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Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

Background: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies. Patients and methods: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected. Results: 425 cases of uterine and ovarian carcinosarcomas (n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III–IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen (n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3–20.6) and 14.8 months (95% CI 13.1–17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2–49.2) and 30.6 months (95% CI 24.1–40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0–NR) and 18.9 months (95% CI 14.0–45.6) for UCS stages I–II and stages III–IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy (n = 24) was not reached (95% CI 22.2–NR), while mPFS for untreated patients (n = 62) was 19.9 months (95% IC 13.9–72.9) (HR 0.44 (0.20–0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5–5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1–8.5) and 2.2 months (95% CI 1.9–2.9) with a combination of chemotherapy or monotherapy, respectively (p < 0.001). Conclusions: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the expression of integrin α5 and its prognostic impact in a glioblastoma series of patients scheduled to undergo the Stupp protocol as first-line treatment for GBM. The integrin α5 protein expression level was estimated in each tumor by the mean fluorescence intensity (MFI) and allowed us to identify two subpopulations showing either a high or low expression level. The distribution of patients in both subpopulations was not significantly different according to age, gender, recursive partitioning analysis (RPA) prognostic score, molecular markers or surgical and medical treatment. A high integrin α5 protein expression level was associated with a high risk of recurrence (HR = 1.696, 95% CI 1.031–2.792, p = 0.0377) and reduced overall survival (OS), even more significant in patients who completed the Stupp protocol (median OS: 15.6 vs. 22.8 months; HR = 2.324; 95% CI 1.168–4.621, p = 0.0162). In multivariate analysis, a high integrin α5 protein expression level was confirmed as an independent prognostic factor in the subpopulation of patients who completed the temozolomide-based first-line treatment for predicting OS over age, extent of surgery, RPA score and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (p = 0.029). In summary, for the first time, our study validates that a high integrin α5 protein expression level is associated with poor prognosis in GBM and confirms its potential as a therapeutic target implicated in the Stupp protocol resistance.

Precision oncology is currently based on pairing molecularly targeted agents (MTA) to predefined single driver genes or biomarkers. Each tumor harbors a combination of a large number of potential genetic alterations of multiple driver genes in a complex system that limits the potential of this approach. We have developed an artificial intelligence (AI)-assisted computational method, the digital drug-assignment (DDA) system, to prioritize potential MTAs for each cancer patient based on the complex individual molecular profile of their tumor. We analyzed the clinical benefit of the DDA system on the molecular and clinical outcome data of patients treated in the SHIVA01 precision oncology clinical trial with MTAs matched to individual genetic alterations or biomarkers of their tumor. We found that the DDA score assigned to MTAs was significantly higher in patients experiencing disease control than in patients with progressive disease (1523 versus 580, P  = 0.037). The median PFS was also significantly longer in patients receiving MTAs with high (1000+ <) than with low (<0) DDA scores (3.95 versus 1.95 months, P  = 0.044). Our results indicate that AI-based systems, like DDA, are promising new tools for oncologists to improve the clinical benefit of precision oncology.

In human epidermal growth factor receptor 2 (HER2) positive early breast cancer (EBC) patients, with residual invasive disease after neoadjuvant chemotherapy (NACT) plus HER2-targeted therapy, the KATHERINE trial demonstrated a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. A retrospective bicentric cohort study was set to assess the real-world efficacy and safety of T-DM1 as adjuvant therapy in HER2-positve EBC patients treated at Institut Curie Hospitals. N = 102 patients consecutively treated from September 2019 to January 2021 were included. All patients had previously received neoadjuvant trastuzumab (plus pertuzumab in one patient) and chemotherapy, N = 95 (93%) with anthracyclines. Post-neoadjuvant residual cancer burden was RCB I, II and III in N = 28 (27%), 62 (61%) and 11 (11%) patients, respectively, while N = 70 (69%) had an estrogen receptor-positive disease. After a median follow-up of 44 months (range 4.5–54), N = 7 (7%) patients experienced distant tumor recurrence, including central nervous system (CNS) metastases in N = 5 patients, leading to death in N = 2 patients, while no local recurrence was reported. The 4-years disease-free survival (DFS) rate was 92.5% (95%CI=[87;98]), lymph node involvement at diagnosis (cN+) being the only factor associated with a higher risk of relapse (p = 0.025, no event in the node negative group in our population). Dose reductions of T-DM1 were required in N = 34 patients (33%) after a median of 5 cycles, mainly because of peripheral neuropathy (N = 14), increased alanine and/or aspartate aminotransferase level (N = 9), and thrombopenia (N = 6). Adverse event leading to drug discontinuation occurred in N = 23 patients (23%), after a median of 9 cycles, mostly peripheral neuropathy (N = 10) and thrombopenia (N = 9). Grade 3–4 toxicity affected N = 9 patients (9%), with no related death to T-DM1. With a low relapse rate and although more dose reductions and treatment discontinuation were observed in our cohort, our results are consistent with those of the KATHERINE trial. CNS as the most frequent site of relapse points to a potential role for drugs with higher activity against CNS metastases.

Combining immunotherapy with chemoradiation is effective in locally advanced cervical cancer. However, the impact of induction combination immunotherapy on immune modulation and treatment response is poorly understood. In this phase II trial (NCT04256213), 40 females with locally advanced cervical carcinoma received one cycle of nivolumab-plus-ipilimumab immunotherapy before standard chemoradiation, followed by maintenance nivolumab. We show, using multiplex-immunofluorescence tissue imaging, a significantly increased CD8 + /FOXP3 + cell ratio (primary endpoint; increase of 0.87 cells/mm², P  = 0.0164) and proliferative CD8 + T-cell density after one cycle of combination immunotherapy. HOT score (27-gene-based signature identifying immunologically active tumors) also increased significantly (exploratory analysis; 0.17, P  < 0.0001). Objective response rates (secondary endpoint) were 13% immediately after combination immunotherapy, 98% (65% complete response) after chemoradiation, and 90% at treatment completion. High HOT score at baseline and immune changes induced by combination immunotherapy were associated with complete response at treatment completion. Induction immunotherapy may prime tumors for improved response to standard therapy. Pre-treatment dual immune checkpoint blockade in cervical cancer remains understudied. In this trial, the authors show that neoadjuvant immune checkpoint blockade enhances immune activation and correlates with improved response to subsequent chemoradiation in patients with cervical carcinoma.

Pathological complete response (pCR) after neoadjuvant chemoimmunotherapy (NACi) is associated with improved patient outcomes in early triple-negative breast cancer (TNBC). This study aimed to identify factors associated with pCR after NACi. This cohort included all patients with stage II-III TNBC treated with NACi who underwent surgery at Institut Curie hospitals between 08/2021-06/2023. Among 208 patients, the overall pCR rate was 70% and was similar in ER < 1% (69%) and ER-low TNBC (73%, p  = 0.6). In a multivariate model, Ki-67 ≥ 30% (OR 5.19 [1.73–17.3]), centralized TILs ≥ 30% (OR = 3.08 [1.42–7.04]), absence of DCIS at initial biopsy (OR = 2.56 [1.08–6.25]) and germline mutations in homologous recombination genes (OR = 9.50 [2.37–67.7]) remained strong independent predictors of pCR. These findings may guide treatment decisions in patients with TNBC undergoing NACi. Almost all patients with germline mutations in HR genes achieved pCR, supporting de-escalation trials. We suggest that ER-low tumors should be managed as TNBC tumors.

Background Immune checkpoint inhibitors have been demonstrated to improve overall survival. Atypical patterns of response have been reported, including dissociated response (DR). We evaluated the prevalence of DR. Patients and methods Patients had to have a baseline computed tomography (CT) scan and at least one follow-up CT scan and two target lesions (TLs). Three types of DR were evaluated using RECIST1.1: DR1, defined as at least one progressive and one responding TL; DR2, defined as at least one progressive and one stable TL; and DR3, defined as at least one stable and one responding TL. Results A total of 1244 measurements of 272 TLs were performed in 100 patients. Forty-nine out of the 272 TLs (18%) had received old or recent radiotherapy, and 42 (15%) had been biopsied. An objective response was observed in 22 patients (22%) and on 52 TLs (19%). DR1 were observed in 8% of patients. At the tumor measurement level, the response rate was lower in the case of prior radiotherapy (29% vs 34%, p = 0.01) and higher in the case of prior biopsy (40% vs 32%, p = 0.02). Conclusions A DR was observed in 8% of patients. Response rate was lower in the case of prior radiotherapy and higher in the case of prior biopsy.

SOLAR-1 and BYLieve trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA -mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP) opened to PIK3CA -mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant. Primary endpoint was PFS by local investigators using RECIST1.1. Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1–16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95% CI: 4.7–6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95% CI: 37.8–52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age < 60 years (HR = 1.5, 95% CI = 1.1–2.1), >5 lines of prior treatments (HR = 1.4, 95% CI = 1.0–2.0) and the C420R PI3KCA mutation (HR = 4.1, 95% CI = 1.3–13.6). N  = 91 (39.1%) patients discontinued alpelisib due to adverse events. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.

Purpose Recurrence of glioblastoma (GB) occurs in most patients after standard concomitant temozolomide-based radiochemotherapy (CTRC). Bevacizumab (BV), an anti-VEGF antibody, has an effect on progression-free survival (PFS) but not on overall survival (OS). However, a small part of the patients experience a survival, longer than expected. This retrospective study aims to characterize long responder (LR) patients treated with BV for a first or second GBM recurrence. Methods Medical records from patients (814) who received BV for a first or second recurrence of primary glioblastoma between September 2010 and September 2015, and initially treated by CTRC were analyzed. Patients, who had at least a stable disease according to RANO criteria at 12 months from the start of BV, were included. Patients who had, a secondary GB, or received BV in neoadjuvant or adjuvant setting were excluded. Results We focused on 65 LR patients without progression 12 months after the first injection of BV (8%). Median PFS was 21.7 months [95% CI (19.3; 27.2)] and median OS was 31.1 months [95% CI (24.3; 37.5)] from the start of BV. No prognostic factor was associated with OS in multivariate analysis. Karnofsky performance status, neurological status and corticosteroid dose were stable at 12 months. Conclusions Our results highlight that among patients receiving bevacizumab in first or second recurrence, one patient out of twelve could be classified as LR. A median OS of 31.1 months from the start of BV could be expected in this subpopulation. These findings reinforce the potential benefit of the use of BV in the situation of recurrence. 256 words