Median Prolonged Progression-free Survival Research Articles

Unleashing the potential: transarterial chemoembolization combined with intra-arterial infusion of bevacizumab for unresectable hepatocellular carcinoma.

The purpose of this study is to compare the efficacy and safety of transarterial chemoembolization (TACE) alone with transarterial chemoembolization combined with the arterial infusion of bevacizumab (TACE + Bev) in patients with unresectable hepatocellular carcinoma (uHCC). A retrospective analysis was conducted on 446 uHCC patients treated with TACE or TACE + Bev between January 2021 and March 2023. The study evaluated objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events in both treatment groups. Finally, the TACE group comprised 295 patients, and the TACE + Bev group comprised 151 patients. Patients in the TACE + Bev group exhibited significantly prolonged median PFS (7.9months vs. 10.3months, P = 0.013) and median OS (16.1months vs. 21.4months, P = 0.041), improved ORR (26.8% vs. 37.7%, P = 0.017) and DCR (71.5% vs. 80.8%, P = 0.033) compared to the TACE group. Multifactorial Cox analysis identified alpha-fetoprotein (AFP) > 400ng/ml as an independent prognostic factor for PFS and OS. Meanwhile, portal vein cancer thrombosis and distant metastasis are poor prognostic factors for OS. The overall incidence of adverse events was similar between the two groups. In comparison with the TACE group, the TACE + Bev group demonstrated efficacy in improving outcomes for patients with uHCC with a manageable safety profile.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells wasassociated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. NCT03534453. Registered at May 23, 2018.

Molecular profiling of metastatic breast cancer and target-based therapeutic matching in an Asian tertiary phase I oncology unit

IntroductionMolecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre.MethodsPatients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014–2017) prior to institutional change to FoundationOne CDx (FM1; 2017–2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022.ResultsA total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes PIK3/AKT/PTEN affected in 62% (98/158) patients and 43% of tumours harbouring a PIK3CA alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] versus 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of PIK3/AKT/PTEN-altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment versus unmatched, with median OS (mOS) of 30.1 versus 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% versus 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75).ConclusionsBroad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS.

Abstract PS17-02: Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial

Abstract Background: The EMERALD trial reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with elacestrant vs standard of care (SOC) endocrine therapy in patients (pts) with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following progression on prior endocrine therapy (ET). EMERALD is the only pivotal oral SERD clinical trial where prior CDK4/6i usage was mandated. Duration of prior CDK4/6i was shown to be a predictor of efficacy in patients with ESR1 mutations (ESR1-mut) receiving elacestrant, with median PFS (mPFS) for patients with ESR1-mut receiving at least 12 months of CDK4/6i achieved 8.61 months (elacestrant) vs 1.91 months (SOC) (SABCS 2022). This analysis evaluates the clinical benefit of single-agent elacestrant in key clinically relevant subgroups, including biomarkers, usually associated with poorer prognosis. Methods: Patients with ER+/HER2- advanced or mBC who previously had 1-2 lines of endocrine therapy, and prior CDK4/6i, were randomized 1:1 to receive elacestrant or SOC (aromatase inhibitor or fulvestrant). A subgroup analysis was performed on patients with ESR1-mut, by prior duration of CDK4/6i plus ET with at least 12 months in the advanced or metastatic setting, with concomitant presence of liver and/or lung metastases, PIK3CA mutations, TP53 mutation, and HER2 low expression. Results: Overall, 478 patients were randomized to elacestrant (n=239) or SOC (n=239), 228 pts (47.7%) had ESR1-mut, and 159 pts (71.6%) received at least 12 months of prior CDK4/6i. Out of these 159 pts, 113 pts (71%) had liver and/or lung metastases, 62 pts (39%) had a PIK3CA-mut, 61 pts (38%) had TP53m, and 77 pts (48%) had HER2 low expression. A clinically meaningful improvement in PFS favoring elacestrant compared to SOC was consistent across all relevant subgroups in pts with ESR1-mut. Conclusions: Elacestrant showed significantly greater PFS when prior treatment duration with CDK4/6i was at least 12 months, suggesting prior exposure to CDK4/6i is a surrogate marker for endocrine sensitivity. In this population, elacestrant demonstrated superior efficacy, compared to SOC, even in patients with concomitant PIK3CA or TP53 mutations, expression of HER2 low, or presence of liver and/or lung metastases. These results suggest an active ER-driven pathway for this group despite the presence of other resistance mechanisms, where single-agent oral elacestrant could be an attractive option compared to combination therapies or intravenous HER2 low-targeted ADCs. NCT number: NCT03778931 Table. a. Includes E545K, H1047R, E542K amongst others b. HER2 IHC 1+, and 2+ with no ISH amplification Citation Format: Aditya Bardia, Joyce O'Shaughnessy, Francois-Clement Bidard, Patrick Neven, José Ángel García-Sáenz, Philippe Aftimos, Javier Cortés, Janice Lu, Giulia Tonini, Kathy Puvana Theall, Alessandro Paoli, Virginia Kaklamani. Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-02.

Abstract PO1-06-01: Clinical Efficacy of Tumor Organoid-Guided Cancer Therapy for Locally Advanced Unresectable or Metastatic Breast Cancer

Abstract Purpose: Patient-derived organoids (PDOs) may facilitate treatment selection, but the feasibility of using breast cancer PDOs to guide personalized treatment in clinical practice has not been fully investigated. This study aimed to assess the clinical efficacy of treatment guided by PDO drug sensitivity tests (OGT) versus treatment of physician’s choice (TPC) in patients with locally advanced unresectable or metastatic breast cancer (MBC) and to explore the potential of PDOs to reveal mechanisms underlying treatment resistance. Methods: Patients diagnosed with MBC were recruited between January 2020 and August 2022. PDOs were established from biopsies specimens or malignant effusion samples. The efficacy of customized drug panels was determined by measuring cell mortality after drug exposure. Patients receiving OGT were matched 1:2 by nearest neighbor propensity scores with patients receiving TPC. The primary clinical outcome was progression-free survival. Secondary outcomes included objective response rate and disease control rate. Targeted gene sequencing and pathway enrichment analysis were performed. Results: 46 PDOs (46 of 51, 90.2%) were generated from 45 MBC patients. PDO drug screening showed an accuracy of 81.1% (95% CI 67.6%-91.9%) in predicting patients' clinical responses. 36 OGT patients were matched to 69 TPC patients. OGT was associated with prolonged median progression-free survival (11.0 months vs 5.0 months; unadjusted hazard ratio 0.53 [95% CI 0.33-0.85]; P=0.01) and improved disease control (88.9% vs 63.8%; unadjusted odd ratio 4.26 [1.44-18.62]) compared with TPC. The objective response rate of both groups was similar. Pathway enrichment analysis uncovered differentially modulated pathways implicated in DNA repair and transcriptional regulation in patients less sensitive to capecitabine/gemcitabine, and pathways associated with cell cycle regulation in patients less sensitive to palbociclib. Conclusions: MBC patients treated with OGT were associated with superior progression-free survival and disease control compared with TPC. PDO-based functional precision medicine is a feasible strategy for treatment optimization and customization in MBC and may enhance our understanding of therapeutic resistance. Citation Format: Ying-Yi Lin, Hong-Fei Gao, Hong Li, Bo-Lei Du, Min-Yi Cheng, Jia-Chen Zou, Xing-xing Zheng, Teng Zhu, Ting-Ting Li, Sheng Li, Kun Wang. Clinical Efficacy of Tumor Organoid-Guided Cancer Therapy for Locally Advanced Unresectable or Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-01.

Abstract CT074: ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC)

Abstract Background: Endocrine therapy (ET) + cyclin dependent kinase 4/6 inhibitor (CDK4/6i) is the mainstay for the management of ER+/HER2- mBC as 1st-line therapy. However, tumors eventually develop resistance to ET, leading to disease progression. In the EMERALD phase 3 trial, single-agent elacestrant was associated with significantly prolonged progression-free survival (PFS) and a manageable safety profile vs standard of care (SOC) ET, leading to the first oral SERD approval. Patients receiving elacestrant experienced a median PFS (mPFS) of 3.8 months vs 1.9 months with SOC (Bidard, 2022). Patients who received ≥12 months of prior CDK4/6i experienced a mPFS of 8.6 months with elacestrant vs 1.9 months with SOC (SABCS, 2022). Currently, there are no approved systemic treatments for patients with ER+/HER2- BC who have brain metastasis. The rationale for the ELECTRA study is to combine elacestrant with abemaciclib in patients with brain metastasis, given both compounds have demonstrated the ability to cross the blood-brain barrier (Conlan, 2020; Tolaney, 2020). Methods: ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib. Eligibility includes patients with ER+/HER2- locally advanced or metastatic BC and measurable brain metastasis. For phase 1b, the presence of brain metastasis is not required for eligibility. For phase 2, patients must have ≥ 1 active and measurable brain metastasis per RECIST v1.1. Patients must have received prior therapy in the metastatic setting, including ≥ 1 endocrine therapy, ≤ 2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). The phase 1b primary objective is to determine the recommended phase 2 dose (RP2D); secondary objectives include safety, pharmacokinetics (PK), overall response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), PFS, and overall survival (OS). The phase 2 primary objective is ORR per RECIST v1.1; secondary objectives include intracranial response rate, DoR, CBR, PFS, OS, PK, and quality of life. The phase 1b portion of the trial is actively ongoing to determine the RP2D with study sites open worldwide. Citation Format: Erika Hamilton, Sung-Bae Kim, Nancy U. Lin, Ahmad Awada, Eva Ciruelos Gil, Alessandro Di Sanzo, Bartomeu Piza Vallespir, Kathy Puyana Theall, Nuhad Ibrahim. ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT074.

Abstract 4170: Artificial intelligence (AI)-based multi-modal approach using H&E and CT image for predicting treatment response of immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC)

Abstract Background: Previously, AI-powered spatial tumor-infiltrating lymphocyte analysis in H&E whole-slide image (WSI) showed promising performance in predicting ICI outcomes. However, there were several innate limitations of tissue analysis, including the time lag between tissue biopsy and actual ICI administration, during which tumor microenvironment (TME) has changed, and analyzing a part of a single tumor tissue would not fully assess immunogenicity of multiple metastatic tumors. To overcome the challenges, we developed multiple-instance learning (MIL)-based models and applied them to predict the treatment response of ICI in a real-world dataset. Method: MIL-based models were trained under the cross-validation scheme for CT scans (N=456) separately, based on CT image analyzers. Lunit SCOPE IO (Lunit, South Korea), an AI-based H&E WSI analyzer, identifies various classes of cells within TME and segments tumor regions from WSI (AI-HE-TIL). An AI-based CT image analyzer detects nodules on the CT image (AI-CT). The final ensemble score per patient is computed by the average of all model predictions from CT and pathology image inputs. Single and ensemble performances for predicting responder and non-responder patients to ICI are measured in an independent cohort of 208 NSCLC patients. Results: In the overall cohort, the AUROC values for AI-HE-TIL, AI-CT, and the ensemble were 0.6372, 0.6759, and 0.7307, respectively. The high ensemble score group (≥ median) has prolonged progression-free survival (PFS) of ICI (median PFS 5.0 months vs 2.1 months, hazard ratio [HR] 0.54, P < 0.0001). It correlates with PD-L1 expression, as tumor proportion score (TPS) ≥ 50% subgroup had higher ensemble score (median 0.312 vs 0.257, P = 0.0295). Interestingly, among TPS ≥ 50% subgroup, the high ensemble score shows significantly favorable PFS of ICI (median PFS 6.7 months vs 2.9 months, HR 0.46, P = 0.0002). In subgroup analysis according to tissue harvest site (primary tumor vs lymph node or distant metastasis), the AUROC values of AI-HE-TIL and AI-CT for the subgroup harvested from the primary tumor (N=111) were 0.6568 and 0.6658, respectively, and those for the subgroup harvested from the metastatic lesion (N=97) were 0.6162 and 0.6973, respectively, implying AI-CT is relatively not affected by tissue harvest site. Conclusion: AI-powered multi-modal approach of using H&E image and CT image shows complimentary, and synergistic effect to predict ICI clinical outcomes in advanced NSCLC, even in the subgroup of PD-L1 high population. Citation Format: Dong Young Jeong, Jongchan Park, Heon Song, Jimin Moon, Taebum Lee, Changho Ahn, Sehhoon Park, Se-Hoon Lee, Chan-Young Ock, Ho Yun Lee. Artificial intelligence (AI)-based multi-modal approach using H&E and CT image for predicting treatment response of immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4170.

Factors associated with prolonged progression-free survival of patients treated with first-line afatinib for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

This study aimed to investigate the factors associated with prolonged progression-free survival (PFS) (>36 months) of advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations treated with first-line afatinib. We performed a retrospective analysis of data of patients with advanced EGFR-mutated NSCLC receiving first-line afatinib at two tertiary care referral centers, Linkou and Kaohsiung Chang Gung Memorial Hospital, in Taiwan between June 2014 and April 2022. The data of 546 treatment-naïve EGFR-mutated advanced NSCLC patients were analyzed. Median PFS and overall survival were 14.5 months and 27.2 months, respectively. The PFS of 462 patients (84.6%) was less than 36 months and of 84 patients (15.4%) was more than 36 months. The PFS > 36 months group had a significantly higher percentage of patients with uncommon mutations (p = 0.002). The PFS ≤36 months group had significantly higher incidences of bone, liver, and adrenal metastases (all p < 0.05) and a higher rate of multiple distant metastases. Multivariate logistic regression analysis showed that liver metastasis was negatively and independently associated with prolonged PFS (adjusted odds ratio = 0.246 [95% CI: 0.067-0.908], p = 0.035). The median overall survival of the PFS >36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log-rank test, p < 0.001). We found that EGFR-mutated NSCLC patients receiving first-line afatinib were prone to shorter PFS if they had distant organ metastasis, especially liver metastasis.

Contribution of Enhanced Locoregional Control to Improved Overall Survival with Consolidative Durvalumab After Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: Insights from Real-World Data.

This study aimed to assess the real-world clinical outcomes of consolidative durvalumab in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) and to explore the role of radiotherapy in the era of immunotherapy. This retrospective study assessed 171 patients with unresectable LA-NSCLC who underwent concurrent chemoradiotherapy (CCRT) with or without consolidative durvalumab at Asan Medical Center between May 2018 and May 2021. Primary outcomes included freedom from locoregional failure (FFLRF), distant metastasis free survival (DMFS), progression free survival (PFS), and overall survival (OS). Durvalumab following CCRT demonstrated a prolonged median PFS of 20.9 months (p=0.048) and a 3-year FFLRF rate of 57.3% (p=0.008), compared to 13.7 months and 38.8%, respectively, with CCRT alone. Furthermore, the incidence of in-field recurrence was significantly greater in the CCRT alone group compared to the durvalumab group (26.8% vs. 12.4%, p=0.027). While median OS was not reached with durvalumab, it was 35.4 months in patients receiving CCRT alone (p=0.010). Patients positive for programmed cell death ligand 1 (PD-L1) expression showed notably better outcomes, including FFLRF, DMFS, PFS, and OS. Adherence to PACIFIC trial eligibility criteria identified 100 patients (58.5%) as ineligible. The use of durvalumab demonstrated better survival regardless of eligibility criteria. The use of durvalumab consolidation following CCRT significantly enhanced locoregional control and OS in patients with unresectable LA-NSCLC, especially in those with PD-L1-positive tumors, thereby validating the role of durvalumab in standard care.

Albumin-to-D-dimer ratios: A novel prognostic factor for evaluating first-line chemotherapy efficacy in advanced lung adenocarcinoma patients.

The prognosis of advanced lung adenocarcinoma (LUAD) remains unfavorable, with chemotherapy constituting a primary treatment modality. Discerning the efficacy of chemotherapy for advanced LUAD is imperative. Prior investigations have demonstrated the prognostic value of albumin and D-dimer individually for malignancies; however, the predictive capacity of albumin-to-D-dimer ratios (ADR) for advanced LUAD subjected to first-line platinum-based chemotherapy remains unexplored. A cohort of 313 patients with advanced LUAD was retrospectively examined in this study, spanning from January 2017 to January 2021. ADR threshold values were ascertained via receiver operating characteristic analysis, followed by the evaluation of the association between pretreatment ADR and clinicopathological characteristics, disease control rate (DCR), and overall response rate (ORR) pertinent to first-line chemotherapy. Prognostic factors for progression-free survival (PFS) were determined employing Cox univariate and multivariate analyses. Subsequently, survival data were illustrated utilizing the Kaplan-Meier method and scrutinized through the log-rank test across the entire and subgroup populations. ADR demonstrated a superior area under the curve (AUC) value relative to albumin and D-dimer individually and exhibited enhanced prognostic predictive capability compared to albumin-to-fibrinogen ratios (AFR) for advanced LUAD (AUC: 0.805 vs. 0.640, DeLong test: p<0.001). ADR yielded a cut-off value of 16.608. A greater proportion of non-smokers was observed within the high-ADR group (ADR>16.608) compared to the low-ADR group (ADR≤16.608). Patients in the high-ADR group displayed elevated BMI and Na+ levels and reduced neutrophil count, monocyte count, globulin, and alkaline phosphatase (all p<0.05). Notably, the high-ADR group exhibited heightened DCR (96.7% vs. 89.2%, p=0.008) and ORR rates (70.1% vs. 51.0%, p=0.001) relative to the low-ADR group. Multivariate analysis outcomes indicated that high ADR constituted an independent risk factor for PFS (hazard ratio: 0.24, p<0.001). Furthermore, patients in the high-ADR cohort displayed a significantly prolonged median PFS (254 vs. 142 days, p<0.0001) compared to their low-ADR counterparts. In subpopulations exhibiting favorable implications for PFS, as determined by multivariate analysis, high-ADR patients consistently demonstrated extended PFS durations relative to the low-ADR group (all p<0.0001). Collectively, our findings suggest that ADR constitutes a novel and promising prognostic indicator for advanced LUAD patients, surpassing the accuracy of albumin and D-dimer individually and AFR. ADR thus serves as a potent instrument for assessing treatment effects and PFS in advanced LUAD patients undergoing first-line chemotherapy.

Carfilzomib, Daratumumab, and Dexamethasone (KdD) Vs Carfilzomib and Dexamethasone (Kd) for Relapsed/Refractory Multiple Myeloma (RRMM) in the Phase 3 Candor Study: Subgroup Analysis According to Renal Functioning

Renal impairment frequently occurs in patients (pts) with multiple myeloma (MM) and is associated with poor survival outcomes. In the phase 3 CANDOR trial, carfilzomib, dexamethasone, and daratumumab (KdD) met its primary endpoint of prolonged progression-free survival (PFS) vs carfilzomib and dexamethasone (Kd) (28.4 vs 15.2 mo; hazard ratio [HR]: 0.64; 95% CI: 0.49-0.83) after 50 months (mo) follow-up (Usmani Blood Adv 2023). The study aim was to perform a prespecified subgroup analysis of efficacy and safety by baseline renal function in pts with relapsed/refractory MM (RRMM) receiving KdD vs Kd in the CANDOR trial. Adult pts with RRMM were randomized 2:1 to KdD or Kd in the open-label, phase 3 CANDOR trial (NCT03158688) (Dimopoulos Lancet 2020). RRMM pts with measurable disease who had received 1-3 prior lines of therapy, with partial response or better to ≥1 line of therapy were eligible. Dialysis was an exclusion criterion. All pts received carfilzomib (K) as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m 2 on days 1 and 2 during cycle 1 and 56 mg/m 2 thereafter). Daratumumab (8 mg/kg) was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks (wks) for 4 cycles (cycles 3 to 6), and every 4 wks thereafter. All pts received 40 mg dexamethasone oral or IV weekly (20 mg for pts &amp;gt;75 years). Pts were grouped according to baseline renal function (creatinine clearance [CrCl] ≥15-&amp;lt;60 mL/min, ≥60-&amp;lt;90 mL/min, and ≥90 mL/min (Dimopoulous J Clin Onc 2016). The Cockcroft-Gault formula was used to calculate baseline and on study renal function. PFS and overall response rates (ORRs) were protocol-derived/investigator-assessed. Median PFS was estimated using the Kaplan-Meier method, with HRs and corresponding 95% CIs estimated using a stratified Cox proportional hazards model. Response rates were summarized descriptively, with odds ratios (ORs) and corresponding 95% CIs estimated by Mantel-Haenszel methods using stratified randomization. Renal response was defined as pt CrCl improvement to ≥60 mL/min in any 2 consecutive study visits in pts with baseline CrCl of &amp;lt;50 mL/min. A total of 466 pts were randomized; renal subgroups were CrCl ≥15-&amp;lt;60 mL/min (renal impairment), n=67 and n=36; ≥60-&amp;lt;90 mL/min, n=112 and n=57; and ≥90 mL/min, n=132 and n=61 for KdD and Kd, respectively. One pt in the KdD arm with missing baseline CrCl was excluded. Baseline characteristics were generally balanced between treatment arms and renal subgroups ( Table 1). After a median follow-up of ~50 mo (data cutoff: April 15, 2022), pts treated with KdD vs Kd had improved median PFS across all renal subgroups; median PFS was 24.9 mo vs 8.4 mo (HR, 0.61; 95% CI, 0.35-1.06), 31.6 mo vs 19.9 mo (0.63; 0.41-0.96), and 27.4 mo vs 15.3 mo (0.64; 0.43-0.95) for pts with CrCl ≥15-&amp;lt;60 mL/min, ≥60-&amp;lt;90 mL/min, and ≥90 mL/min, respectively ( Table 2). Median overall survival (OS) for KdD vs Kd was 44.6 mo vs 25.2 mo (HR, 0.58; 95% CI, 0.32-1.03), 48.0 mo vs 43.7 mo (0.91; 0.58-1.43), and NE vs NE (0.74; 0.46-1.20), respectively. ORRs were 87% vs 50% (OR, 8.02; 95% CI, 2.84-22.65); 85% vs 82% (1.26; 0.49-3.27); and 86% vs 80% (1.59; 0.69-3.68), respectively. Complete response rates were 36% vs 8% (7.43; 1.85-29.74); 44% vs 21% (3.17; 1.47-6.87); and 38% vs 21% (2.20; 1.08-4.49), respectively. Among 38 KdD pts and 27 Kd pts with baseline CrCl &amp;lt;50 mL/min, the renal response rate was 21% vs 11% (OR, 2.65; 95% CI, 0.63-11.11), respectively. In pts with renal impairment, most common grade ≥3 TEAEs were thrombocytopenia (38% [25/66] vs 23% [8/35]), hypertension (24% [16/66] vs 20% [7/35]), anemia (24% [16/66] vs 29% [10/35]), and pneumonia (23% [15/66] vs 9% [3/35]) in the KdD arm vs Kd arm. Most common grade ≥3 TEAEs of interest in pts with renal impairment were respiratory tract infections (32% vs 14%), hypertension (26% vs 20%), and infusion reaction on the same date of any carfilzomib dosing (14% vs 11%), respectively. Grade ≥3 acute renal failure occurred in 6% vs 11%, 4% vs 7%, and 2% vs 3% of pts with baseline CrCl ≥15-&amp;lt;60 mL/min, ≥60-&amp;lt;90 mL/min, and ≥90 mL/min, respectively. Overall, the safety profile in each subgroups was consistent with the established carfilzomib safety profile (Usmani Blood Adv 2023). KdD showed consistent clinical benefit vs Kd in median PFS, ORR and OS irrespective of the baseline renal function. Safety findings were consistent with the overall study population.

The Phase 2 CARTITUDE-2 Trial: Updated Efficacy and Safety of Ciltacabtagene Autoleucel in Patients with Multiple Myeloma and 1-3 Prior Lines of Therapy (Cohort A) and with Early Relapse after First Line Treatment (Cohort B)

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel), an anti-BCMA chimeric antigen receptor (CAR)-T cell therapy, in various populations of patients with multiple myeloma (MM). We previously reported 17-month median follow-up results from cohort A (1-3 prior lines of therapy [LOT] and lenalidomide [len]-refractory) and 18-month median follow-up results from cohort B (early relapse: ≤12 months after either autologous stem cell transplant [ASCT] or start of initial anti-myeloma treatment, if not transplanted). Cilta-cel is also under evaluation in patients with len-refractory MM after 1-3 LOT in the phase 3 CARTITUDE-4 study, which showed cilta-cel significantly prolonged progression-free survival (PFS) vs standard of care (HR, 0.26) at a median follow-up of 16 months. Here, we present updated efficacy and safety data from CARTITUDE-2 cohorts A and B, both with a median follow-up of ~29 months. Methods: Patients in cohorts A and B, all naive to CAR-T and/or anti-BCMA therapies, received a single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) 5-7 days after lymphodepletion. In both cohorts, the primary endpoint was minimal residual disease (MRD)-negativity (10 -5 threshold, by next-generation sequencing or next-generation flow cytometry). Management strategies were implemented after the phase 1b/2 CARTITUDE-1 study to reduce risk of movement and neurocognitive treatment-emergent adverse events (MNTs). Results: As of April 2023, 20 patients in cohort A had received cilta-cel (median follow-up, 29.9 months; 35% with high-risk cytogenetics; median 2 prior LOT; 95% refractory to last LOT; 40% triple-class refractory; 85% with prior ASCT). At the same data cut-off, 19 patients in cohort B hadreceived cilta-cel (median follow-up, 27.9 months; 16% with high-risk cytogenetics; 79% refractory to last LOT; 16% triple-class refractory; 79% with prior ASCT). All (100%) 17 MRD-evaluable patients in cohort A and 14 (93%) of 15 MRD-evaluable patients in cohort B achieved MRD negativity (10 -5 threshold). Eight (40%) of 20 patients in cohort A and 10 (53%) of 19 patients in cohort B sustained MRD negativity at 10 -5 for ≥6 months (Table 1). In the 20 patients in cohort A and 19 in cohort B, cilta-cel led to overall response rates of 95% (complete response or better [≥CR], 90%) and 100% (≥CR, 90%), respectively. Median PFS was not reached in either cohort, and 24-month PFS rates were 75% in cohort A and 73% in cohort B; respective 24-month overall survival rates were 75% and 84%. In cohort A, hematologic treatment-emergent adverse events (TEAEs) occurring between 17.1- and 29.9-month median follow-up included maximum grade (gr) 3/4 leukopenia in 1 patient (all gr,12 total; 60%), maximum gr 3/4 lymphopenia in 2 patients (all gr,16 total; 80%), and maximum gr 3/4 thrombocytopenia in 1 patient (all gr,16 total; 80%). In cohort B, no new patients reported hematologic TEAEs between 18.0- and 27.9-month median follow-up (Table 2). In cohort A, no new patients had CAR-T cell neurotoxicity, and no patients had a second primary malignancy (SPM). In cohort B, no new patients had MNTs, but other neurotoxicity (gr 2 sensory loss) occurred in 1 additional patient (all gr, 5 total; 26%) and resolved; and SPM (gr 4 choroid melanoma) occurred in 1 additional patient (all gr, 2 total; 11%). One new death (total 5) occurred in cohort A on day 666 due to progressive disease, and 1 new death (total 4) occurred in cohort B on day 749 due to cardiac arrest (not treatment related). Conclusions: These longer-term follow-up data show that patients treated with cilta-cel in earlier LOT, both those with len-refractory MM after 1-3 LOT (cohort A) and those with early relapse (cohort B), experienced deep and durable responses. No new CAR-T-related safety signals, except for 1 additional CAR-T cell neurotoxicity in cohort B, were reported. Cohort A provides insight into potential longer-term survival outcomes that may be expected in the phase 3 CARTITUDE-4 trial, which enrolled the same patient population but has shorter follow-up thus far. The long-term cohort B data highlight the durable efficacy of cilta-cel in patients who had early relapse; this is a functionally high-risk population for whom standard risk factors, including a high-risk cytogenetic profile, may not predict risk of relapse and for whom there is significant unmet need.

Outcomes of Patients with Newly Diagnosed Multiple Myeloma Experiencing Treatment Failure after Upfront Quadruplet Therapy and Autologous Stem Cell Transplantationgayathri Ravi 1, Susan Bal 1, Kelly Godby 1, Smith Giri 1, Clare Ubersax 1, Abigail Tucker 1, Luciano J Costa 1

Background The combination of a proteasome inhibitor (PI) an immunomodulatory agent (IMiD), an anti-CD38 monoclonal antibody (anti-CD38MoAb) and dexamethasone, i.e. quadruplet therapy (QUAD) leads to highest rate of complete responses (CR) and prolonged progression-free survival (PFS) in newly diagnosed multiple myeloma (NDMM) in the context of autologous stem cell transplantation (ASCT). While there are treatment failures reported after QUADs and they may be exquisitely challenging to treat the published literature in this setting is scarce. Methods We included all patients treated with QUADs between January 2016 and May 2023 with intention to proceed with ASCT to identify treatment failures and report outcomes. Treatment failures were classified into primary failure (PF) defined as lack of objective response after at least 4 QUAD cycles or progression during or within 60 days of completing QUAD therapy; early progression (EP), defined as disease progression 2-12 months of completing QUAD therapy, and late progression (LP) defined as disease progression &amp;gt; 12 months from completing QUAD therapy. For each of these groups we analyzed disease features, treatment refractoriness (as patients in EP and LP may have varying refractoriness depending on maintenance therapy received), response to subsequent therapy and outcomes- Overall response rates(ORR), Progression free survival(PFS) and Overall Survival(OS). Results We identified 248 sequential patients treated with QUADs, including 191 (77%) treated with daratumumab, bortezomib, lenalidomide and dexamethasone (D-VRd), and 57 (23%) treated with daratumumab, carfilzomib, lenalidomide and dexamethasone (D-KRd). Median follow up for all patients is 20.4 months (IQR 11.3-34.0) from onset of QUAD therapy. We found 11 patients with PF, 9 with EP and 11 with LP (Table) for a total of 31 treatment failures. Patients with QUAD failures were more likely to have ISS-3, R-ISS3 and 2+ high-risk chromosome abnormalities than the overall QUAD population. Median follow up from QUAD failure is 5.2 months for PF, 11.2 months for EP and 10.7 months for LP. All 31 patients with QUAD failure received subsequent therapy and 28 patients have &amp;gt; 1 month follow up enable assessment of response to subsequent therapy (Table). Cytotoxic chemotherapy was frequently used in patients with PF (60%) whereas anti-CD38 monoclonal Ab containing regimen was commonly used with increasing time from initial QUAD therapy reaching 89% in patients with LP. ORR to next line of therapy was 20% for PF, 33% for EP and 67% for LP. Of the 28 patients, 13(46%) participated in subsequent treatment clinical trial and 16(57%) received subsequent T-cell redirecting therapy either bispecific antibody or CAR-T cell therapy . Median PFS on next line of therapy was 2.4 months for PF, 3.7 months for EP and 7.4 months for LP. Median OS from QUAD failure was only 6.3 months for PF and 11.5 months for EP. No deaths (0/11) observed in LP group (Figure). Conclusions Multiple myeloma patients with delayed progression (&amp;gt;12 months) from end of QUADs have reasonable response to subsequent therapy. Despite access to experimental therapies including T-cell redirected therapies, patients with earlier failure of QUAD therapy (0-12 months) have poor response rates to subsequent treatments and significantly shorter survival. These findings highlight the urgent need for better predictive models to identify patients with QUAD failure and preemptively deploy treatments with novel mechanisms of action.

Salvage Autologous Stem Cell Transplant for the Treatment of First Relapse Multiple Myeloma: Evidence of Its Clinical Role from a Multicenter Italian Study

Background: Salvage autologous stem cell transplant (sASCT) has been indicated as possible therapeutic option at first (1 st) relapse, alternative to continuous treatment with novel agent combinations in selected Multiple Myeloma (MM) patients (pts). Particularly, MM pts who are eligible for a transplant procedure at the time of relapse and who have prolonged progression free survival (PFS) after the 1 st ASCT - i.e. at least 36 or 18 months, respectively, with or without Lenalidomide (Len) maintenance - are those who could benefit most from sASCT. There are limited data regarding the frequency of choice for sASCT in the current therapeutic scenario and the outcome of sASCT when incorporating novel Len-based triplets KRd (Carfilzomib-Lenalidomide-Dexamethasone) and DaraRd (Daratumumab-Lenalidomide-Dexamethasone) as induction regimens before sASCT. Aims: To explore the real-life use, efficacy, and outcome of sASCT preceded by novel agent-based re-induction therapy in a population of unselected Len-sensitive MM population in the 1 st relapse. Patients and methods: We planned a retrospective multicenter study, approved by local ethic committees, aimed at identifying MM Len-sensitive pts in the 1 st relapse addressed to sASCT. On a final cohort of 663 MM pts addressed in 22 Italian centers to Len-based triplets salvage therapy from 2017 to December 2022, sASCT after Len-based re-induction was the therapy of choice for 123 pts (18.6%), while the remaining 540 pts (81,4%) were addressed to continuous Len-based triplets until progression or unacceptable toxicity. The rate of pts addressed to sASCT at the time of the 1 st relapse was distributed as follows: 81 pts out of 512 pts (15.8%) received sASCT in the time window 2017-2019, 42 pts out 151 (27.8%) between 2020-2022 (p=0.001). Table 1 summarizes patients' characteristics and treatment history details. In our series 1 st ASCT was performed without Len maintenance. All pts entering the analysis received re-induction treatment before sASCT as well as continuous therapy with DaraRd or KRd according to standard schedule and doses. sASCT consisted of Melphalan 200 mg/m 2 as a conditioning regimen followed by infusion of ≥2*10 6 CD34* cells per kg body weight. The option to perform maintenance therapy following sASCT was chosen by the attending physician. The response was assessed according to IMWG criteria. Compared with pts treated with continuous Len-based triplets, those addressed to sASCT were younger (62 vs 68 years, p&amp;lt;0.001), with a longer time from diagnosis (3.9 vs 2.5 years, p&amp;lt;0.001), and they received a higher rate of prior ASCT (80.5% vs 53.8%, p&amp;lt;0.001). Regarding the sASCT program, KRd was the most common choice for the re-induction phase (102 pts, 82.9%), DaraRd was used in the remaining 21 pts (17.1%). The median number of cycles before sASCT was 6 (range 4-10), and maintenance after transplant was performed only in 18 pts (14.9%). sASCT was associated with an overall response rate (ORR) of 94.3% (116 pts), with 78% (96 pts) of very good partial response or better (≥VGPR), and 35.5% (43 pts) of CR. No case of transplant-related mortality was documented. After a median follow-up of 33.6 months (IQR 21.3-51.8), the median PFS of pts addressed to sASCT was 36.6 months, with 24-month PFS of 75% (95%CI 65-82%)(Figure 1). When a multivariableCox regression model was carried out including 1 st ASCT, the best response to 1 st line therapy and ≥36 months PFS after 1 st line therapy, as well as the number of re-induction KRd/DaraRd cycles as covariates, only PFS ≥36 months after 1 st-line therapy retained an independent statistically significant association with a reduced progression/death risk after sASCT (HR=0.5, 95%CI; 0.2-1.0, p=0.049). The median overall survival (OS) was not yet reached with a 2-year OS of 89% (95%CI: 81-93%). Conclusions: This study on 663 consecutive MM cases in the first relapse showed that salvage transplants retained a significant role in the current clinical management of MM, accounting for around 19% of selected salvage strategies. The incorporation of the highly active combinations KRd and DaraRd used as re-induction regimens before sASCT was associated with a significantly high rate of deep and long-lasting response, representing a possible alternative strategy to continuous therapy with Len-based triplets. The major benefit of Len-based triplets followed by sASCT was related to prolonged remission after first-line therapy.

Real-World Analysis of Obinutuzumab-Based Immunochemotherapy in Follicular Lymphoma in Chinese Population

Background Obinutuzumab is a first-in-class glycoengineered humanized type II anti-CD20 antibody. Immunochemotherapy based on obinutuzumab has demonstrated an advantage in prolonging progression-free survival (PFS) in pts with follicular lymphoma(FL) in a number of clinical trials(Marcus R, et al. N Engl J Med. 2017; Cheson BD, et al. J Clin Oncol. 2018). In Jun, 2021, obinutuzumab came into the market of China. However, few studies have investigated the efficacy and safety of obinutuzumab-based immunochemotherapy aiming at Chinese population. Therefore, we retrospectively analyzed the data of Chinese pts with treatment-naïve(TN) or relapsed/refractory(R/R) follicular lymphoma who received obinutuzumab-based immunochemotherapy in our center, hoping to provide treatment reference for Chinese pts. Methods Eligible pts were age ≥18 years with histologically documented, CD20-positive follicular lymphoma (grade 1 to 3a, stage III/IV or stage II with tumor ≥7 cm in the greatest dimension), and at least 2 cycles of obinutuzumab-based treatment. Efficacy was assessed by objective response rate (ORR) and best of response (BOR), with toxicity evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) (The 5th Edition). In addition, we recorded the incidence and severity of corona virus disease 2019 (COVID-19) infection according to Scheme for Diagnosis and Treatment of COVID-19 (The 10th Trial Edition). Results Between Nov 1, 2021 and Apr 1, 2023, the data of 27 pts with TN FL who received G-CHOP (obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen and 7 R/R pts treated with GB (Obinutuzumab, bendamustine) regimen was collected. The demographic and clinical characteristics at baseline were shown in Table 1. The median age of TN pts was 52 years, and 63.0% were female. The efficacy evaluation of TN pts was displayed in Figure 1. All of 27 pts achieved partial response (PR) after 2 cycles of GCHOP regimen. Eventually, 21 patiens completed 6 cycles of treatment, with 95.5% (21/22) assessed as complete response (CR) and 4.5% (1/21) maintaining PR. Three pts discontinued treatment due to COVID-19 infection and 2 for severe infections of other reasons. The end of treatment (EOT) ORR was 100% and the BOR of 96.3% (26/27) pts was assessed as CR. In 7 R/R pts, 5, 1 and 1 pts received 1, 2 and 3 lines of previous treatment regimens, respectively. The median age of this subgroup was 56 years. Totally, 6 pts achieved CR with an ORR of 85.7%, except for one pt who was evaluated as SD after 2 cycles of GB regimen and switched to another regimen. Two pts continued with maintenance therapy of obinutuzumab, and the rest 5 pts went on with autologous hematopoietic stem cell transplantation. By the end of follow-up, no pts showed progressive disease (PD) except for one who died of COVID-19 infection. All these pts in this study were infected with COVID-19 during the pandemic in China. For TN pts, mild, ordinary, severe and critical cases accounted for 14.8%, 44.4%, 29.6% and 11.1% respectively, and no pt died of COVID-19 infection. The median duration of COVID-19 infection was 23 (14-68) days, and over half of them were tested positive for more than 3 weeks. Of the R/R pts, 57.1% (4/7) presented severe, 14.3% (1/7) was critical and finally died of respiratory failure. The median duration of positive was 26 (21-95) days. Among pts treated wih GCHOP regimen, common grade 3-5 adverse events included infection (excluding COVID-19 infection) (25.9%) and hematological adverse events consisting of neutropenia (51.8%), thrombocytopenia (22.2%). Grade 3 infection, neutropenia and thrombocytopenia were observed in 14.3% (1/7) R/R pt each. The median follow-up time of TN pts and R/R pts was 8.9 (12.1-13.7) months and 11.7 (11.2-14.0) months, respectively. The median PFS of both was not achieved, 1-year PFS rate was 100% and 85.7% in TN and RR pts, respectively. Conclusions This real-world analysis with small sample size indicates that similar efficacy and toxicity was observed in Chinese patients with FL who were treated with obinutuzumab-based immunochemotherapy to that reported in literature. However, it is noteworthy that long-lasting immunosuppression may result in higher incidence and severity of COVID-19 infection in these patients compared to the general population.

Novel Agents May be Preferable to Standard Chemotherapy in Second-Line for Early Relapsing Follicular Lymphoma (FL) Patients

Introduction Early progression of FL after first line treatment is associated with poor outcomes. Disease progression within 24 months of initial therapy (POD24) is well-established adverse prognostic factor, while maintaining a complete remission (CR) at 30 months after initiation of induction therapy is considered a good surrogate for a prolonged progression-free survival (PFS). Nevertheless, treatment strategies in the second-line setting for these early relapsing patients are not clearly established, being their management heterogeneous across centers. The aim of our study was to analyze treatment patterns in this setting and to compare outcomes for patients who received chemotherapy (CT)-based regimens and immunotherapy (IT) approaches. Methods We conducted a retrospective review of patients diagnosed with grade 1-3a FL treated with upfront (CT) that progressed within 30 months of initial therapy (POD30) in 9 centers from January 2015 to June 2023. Patients who received single agent monoclonal antibodies or radiotherapy as first line treatment, and patients with FL grade 3b or histological transformation were excluded from the analysis. We defined 2 groups of patients according to the second-line regimen: the CT group, comprised by patients who received bendamustine-based regimens or other CT combinations, and the IT group that included patients who received monoclonal antibodies with lenalidomide and/or CD20xCD3 bispecific antibodies. Outcomes of interest were overall and complete response rate (ORR/CRR), PFS and overall survival (OS). Results Among 114 POD30 FL patients, 93 received CT and 21 received IT as second line treatment. Median age for the overall cohort was 56 years, with no differences according to salvage therapy (57 vs 53 years, p=0.19). Fifty-nine patients (52%) were female and 104 (94%) presented an advanced stage disease. Most of the patients in both groups had a high-risk FL at diagnosis (68% vs 67%, p=0.89) and at the time of first relapse (51% vs 24%, p=0.03), respectively. Distribution of first line treatment was well balanced between both groups. CHOP-based regimens were administered in 81% patients from the CT group and 90% in the IT group while bendamustine-based regimens were administered in 6% patients from the CT group and 10% in the IT group. In terms of best response to frontline therapy, 28 patients (25%) attained a CR, 59 patients (52%) a partial response (PR), 7 patients (6%) a stable disease (SD) and 20 patients (18%) a progressive disease (PD). Maintenance treatment was administered in 78 patients (68%), 59 patients (63%) from the CT group and 19 patients (90%) from the IT group ( p=0.03). Second-line treatment in the CT group included bendamustine-based regimens (n=40, 43%), ESHAP (n=31, 33%), gemcitabine-based (n=7, 8%), and other regimens (n=15, 16%), while the IT cohort comprised patients treated with lenalidomide in combination with monoclonal antibodies (n=5, 24%) and bispecific antibodies (n=16, 76%). For the full set of patients, best response included CR in 47 patients (43%), PR in 23 patients (21%), SD in 10 patients (9%) and PD in 30 patients (18%). For the CT and IT groups, there were no significant differences in terms of ORR (64% vs 60%, p=0.66) or CRR (42% vs 45%, p=0.87), respectively. Autologous stem cell transplantation (ASCT) was performed as a consolidative strategy in 27 patients (24%) from the overall cohort (29% for the CT cohort and 5% for the IT, p=0.05). Median follow up was 39.2 from diagnosis and 15.4 months from second-line treatment. Median PFS for patients receiving CT as second line of treatment was 11 months (95% CI: 6.3 - 15.2), compared to 16 months (95% CI: 13.01 - NA) for patients receiving IT (HR: 0.5, CI 95% 0.25-1; p=0.05). Finally, median OS for patients receiving CT as salvage therapy was 45.6 months (95% CI: 24.15% - NA), while median OS was not reached for patients receiving IT (HR: 0.19, CI 95% 0.03-1.4; p=0.1). Conclusions Treatment approaches for early relapsing FL are heterogeneous across centers, with many patients receiving chemotherapy as salvage therapy. Nevertheless, in our study a trend to a prolonged PFS and OS is observed in the group of patients receiving immunotherapy as salvage treatment. Novel agents such as lenalidomide and bispecific antibodies alone or in combination seem to improve the outcome in this population of FL with poor prognosis.

Subgroup Analyses of Progression-Free Survival from the Phase 3 Octans and Alcyone Studies in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Bortezomib, Melphalan, and Prednisone with or without Daratumumab

Introduction:Daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown clinical efficacy in combination with standard-of-care regimens in patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved clinical outcomes vs bortezomib, melphalan, and prednisone (VMP) in phase 3 studies in Asian patients (OCTANS) and a global population (ALCYONE) with transplant-ineligible (TIE) NDMM. Here, we present subgroup analyses of progression-free survival (PFS) by measurable residual disease (MRD) and cytogenetic risk status from OCTANS and ALCYONE. Methods: Eligible patients from OCTANS (NCT03217812) and ALCYONE (NCT02195479) had a diagnosis of NDMM and were TIE due to age or comorbidities. Patients were randomized to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 wk in Cycles 2-9, and every 4 wk thereafter until disease progression or unacceptable toxicity). MRD negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and next-generation sequencing in ALCYONE. Cytogenetic risk was assessed by FISH or karyotype testing. Results:A total of 220 Asian patients were randomized (D-VMP, n = 146; VMP, n = 74) in OCTANS, and 706 global patients were randomized (D-VMP, n = 350; VMP, n = 356) in ALCYONE. With a median follow-up of 41.2 mo (range, 0.0-59.9) in OCTANS, the median PFS was 38.7 mo with D-VMP and 19.2 mo with VMP (HR, 0.35; 95% CI, 0.23-0.52; P &amp;lt;0.0001). With a median follow-up of 40.1 mo (range, 0.0-52.1) in ALCYONE, the median PFS was 36.4 mo with D-VMP and 19.3 mo with VMP (HR, 0.42; 95% CI, 0.34-0.51; P &amp;lt;0.0001). The rates of overall and sustained MRD negativity were higher with D-VMP vs VMP. In OCTANS, the MRD-negativity rate was 40.4% with D-VMP vs 10.8% with VMP ( P &amp;lt;0.0001), and more patients in the D-VMP group had sustained MRD negativity lasting ≥12 mo (24.7% vs 1.4%; P &amp;lt;0.0001) and ≥18 mo (15.1% vs 1.4%; P = 0.0008). Similarly, in ALCYONE, the MRD-negativity rate was 28.3% with D-VMP vs 7.0% with VMP ( P &amp;lt;0.0001), with more patients in the D-VMP group having sustained MRD negativity lasting ≥12 mo (14.0% vs 2.8%; P &amp;lt;0.0001) and ≥18 mo (8.9% vs 1.7%: P &amp;lt;0.0001). In both studies, longer PFS was observed for patients who achieved MRD negativity vs those who did not within each treatment group; however, the PFS benefit observed for D-VMP vs VMP was maintained irrespective of MRD status ( Figure). In multivariate analyses, achievement of sustained MRD negativity lasting ≥12 mo was associated with longer PFS vs MRD negativity &amp;lt;12 mo in both OCTANS (HR, 0.23; 95% CI, 0.09-0.62; P = 0.004) and ALCYONE (HR, 0.13; 95% CI, 0.06-0.32; P &amp;lt;0.0001). No other factors showed a significant association with PFS in the multivariate analysis for OCTANS; other factors associated with longer PFS in ALCYONE included age &amp;lt;75 vs ≥75 y (HR, 0.38; 95% CI, 0.20-0.75; P = 0.005) and ISS disease stage I vs II (HR, 0.20; 95% CI, 0.05-0.86; P = 0.03). Data from OCTANS and ALCYONE were pooled for an analysis of PFS by cytogenetic risk subgroup (D-VMP, n = 496; VMP, n = 430). D-VMP prolonged median PFS vs VMP in patients with standard cytogenetic risk (not estimable vs 18.9 mo; HR, 0.33; 95% CI, 0.26-0.42) and high cytogenetic risk (25.6 vs 18.9 mo; HR, 0.54; 95% CI, 0.41-0.71), defined by the presence of t(4;14), t(14;16), del(17p), t(14;20), gain(1q21), and/or amp(1q21). Median PFS was also longer with D-VMP vs VMP for patients with gain and/or amp(1q21) (31.9 vs 18.9 mo; HR, 0.45; 95% CI, 0.32-0.63), 1 high-risk cytogenetic abnormality (HRCA; 24.4 vs 19.3 mo; HR, 0.62; 95% CI, 0.44-0.86), and ≥2 HRCA (28.2 vs 17.5 mo; HR, 0.36; 95% CI, 0.20-0.63). Conclusions:In this subgroup analysis of OCTANS and ALCYONE, the prolonged PFS observed with D-VMP vs VMP in the overall study populations was maintained irrespective of the achievement of MRD negativity or the presence of high cytogenetic risk. In addition, the rates of MRD negativity and sustained MRD negativity were higher with D-VMP vs VMP, and achievement of these deep responses translated into longer PFS, consistent with a prior pooled analysis of the MAIA and ALCYONE studies. These results further support the use of daratumumab in combination with VMP in both Asian and global patients with TIE NDMM.

CTNI-51. A RANDOMIZED DOUBLE-BLIND PHASE 3 STUDY OF VORASIDENIB VS PLACEBO IN PATIENTS WITH MUTANT IDH1/2 DIFFUSE GLIOMA (INDIGO): EXPLORATORY ANALYSIS OF VARIANT ALLELE FREQUENCY AND PROGRESSION-FREE SURVIVAL

Abstract INTRODUCTION Vorasidenib is an oral, brain-penetrant, inhibitor of mutant isocitrate dehydrogenase (mIDH) 1/2 enzymes. The INDIGO study (NCT04164901) showed significantly improved radiographic progression-free survival (PFS) by blinded independent review committee (BIRC) with vorasidenib, compared with placebo, in patients with mIDH1/2 adulttype diffuse glioma (hazard ratio [HR] 0.39, 95% CI 0.27–0.56; one-sided P = 0.000000067 [Mellinghoff N Engl J Med 2023]). The key secondary endpoint of time-to-next-intervention was also met. METHODS In this double-blind Phase 3 study, patients aged ≥ 12 years with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma, measurable non-enhancing disease, and no prior treatment for glioma were randomized 1:1 to receive vorasidenib 40 mg or placebo daily in 28-day cycles. An investigational clinical trial assay centrally confirmed IDH1 R132H/C/G/S/L or IDH2 R172K/M/W/S/G mutation variants. Pretreatment (archival) tumor tissue was analyzed by next-generation sequencing for CDKN2A/B homozygous deletion and other co-mutations (ACE Extended Cancer Panel). RESULTS As of Sep 6, 2022 (preplanned second interim analysis), 168 patients were randomized to vorasidenib and 163 to placebo (median age, 40.0 years; Karnofsky performance scale = 100, 53.5%; oligodendroglioma, 172; astrocytoma, 159; mIDH1, 315; mIDH2, 16). Two patient subgroups were defined by baseline IDH1/2 variant allele frequency (VAF): lower/higher than the median value (0.377). The median PFS results favored vorasidenib over placebo in both subgroups (low VAF, one-sided P = 0.0116; high VAF, one-sided P &amp;lt; 0.0001). Vorasidenib and placebo groups had similar and a low number of co-mutations in known/likely oncogenic genes at baseline (median number of co-mutations across both groups was 4). CDKN2A homozygous deletion was detected in only two participants (both in the placebo group). Additional data will be presented. CONCLUSION In the first randomized Phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, vorasidenib prolonged median PFS by BIRC, relative to placebo, irrespective of IDH1/2 VAF.

Clinical Impact of CDK4/6 Inhibitors in De Novo or PR- or Very Elderly Post-Menopausal ER+/HER2- Advanced Breast Cancers.

The CDK4/6 inhibitors significantly increase progression-free survival (PFS) in ER+/HER2- advanced breast cancer patients. In clinical trials, overall survival (OS) improvement has been demonstrated for ribociclib and abemaciclib but not for palbociclib. We undertook a real-world evaluation of PFS and OS in 227 post-menopausal patients who received first-line CDK4/6 inhibitors. There is no significant difference in median PFS (27.5 months vs. 25.7 months, p = 0.3) or median OS (49.5 months vs. 50.2 months, p = 0.67) in patients who received either palbociclib or ribociclib, respectively. De novo disease is significantly associated with prolonged median PFS and median OS compared with recurrence disease (47.1 months vs. 20.3 months (p = 0.0002) and 77.4 months vs. 37.3 months (p = 0.0003), respectively). PR- tumours have significantly reduced median PFS and OS compared with PR+ disease (19.2 months vs. 38 months (p = 0.003) and 34.3 months vs. 62.6 months (p = 0.02), respectively). In the very elderly (>80 years), median PFS and OS are significantly shorter compared with patients who are 65 years or below (14.5 months vs. 30.2 months (p = 0.01), and 77.4 months vs. 29.6 months (p = 0.009), respectively) in the palbociclib group. Our data suggest that the benefit in the very elderly is limited, and PR+/de novo disease obtains the maximum survival benefit.

Relationship between plasma circulating cell-free DNA concentration and treatment outcomes including prognosis in patients with advanced non-small cell lung cancer

BackgroundSome research found that elevated plasma cell-free DNA (cfDNA) concentrations and poor prognosis are associated in non-small cell lung cancer (NSCLC). However, more studies need to be carried out to verify this conclusion. Therefore, this study investigated the relationship between cfDNA concentration and treatment outcomes including prognosis in patients with advanced NSCLC.MethodsWe retrospectively collected medical records and cfDNA data from 160 patients with advanced NSCLC. Progression-free survival (PFS) were calculated using the Kaplan-Meier method and were compared between groups using the log rank test. Cox regression analysis was used for estimating the independent predictors of PFS. And we used logistic regression to evaluate the relationship between baseline biomarkers and efficacy. In our study, BT1 cfDNA, BT2 cfDNA, and BT3 cfDNA were defined as cfDNA concentration before the first treatment (baseline cfDNA concentration), cfDNA concentration before the second treatment, and cfDNA concentration before the third treatment, respectively.ResultsPatients with low cfDNA (BT1 cfDNA < 15 (ng/mL)) were reported a significantly prolonged median progression-free survival (mPFS) compared with patients with patients with high cfDNA (BT1 cfDNA ≥ 15(ng/mL)) (mPFS: 14.6 vs. 8.3 months, P = 0.002), as well as patients with neutrophil/lymphocyte ratio (NLR)<2.98 (mPFS: 13.1 vs. 7.9 months, P = 0.023). In addition, Cox proportional hazards regression analysis identified independent indicators associated with PFS including BT1 cfDNA ≥ 15 (ng/mL), NLR ≥ 2.98 and extrapulmonary metastasis. The best cut-off value for BT3 cfDNA for predicting disease progression is 41.46 (ng/mL) (Area Under the Curve (AUC): 0.652, 95%CI: 0.516–0.788), achieving 90.7% sensitivity and 37.5% specificity for the prediction of disease progression. BT3 cfDNA (OR = 6.08, 95% CI: 1.94–19.57, P = 0.002) was an independent factor for disease progression in patients with advanced NSCLC.ConclusionsBT1 cfDNA may be a biomarker to assess the prognosis of advanced NSCLC. Patients with advanced NSCLC with lower cfDNA and NLR before treatment had a better prognosis. Increased BT3 cfDNA concentration was an independent factor of disease progression in advanced NSCLC patients. These findings may assist in identifying high-risk patients and guiding treatment strategies.