BACKGROUND:A growing number of patients with multiple myeloma are anti-CD38 antibody-exposed and lenalidomide-exposed at first relapse, subsequently limiting their treatment options. Mezigdomide, a potent cereblon E3 ligase modulator, induces maximal, rapid Ikaros and Aiolos degradation, resulting in enhanced myeloma cell cytotoxicity and immune stimulation versus immunomodulatory drugs. The SUCCESSOR-2 trial evaluates the efficacy and safety of mezigdomide in combination with carfilzomib and dexamethasone versus carfilzomib plus dexamethasone. METHODS:This phase 3, open-label, randomised controlled trial was conducted at 160 hospital-based sites in 26 countries using a two-stage, inferentially seamless design. Eligible adult patients had measurable multiple myeloma, had received at least one previous regimen (including anti-CD38 antibodies and lenalidomide) on which they had achieved minimal response or better, and documented disease progression during or after their most recent treatment. Interactive response technology was used to randomly assign patients, stratified by age (≤70 years or >70 years), number of previous lines of therapy (≤2 or >2), and International Staging System stage (I, II, or III). Patients received oral mezigdomide (days 1-21 of each 28-day cycle) plus intravenous carfilzomib (56 mg/m2 weekly) and oral or intravenous dexamethasone (40 mg weekly) or carfilzomib (56 mg/m2 twice weekly or 70 mg/m2 weekly) and dexamethasone (20 mg twice weekly or 40 mg weekly). In stage 1, mezigdomide dosing across three levels was optimised. In stage 2, patients were randomly assigned to the selected mezigdomide dose (1·0 mg) plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone. The primary endpoint was progression-free survival (PFS) evaluated in patients who received 1·0 mg mezigdomide plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone across both study stages. No imputation was planned for missing efficacy endpoint values or missing safety evaluations. The trial is registered with ClinicalTrials.gov (NCT05552976) and EUClinicalTrials.eu (EUCT number 2022-500861-29-00). The trial is active but not recruiting. FINDINGS:Between Feb 3, 2023, and Nov 28, 2025, 762 patients were assessed for eligibility, of which 606 patients were enrolled and 479 were included in the analyses (288 patients in the mezigdomide-carfilzomib-dexamethasone group and 191 patients in the carfilzomib-dexamethasone group). 252 (53%) patients were male, 411 (86%) were anti-CD38 antibody-refractory, and 363 (76%) were lenalidomide-refractory, with a median of two previous lines of therapy (IQR 2-4). At 10·6 months median follow-up, mezigdomide-carfilzomib-dexamethasone significantly improved PFS compared with carfilzomib-dexamethasone (median 18·0 months vs 8·3 months; hazard ratio 0·48 [95% CI 0·36-0·63]; p<0·0001). Grade 3 or 4 adverse events were observed in 241 (84%) patients receiving mezigdomide-carfilzomib-dexamethasone versus 105 (56%) patients receiving carfilzomib-dexamethasone, including neutropenia (176 [61%] vs 17 [9%]) and infections (98 [34%] vs 29 [16%]). Eight (3%; 95% CI 1-5) and one (1%; 95% CI 0-3) treatment-related grade 5 adverse events were reported with mezigdomide-carfilzomib-dexamethasone and with carfilzomib-dexamethasone, respectively (rate difference 2%; 95% CI -1 to 5). Deaths occurred in 62 (22%) patients in the mezigdomide-carfilzomib-dexamethasone group and 51 (27%) patients in the carfilzomib-dexamethasone group, mainly due to disease progression. INTERPRETATION:Mezigdomide-carfilzomib-dexamethasone provided a significant PFS benefit compared with carfilzomib-dexamethasone alone, with higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care. These findings support mezigdomide-carfilzomib-dexamethasone as a clinically meaningful treatment option as early as first relapse in predominantly triple-class-exposed, anti-CD38 antibody-refractory and lenalidomide-refractory patients, a growing population with substantial unmet need. FUNDING:Bristol Myers Squibb.
Background Immune checkpoint inhibitor doublet (ICI–ICI) and ICI plus tyrosine kinase inhibitor (ICI–TKI) regimens are the cornerstone of treatment for metastatic renal cell carcinoma (mRCC), although no head-to-head comparisons are currently available. This study aimed to compare the real-world effectiveness of ICI-ICI vs ICI-TKI combinations in patients with intermediate- and poor-risk mRCC according to International Metastatic RCC Database Consortium (IMDC). Methods The Meet-URO 33 study is a multicentre retrospective-prospective registry collecting real-world data on patients with mRCC. Multivariable logistic and Cox models were built for objective response rate (ORR), PFS and OS, with a propensity score (PS) adjustment for baseline imbalances. Results Among 1497 patients, 755 were intermediate-risk (199 ICI-ICI, 556 ICI-TKI) and 312 poor-risk (77 ICI-ICI, 212 ICI-TKI). Median follow-up was 14.2 months (8.0 months and 14.5 months in poor- and intermediate-risk subgroups, respectively). In poor-risk patients, median OS was 20.3 vs 12.9 months (HR 0.87, 95% CI: 0.59–1.28, p = 0.49), and median PFS was 6.7 vs 8.7 months (HR 1.10, 95% CI: 0.79–1.54, p = 0.53), for ICI–ICI vs ICI–TKI, respectively. In the intermediate-risk patients treated with ICI-ICI vs ICI-TKI, median OS was 37.8 vs 35.5 months (HR: 1.08; 95% CI: 0.77–1.50; p = 0.65), and median PFS was 17.8 vs 18.6 months (HR 1.29, 95% CI: 1.00–1.66, p = 0.050). ORR was 42.9% vs 45.8% in poor-risk patients (OR 0.72, 95% CI: 0.39–1.34, p = 0.303) and 48.1% vs 54.3% in intermediate-risk patients (OR 0.71, 95% CI: 0.48–1.04, p = 0.075). Conclusions No statistically significant differences in survival or response were observed between ICI-ICI and ICI-TKI combinations in patients with IMDC intermediate- and poor-risk mRCC.
Objectives The APC I1307K variant is a known moderate-risk allele for colorectal cancer (CRC), especially among Ashkenazi Jewish (AJ) individuals. However, its role in other cancers, particularly in male breast cancer (MBC), remains unclear. This study aimed to evaluate whether APC I1307K contributes to MBC risk in the Italian (non-AJ) population.Methods A multicenter case-control study was conducted involving 1028 MBC cases and 2,126 geographically matched healthy male controls. Genotyping was performed via Next Generation Sequencing or TaqMan assays. Associations between APC I1307K and MBC risk were analyzed using logistic regression models, including multivariate adjustments for age, enrollment center, and BRCA1/2 status.Results The APC I1307K variant was detected in 4 MBC cases (0.4 %) and 5 controls (0.2 %). No statistically significant association with MBC risk was observed (multivariate odds ratio [OR]=3.7, 95 % CI: 0.8-17.0, p=0.09). Clinical-pathologic comparisons revealed no distinguishing features among variant carriers. None of the carriers harbored BRCA1/2 pathogenic variants (PVs) or had personal histories of CRC or familial adenomatous polyposis.Conclusions These findings suggest that APC I1307K does not confer a significant risk for MBC in the Italian population.
8015 Background: Stage III Non-Small Cell Lung Cancer (NSCLC) is a heterogeneous group of tumors with a wide spectrum of clinical presentations and no single definitive therapeutic approach. The role of neoadjuvant alectinib in stage III ALK-positive NSCLC is still unclear. Here, we present the final analysis of the phase II, open-label, single-arm, multicenter study aimed at investigating the activity and safety of alectinib in potentially resectable locally advanced stage III ALK-positive NSCLC patients (ALNEO trial, EUDRACT number 2020-003432-25). Methods: Treatment-naïve patients with potentially resectable stage III ALK-positive NSCLC, ECOG PS≤1 were registered to receive neoadjuvant alectinib for 2 cycles (8 weeks) followed by surgery and adjuvant alectinib for 24 cycles (96 weeks). The primary endpoint was major pathological response (MPR) by Blinded Independent Central Review (BICR). Secondary endpoints included pathological complete response (pCR) by BICR, objective response (OR), event-free survival (EFS), disease-free survival (DFS), overall survival (OS) and adverse events (AEs). According to the Simon’s design (P0=20%, P1=40%), 18 and 33 patients were required for the first and second stage, respectively. Results: A total of 33 patients were registered in 20 Italian Oncology Centers from May 2021 to July 2024. Median age was 62 years (Interquartile Range [IQR], 49–74 years), 23 (70%) patients were female and 17 (52%) were never smokers. Clinical stage according to the 8th AJCC TNM was IIIA in 21 (64%) and IIIB in 12 (36%) patients. The most represented stage was T3N2 (n=8, 24%), followed by T1aN2 (n=4, 12%), T2aN2 (n=4, 12%), T4N0 (n=4, 12%) and T4N2 (n=4, 12%). All the patients completed the neoadjuvant phase and 28 (85%) underwent surgery, which consisted of lobectomy in 21 (64%), pneumonectomy in 3 (9%) and other surgery in 4 (12%) patients. Among patients who completed surgery, R0 was achieved in 24 (86%) patients. According to the BICR, MPR was documented in 15 (46%, 90% Confidence Interval [CI]: 31%–61%) patients and pCR in 4 (12%, 95% CI: 3%–28%) patients. Overall, an OR was observed in 22 (67%) patients. Adjuvant treatment was started in 26 (79%) patients with a median interval from surgery of 5.1 weeks (IQR, 3.6–6.0 weeks). After a median follow-up of 15.2 months (IQR, 6.8–27.8 months), 31 (94%) patients were alive and 5 (19%) patients completed the adjuvant treatment. Median EFS and OS were not reached. A total of 6 (18%) patients experienced disease progression/recurrence. Grade≥3 AEs occurred in 3 (9%) and 2 (8%) patients during neoadjuvant and adjuvant phase, respectively. Conclusions: ALNEO study met its primary endpoint, suggesting alectinib as a feasible peri-operative option in resectable locally advanced stage III ALK-positive NSCLC patients. The study was partially supported by Roche S.p.A. Clinical trial information: NCT05015010 .
LBA4004 Background: Preoperative mFOLFIRINOX is a treatment option for patients (pts) with resectable/borderline resectable (R/BR) pancreatic ductal adenocarcinoma (PDAC). Methods: CASSANDRA (NCT04793932) is a multicenter phase 3 superiority trial randomizing pts ≤75y with R/BR PDAC, stratified by site and CA19.9, in a 2 by 2 factorial design to receive either PAXG (oral daily capecitabine 1250 mg/m 2 with biweekly cisplatin 30 mg/m 2 , nab-paclitaxel 150 mg/m 2 , gemcitabine 800 mg/m 2 ; arm A) or mFOLFIRINOX (biweekly 5-fluorouracil 2400 mg/m 2 , irinotecan 150 mg/m 2 , oxaliplatin 85 mg/m 2 ; arm B; 1 st random) for either 6 months before or 4 months before and 2 months after surgery (2 nd random). The results of 1 st random are presented. The primary endpoint is event-free survival (EFS = absence of progression, recurrence, 2 consecutive CA19.9 increases ≥20% separated by ≥ 4 weeks, unresectability, intra-operative metastasis, death) in the intention-to-treat population (ITT). Secondary endpoints are overall survival (OS), radiological, CA19.9, and pathological response rate, resection rate, toxicity, QoL in the ITT. With 173 events (260 pts) the study has a power of 80% to demonstrate a statistically significant difference at 5% two sided stratified logrank test under the alternative hypothesis of HR=0.65. EFS and OS were analyzed by Kaplan-Meier and log-rank test, HR estimated by Cox proportional hazard model. Results: Between Nov 2020 and Apr 2024, 260 eligible pts (tab 1) were randomly assigned to either arm A (N=132) or B (N=128). At data cutoff on March 1, 2025, with a median follow-up of 23.9 mos, 3y EFS was 30% (CI 20% – 40%) in arm A and 14% (CI 5% – 23%) in arm B with HR 0.66 (CI 0.49-0.89, p=0.005). In A/B, disease control rate was 98%/91% (p=0.009); CA19.9 reduction>50% 88/64% (p=<0.001); resection rate 75/67% (p=0.165); pathologic stage < II 35/23% (p=0.03); main G3-4 toxicity was: neutropenia 44/30%; fatigue 8/8%; diarrhea 2/5%; nausea/vomiting 7/10%; neuropathy 7/4%; AST/ALT 3/8%; infections 6/9%. Conclusions: Neoadjuvant PAXG significantly improved EFS compared to mFOLFIRINOX in pts with R/BR PDAC. Clinical trial information: NCT04793932 . A B Age 65 (42-76) 63 (41-76) Females 68 (52%) 62 (48%) KPS 90-100 123 (93%) 117 (91%) cStage I-II III 119 (90%)13 (10%) 115 (90%)13 (10%) RBR 63 (48%)69 (52%) 63 (49%)65 (51%) CA19.9 Normal Increased Median 32 (24%)261 43 (34%)226
