Median age was 69 years, 6 (38%) patients had high-risk cytogenetics, 3 (19%) R-ISS stage III, and 5 (31%) extramedullary disease. Median number of previous treatment lines was 6 (3–12). Manufacturing success rate was 88% (6% required second lymphapheresis, 6% received an out-of-specification product). At 3 months, the overall response rate (ORR) was 69% (44% sCR, 6% CR, 19% VGPR). Cytokine release syndrome (CRS) occurred in 15 (94%) patients (88% G1, 6% G2), immune effector-cell associated neurotoxicity syndrome (ICANS) in 1 (6% G1), febrile neutropenia in 11 (69%), and infections in 5 (31%). Prolonged hematologic toxicity occurred in 4/16 (25%) patients. Other non-hematological toxicities were elevated hepatic enzymes (38%), colitis (6%, G3) and DIC (6%, G2). Responses were more frequent in patients with higher CAR T expansion (100% vs 38%), and lack of decrease or plateau of sBCMA levels was typically observed in non-responders.ConclusionsWe report one of the first cohorts of RRMM treated with commercial ide-cel. The ORR was 69% and safety profile was manageable, but prolonged hematologic toxicity still represents a major challenge. Responses correlated with in vivo CAR T cell expansion, underlining the need of further research to optimize CAR T expansion.

Allogeneic Hematopoietic Cell Transplantation in Advanced Phase Mycosis Fungoides and Sézary Syndrome: A Retrospective Analysis of 57 Consecutive Patients

Background: Advanced stage Mycosis Fungoides (MF) and Sézary Syndrome (SS) are cutaneous T-cell lymphomas (CTCL) associated to dismal prognosis, with 5-year survival rates ranging from 47% for stage IIB to 18% for stage IVA2-IVB and with a high tendency to relapse. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered the only curative treatment option. Recently, allo-HCT from haploidentical donor (Haplo-HCT) has been increasingly used also in MF/SS patients. We hereby report an update on long-term outcome of MF/SS patients who underwent allo-HCT at our Center from 2001 to 2022, currently including a larger population with an increased proportion of Haplo-HCT. Methods: We retrospectively collected clinical data of all consecutive patients with MF/SS transplanted at our Center between September 2001 and May 2022. Conditioning was based on reduced intensity (RIC) regimens, including flaudarabine/cyclophosphamide/TBI200, pentostatin/TBI200, and fludarabine/melphalan in transplants from HLA-identical sibling and unrelated donor (UD), and the thiotepa/fludarabine/cyclophosphamide/TBI200 regimen in Haplo setting. GvHD prophylaxis consisted of CsA, MMF and ATG. Post-transplant cyclophosphamide was added in Haplo-HCT. Results: As of August 2022, 57 CTCL patients underwent allo-HCT at our Institution: 22 (38.5%) from a HLA-identical sibling, 13 (23%) from a 10/10 matched UD, 12 (21%) from a 9/10 or 8/10 matched UD, 1 (1.8%) from cord blood, and 9 (15.7%) from a Haplo donor. Median age at transplant was 55 years (range 20-67). Indication for allo-HCT was MF in 36 patients (63%) and SS in 21 patients (37%). Median number of previous treatment lines was 6 (range 2-11) with a median time from diagnosis to transplantation of 46 months (10-274). Disease status at transplant was complete remission (CR) in 14 cases (24.5%), partial remission (PR) in 35 (61.5%) and progressive disease (PD) in 8 (14%). Stem cell source was peripheral blood in 53 patients (92.9%), bone marrow in 3 (5.2%) and cord blood in 1 (1.8%). After a median follow up of 81 months, 30 patients (52%) were alive, of whom 23 (76%) in CR. Acute GvHD occurred in 29 patients (51%; grade III-IV in 13, 23%), while chronic GvHD in 19 (33%; moderate/severe in 10 patients, 17%). Cause of death was disease progression in 17 patients (62.5%), acute GvHD in 4 (15%), infection in 2 (7.5%) and other in 4 (15%). In the whole cohort, 5-yr overall survival (OS) and disease-free survival (DFS) were respectively 57.6% (95% CI 44-71) and 37.9% (95% CI 25-51). According to donor type, 5-yr OS was 69%, 39% and 89% and DFS 57%, 19% and 57% for HLA-identical sibling, UD and Haplo, respectively (Figure 1). 5-yr OS was significantly higher in SS versus MF patients (78% vs 47%, p=0.03) and in patients who were in CR at the time of transplant (100% vs 43.5%, p<0.001). In the Haplo setting,.disease status at transplant was CR in 1 pt and PR in 8. After a median follow-up of 26 months, 7 out of 9 patients (78%) were still alive and in CR. Acute GvHD occurred in 6 patients (66%), grade III-IV in 2 (22%), while chronic GvHD occurred in 3 patients (33%), moderate/severe in 1 (11%). Two patients relapsed at +5 and +2 months, of whom the latter died 157 days after HCT. Conclusions: After a median follow up of more than 9 years for alive patients, we confirm that RIC allo-HSCT is a powerful therapeutic strategy in selected patients with advanced CTCL, and particularly in SS. With the limitation of a shorter follow-up, transplant outcomes following allo-HCT from haploidentical donor appear to be associated with very low toxicity, excellent OS and DFS comparable to HLA-identical sibling transplants. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal