Progression-free Survival In Patients Research Articles

Efficacité et tolérance du dichlorure de radium 223 chez les patients traités pour cancer de la prostate résistant à la castration avec métastases osseuses

IntroductionThe aim of our study was to evaluate the efficacy and tolerance of 223RaCl2 in patients with mCRPC with bone metastases, then analyse the impact of any change in treatment protocol on the efficacy of 223RaCl2 in mCRPC patients with bone metastases, by determining overall survival, progression-free survival and events occurring during therapeutic monitoring. Materiel and methodsOur retrospective, analytical and descriptive study, carried out in Luxembourg, included patients eligible for le 223RaCl2 treatment who were assessed during and at the end of treatment, and 3 to 4months after the end of treatment. ResultsOur sample included 41 cases. The mean age of patients was 74years (min=52, max=87), with 32 (78.1%) deaths recorded. Median overall survival was 18.0months (95% CI: 12.1–23.9): 11months for those who experienced progression during treatment versus 47 months for those who experienced a partial response. Median progression-free survival was 15.0 months (95% CI: 0.0–36.4). Overall survival was positively correlated with progression-free survival (Rho Spearman=0.713, P-value<0.001); however, a one-month increase in progression-free survival decreased the risk of death by 6% and thus increased overall survival (HR=0.937, 95% CI : 0.903–0.973, P<0.001). ConclusionAdministration of the complete 223RaCl2 protocol improved overall survival and progression-free survival in patients treated for mCRPC with bone metastases, with good hematological tolerability despite the occurrence of complications such as epiduritis and fractures.

Pulmonology: What You May Have Missed in 2023.

The field of pulmonology saw significant advances in 2023. The publications highlighted in this article address advances and changes in practice related to asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, pleural disorders, and sleep-disordered breathing. One article reviews data examining the efficacy of vaccination against respiratory syncytial virus, a respiratory viral illness that has had devastating effects globally. Four studies evaluate the role of various therapies in COPD, including dupilumab, ensifentrine, pulmonary rehabilitation programs, and lung volume reduction versus endobronchial valves. Another study explores the effect on vascular events of positive-pressure ventilation in patients with sleep-disordered breathing and recent stroke. The use of combination therapy with rituximab and mycophenolate mofetil on progression-free survival in patients with nonspecific interstitial pneumonia is the topic of another study. We also highlight an update of clinical recommendations for the evaluation of patients with pleural disorders and a systematic review analyzing the effectiveness of inhaled corticosteroids as a supplement to dual therapy for COPD.

SABR-Dual: a phase II/III trial of two-fraction versus five-fraction stereotactic radiotherapy for localized low- and favorable intermediate-risk prostate cancer.

Dose-escalated radiotherapy is known to improve progression free survival in patients with localized prostate cancer, and recent advances have led to the standardization of ultrahypofractionated stereotactic ablative radiotherapy (SABR) delivered in just 5-fractions. Based on the known effectiveness of the accepted though invasive 2-fraction treatment method of high-dose-rate brachytherapy and given the ubiquity of prostate cancer, a further reduction in the number of treatments of external-beam SABR is possible. This study aims to evaluate the safety, efficacy, and non-inferiority of generalizable 2-fraction SABR compared to the current 5-fraction regimen. 502 patients will be enrolled on this phase II/III randomized control trial. Eligible patients will have previously untreated low- or favorable intermediate-risk adenocarcinoma of the prostate. Patients will be randomized between standard SABR of 40Gy in 5 fractions given every-other-day and 27Gy in 2 fractions at least two days apart but completing within seven days. MRI-based planning, radiopaque hydrogel spacer insertion, and fiducial marker placement are required, and SABR will be delivered on either a standard CT-guided linear accelerator or MR-LINAC. The primary endpoint will be freedom from disease progression, with additional secondary clinical, toxicity, and quality of life endpoints. This study will be the largest prospective randomized trial, adequately powered to demonstrate non-inferiority, comparing 2-fraction SABR to standard 5-fraction SABR for localized prostate cancer. As the protocol does not obligate use of an MRI-LINAC or other adaptive technologies, results will be broadly generalizable to the wider community. This trial is registered on Clinicaltrials.gov: ClinicalTrials.gov Identifier: NCT06027892.

Structural Elucidation and Prognostic Relevance of 297-11A-Sulfated Glycans in Ovarian Carcinoma

Ovarian carcinoma is usually diagnosed at an advanced stage with peritoneal dissemination and/or lymph node metastasis, and the prognosis for such advanced carcinoma is very poor. Therefore, new biomarkers to predict patient prognosis are needed. Miyamoto et al. previously showed that keratan sulfate (KS) detected by the 5D4 monoclonal antibody was expressed in ovarian carcinoma. However, the detailed structure of such KS was not determined, and the biological significance of this finding remained to be clarified. We previously generated the 297-11A monoclonal antibody, which recognizes galactose (Gal)-6-O-sulfated N-acetyllactosamine (LacNAc) located at the nonreducing terminus. Because the 297-11A epitope overlaps with that of 5D4, here we chose to use the 297-11A antibody as a tool to analyze KS and related structures. We conducted immunohistochemical analysis of 98 ovarian carcinoma cases with 297-11A antibody combined with a series of glycosidases and performed mass spectrometry analysis of the human serous ovarian carcinoma cell line OVCAR-3 to deduce the glycan structure of 297-11A-sulfated glycans. We also performed western blot analysis to assess a potential association of 297-11A-sulfated glycans with the mucin core protein mucin 16 (MUC16; also known as cancer antigen 125 (CA125)). Finally, we examined the relationship between 297-11A expression and patient prognosis. Consequently, 297-11A-sulfated glycans were primarily expressed in serous and endometrioid carcinomas and poorly expressed in mucinous and clear cell carcinomas. We reveal that structurally, 297-11A-sulfated glycans expressed in ovarian carcinoma are O-glycans carrying partially sialylated, Gal-6-O-sulfated LacNAc and that these glycans are likely displayed on MUC16 mucin core proteins. Of clinical importance is that expression of 297-11A-sulfated glycans correlated with shorter progression-free survival in patients. Thus, 297-11A-sulfated glycans may serve as a predictor of ovarian carcinoma recurrence.

Incidence and Outcomes of Posterior Circulation Involvement in Moyamoya Disease.

Moyamoya disease (MMD) is a progressive, occlusive disease of the internal carotid arteries and their proximal branches, with the subsequent development of an abnormal vascular network that is rupture-prone. Steno-occlusive changes in the posterior cerebral arteries (PCAs) may contribute to worsened outcomes in patients with MMD; however, there is little information on the incidence and natural history of posterior circulation MMD (PCMMD). We describe clinical PCMMD characteristics in a large cohort of patients with MMD. We retrospectively reviewed patients with MMD treated between 1991 and 2019 at a large academic medical center. Demographics, perioperative outcomes, and radiological phenotypes were recorded for 770 patients. PCA disease was graded as either 0 (no disease), 1 (mild), 2 (moderate), or 3 (severe or occluded) based on cerebral angiography. Patients with angiographically confirmed MMD diagnosis with at least 6 months follow-up and completion of revascularization surgery were included; patients with intracranial atherosclerosis, intracranial dissection, vasculitis, and undefined inflammatory processes were excluded. The presence of stenosis/occlusion was graded radiographically to assess for disease progression and the prevalence of risk factors related to reduced progression-free survival. In all, 686 patients met the inclusion criteria, with PCA disease identified in 282 (41.1%) patients. Of those 282 patients with PCMMD, disease severity ranged from 99 (35.1%) with mild, 72 (25.5%) with moderate, and 111 (39.4%) with severe. The total number of postoperative complications was significantly associated with PCMMD severity (P=0.0067). Additionally, PCMMD severity correlated with worse postoperative modified Rankin Scale scores (P<0.0001). At a mean follow-up of 6.0±3.9 (range, 0.1-25.0) years, a total of 60 (12.6%) patients showed new/worsening PCMMD. The overall postoperative, progression-free survival in patients with PCMMD was 95.4% at 1 year, 82.4% at 3 years, 68.8% at 5 years, and 28.3% at 10 years, with prognostic factors for progression including preoperative PCMMD status, history of tobacco use, and hypertension (P<0.0001, P<0.001, and P<0.0001, respectively). PCA disease involvement in MMD is associated with higher rates of ischemic perioperative complications and worsened functional outcomes, likely due to reduced collateral flow. Ten-year progression of PCA disease is highly likely and should be monitored throughout follow-up; future studies will assess the impact of PCA disease progression on long-term outcomes.

Combining multi-mode thermal therapy with IL-6 and IL-17A neutralization amplifies antitumor immunity to facilitate long-term survival in LLC1-bearing mice

Non-small cell lung cancer (NSCLC) is known for rapid development and chronic inflammation-induced immunosuppression. IL-6 and IL-17A are the essential cytokines that facilitate NSCLC progression and myeloid-derived suppressive cell (MDSC)-mediated evasion. IL-6 or IL-17A targeting, especially IL-6, shown outstanding efficacy in patient NSCLC controlling, but failed to completely eradicate tumor. The local tumor multi-mode thermal therapy developed in our prior research was demonstrated to stimulate systemic and durable tumor-specific immune response thereby promoting long-term tumor-free survival of mice and prolong the progression-free survival of patients, although the therapeutic efficacy was still affected by high-level preoperative MDSCs. To further improve the efficacy, in this study, IL-6 and IL-17A neutralization were combined with multi-mode thermal therapy in mouse LLC1 NSCLC model. Study revealed that combined with single cytokine neutralization only prolonged the survival time while triple combination therapy efficiently improved the survival rate. Additionally, triple combination therapy reduced the accumulation of MDSCs but promoted their maturation with strengthened activation and function of myeloid cells, thereby triggering a Th1-dominant-CD4+ T cell-response and enhancing the malignant cell-killing capacity of immune cells. Our study highlights the extraordinary efficacy of combining multi-mode thermal therapy with IL-6 and IL-17A neutralization, revealing a new strategy for refractory NSCLC patients.Graphical

Predicting Response to Immunotargeted Therapy in Endometrial Cancer via Tumor Immune Microenvironment: A Multicenter, Observational Study.

Only one-third of patients with advanced MSS/pMMR endometrial cancer exhibit a lasting response to the combination treatment of Pembrolizumab and Lenvatinib. The combined administration of these two drugs is based on Lenvatinib's ability to modulate the tumor microenvironment, enabling Pembrolizumab to exert its effect. These findings underscore the importance of exploring tumor microenvironment parameters to identify markers that can accurately select candidates for this type of therapy. An open non-randomized observational association study was conducted at six clinical centers, involving a total of 28 patients with advanced MSS/pMMR endometrial cancer who received Pembrolizumab and Lenvatinib therapy. Using TSA-associated multiplex immunofluorescence, we analyzed the proportion of CD8+ T lymphocytes, CD20+ B lymphocytes, FoxP3+ T regulatory lymphocytes, and CD163+ macrophages in tumor samples prior to immunotargeted therapy. The percentage of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio was significantly higher in patients who responded to treatment compared to non-responders (responders vs. non-responders: 0.24 (0.1-1.24)% vs. 0.08 (0.00-0.15)%, p = 0.0114; 1.44 (0.58-2.70) arb. unit vs. 19.00 (3.80-34.78) arb. unit, p = 0.0031). The sensitivity and specificity of these biomarkers were 85.71% and 70.59%, and 85.71% and 85.71%, respectively. The proportion of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio in the stroma of endometrial cancer serves as both a prognostic marker of response to immunotargeted therapy and a prognostic factor for progression-free survival in patients.

291 Supra-maximal Extent of Resection is Associated With Improved Progression-Free Survival in Patients With IDH Wild-Type Glioblastoma Once Negative TERT Promoter Molecular Margins are Achieved

INTRODUCTION: The standard of care for isocitrate dehydrogenase (IDH) wild-type GBM involves safe maximal resection with subsequent chemoradiation. TERT promoter (TERTp) mutations are clonal in &gt;85% of IDH wild-type GBMs, detectable in all tumor cells. Advances in surgical management have focused on optimizing maximal resection given the positive correlation between extent of resection (EOR) and post-operative outcomes. METHODS: TERTp mutation detection in margin specimens was performed via a novel 30min qPCR-based method. A machine learning algorithm incorporating preoperative anatomic and intraoperative characteristics was developed using 148 patients to predict EOR. This model was prospectively applied to 44 patients to assess the correlation between a TERTp mutation negative margin and survival in cases when GTR was predicted. RESULTS: Retrospective analysis of 148 patients who underwent resection of GBM revealed significant improvement in 36-month survival with residual volume (RV) &lt;4.9 cc). The primary predictive characteristics for achieving this RV were tumor volume, ventricular contact, multifocality, and Sawaya grade. Prospective analysis of 44 patients showed that, in cases where GTR was predicted and achieved, 26% obtained a TERTp negative margin. Although small, this group's PFS was significantly prolonged (0% vs 75% event-free at 30 months, p = 0.02), and a numerically superior prolonged OS was observed, while survival in GTR with positive molecular margin was indistinguishable from STR. CONCLUSIONS: These findings provide novel evidence supporting the utility of supramaximal resection targeting a “molecular margin” to maximize postoperative survival for a subset of patients with “localized” GBM. Further study is warranted to assess intraoperative, quantitative testing of TERTp mutation in GBM specimens to guide marginal resection in these patients.

Nomogram based on MRI and clinical features to predict progression-free survival in patients with stage IIIC1r cervical squamous cell carcinoma: A two-center study

To develop a nomogram based on MRI and clinical features to predict progression-free survival (PFS) of 2018 FIGO stage ⅢC1r cervical squamous cell carcinoma (CSCC). 144 consecutive patients with stage ⅢC1r CSCC from two independent institutions were stratified into training cohort (from Institution 1, n=100) and independent validation cohort (from Institution 2, n=44). Univariate and multivariate Cox regression analyses of MRI and clinical features before treatment were performed to determine independent risk factors for PFS in training cohort. Nomogram was developed based on them. Concordance index (C-index), calibration curves, and receiver operating characteristic (ROC) analyses were performed to assess and validate the nomogram. In training cohort, 2009 FIGO stage, maximum length of the primary tumor, short diameter and roundness index of the maximum metastatic lymph node were independent risk factors of PFS in patients with stage IIIC1r CSCC (all P-values < 0.05). Nomogram based on them to predict 1- and 3-year PFS achieved C-indexes of 0.835 (95% confidence interval (CI): 0.809-0.862) and 0.789 (95%CI: 0.683-0.895) in the training and validation cohorts, respectively. Areas under ROC curves for the nomogram to predict 1- and 3-year PFS were 0.891 (95%CI: 0.829-0.954), 0.921 (95%CI: 0.861-0.981) in training cohort, and 0.902 (95%CI: 0.803-0.999), 0.885 (95%CI: 0.778-0.992) in validation cohort, respectively. Calibration curves indicated the nomogram predictions were in good agreement with actual observations. The nomogram based on MRI and clinical features has high accuracy and stability in predicting PFS of patients with stage IIIC1r CSCC.

A Network Meta-analysis of the Efficacy of Drug Therapy in First-line Treatment of Advanced Hepatocellular Carcinoma.

Systemic therapy is mainly recommended for advanced hepatocellular carcinoma (HCC). Considering the variety of treatments available for HCC, there is a need to understand their relative benefits and risks, especially for the newly approved combination of immune checkpoint inhibitors and vascular endothelial growth factor inhibitors represented by atezolizumab in combination with bevacizumab. A reticulated meta-analysis was used to evaluate the efficacy and safety of atezolizumab-bevacizumab combination therapy compared with other first-line systemic therapies for the treatment of patients advanced HCC. PubMed, The Cochrane Library, Web of Science, and Embase databases were searched from the time of library construction to 01 December 2022, and the data were extracted and analyzed using Stata16.0 for Meta-analysis. The data were extracted separately, and a meta-analysis was performed using the software Stata16.0. 16 clinical studies with 8,779 subjects were identified from 13,417 records and were used to build the evidence network for all trials. TThe combination therapy of atezolizumab and bevacizumab has the advantage of prolonging the OS of patients when treating advanced HCC [HR=5.71, 95%CI (4.30, 7.12), p<0.05] Also, the combination therapy has the advantage of prolonging the patient's progression free survival [HR=1.60, 95%CI (0.89, 2.49), p<0.05]. Atezolizumab-bevacizumab combination therapy can improve clinical outcomes such as OS and PFS in patients with advanced HCC.

Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations.

Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 mutant and triple wild-type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. This was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care. A total of 254 patients with CM who had a CLIA-certified targeted sequencing assay performed on their tumor tissue were included. Of the 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated). The majority of this co-mutation group carried mutations in NF1 (n = 19 or 90%) with co-occurring mutations in BRAF or NRAS, often with a weaker oncogenic variant. Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. The majority of TWT tumors (n = 29, 87.9%) harbor a pathogenic mutation within a known Ras/MAPK signaling pathway component. Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7-266 mutations/Mb). A total of 14 cases (9.1%) were classified as having a low TMB (≤5 mutations/Mb), 64 of 154 (41.6%) had an intermediate TMB (>5 and ≤20 mutations/Mb), 40 of 154 (26.0%) had a high TMB (>20 and ≤50 mutations/Mb) and 36 of 154 (23.4%) were classified as having a very high TMB (>50 mutations/Mb). NRAS mutant melanoma demonstrated significantly decreased overall survival on multivariable analysis (HR for death 2.95, 95% CI 1.13-7.69, p = 0.027, log-rank test) compared with other TCGA molecular subgroups. Of the 116 patients in our cohort with available treatment data, 36 received a combination of dual ICI with anti-CTLA4 and anti-PD1 inhibition as first-line therapy. Elevated TMB was associated with significantly longer progression-free survival following dual-agent ICI (HR 0.26, 95% CI 0.07-0.90, p = 0.033, log-rank test). NRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with a combination of dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

Randomized, Double-Blind Phase III Study of Pazopanib Versus Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease After Metastasectomy: ECOG-ACRIN E2810.

Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo (Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

Abstract 7614: Mutations in MEN1/DAXX/ATRX are associated with improved progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy

Abstract Background: Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTATATE is an effective treatment for metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs). However, it remains unknown why some patients (pts) respond more favorably than others. Pre-clinical data suggests that mutations in the MEN1, DAXX, and/or ATRX genes influence DNA repair capabilities and increase radiation effect in cancer cells. We therefore thought to evaluate the association between response to PRRT and the presence of MEN1, DAXX, and/or ATRX mutations in patients with GEP-NETs. Methods: We retrospectively analyzed CLIA certified tissue-based Next Generation Sequencing (NGS) assay results and clinicopathological data from 28 pts with GEP-NETs treated with PRRT at our center from 2017 to 2023. Genetic findings were correlated with progression-free survival (PFS) using Kaplan-Meier estimators and Cox proportional hazards regression modeling. Objective response was assessed per RECIST v1.1 by investigator review. Results: Pts with mutations in MEN1, DAXX, or ATRX (n = 13, 46.42%) had a longer PFS [mPFS, 26.47 months (95% CI, 17.97 - NA) vs. 12.13 months (95% CI, 9.17 - NA); HR, 0.19; 95% CI, 0.06 - 0.68; p = 0.01] than wildtype (n = 15, 53.58%) pts, when adjusted for surgery prior to PRRT and tumor grade. Pts with mutations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended towards better PFS compared to patients without concurrent mutations [only MEN1mt or DAXXmt/ATRXmt, but not both; mPFS, 31.53 months (95% CI, 28.43 - NA) vs. 17.97 months (95% CI, 11.17 - NA); HR, 0.25; 95% CI, 0.05 - 1.29; p = 0.09]. Among evaluable pts, objective response rate was higher in pts with a mt in MEN1, DAXX, or ATRX compared to wild-type pts (41.67% vs. 15.38%; p = 0.09). In the pancreatic NET (PNET) subset, mutations in either MEN1, DAXX, or ATRX were found in 11/16 pts (68.75%) and were also associated with a better PFS compared to wild type patients [mPFS, 28.43 months (95% CI, 11.50 - NA) vs. 9.83 months (95% CI, 7.83 - NA); HR, 0.21; 95% CI, 0.05 - 0.95; p = 0.04). Conclusions: Mutations in MEN1/DAXX/ATRX correlate with improved PFS in patients with GEP-NETs receiving PRRT. Concurrent mutations in MEN1 and DAXX/ATRX may have additive effects on response to PRRT. If validated in larger studies, these findings may represent a novel biomarker to predict PRRT response. Limitations: Limited sample size precludes generalization of results and might overestimate effect sizes. Citation Format: Rushabh Gujarathi, Sara Abou Azar, Joseph Tobias, Xavier Keutgen, Chih-Yi Liao. Mutations in MEN1/DAXX/ATRX are associated with improved progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy [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 7614.

Abstract 6438: Subcutaneous fat mass predicts progression-free survival in patients treated with antibody-drug-conjugates in early-phase clinical trials

Abstract Background: Antibody drug conjugates (ADCs) have revolutionized the treatment of many solid tumours and hematological diseases. Little is known about the influence of body composition on efficacy and safety of ADCs. Methods: All patients treated with ADCs in early phase clinical trials between 03/2015 and 03/2023 at the Drug Development Department at Gustave Roussy were retrospectively included in the analysis. A deep learning software (Anthropometer3DNet) automatically measured anthropometric parameters in 3D on pretreatment scans, allowing multi-slice measurements of muscle body mass (MBM), fat body mass (FBM), subcutaneous fat mass (SFM) and visceral fat mass (VFM). Other clinical and biological parameters were also retrieved and evaluated. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival analysis was performed using Cox regression models and Kaplan-Meier (KM) estimator. Cut-offs were determined using the maxstat method. Anthropometric parameters’ effect on toxicity was also evaluated using a ROC analysis. Results: A total of 136 patients were treated with ADCs. The most frequent tumor types were non-small cell lung cancer (56 patients, 41%) and colorectal cancer (31 patients, 23%). Median age, ECOG PS, albumin and number of previous lines of treatment were 60.8 years (30 to 85), 1, 42 g/L and 3 respectively. In the overall cohort, median PFS and OS were 2.8 and 8.6 months respectively, 90 (66%) patients had experienced toxicity, of which 46 were grade 3-4. The Royal Marsden Hospital (RMH) prognostic score of 2 or more was significantly associated with worse PFS (HR=2.13, p=0.007) and OS (HR=2.12, p=0.008). The number of treatment lines was significantly associated with worse OS (HR=1.21, p&amp;lt;0.001). For the anthropometric parameters, SFM (HR=0.89, p=0.013) and FBM (HR=0.89, p=0.02) were significantly associated to PFS. Higher SFM (cutoff: 3.3 kg/m2) and FBM (cutoff: 3.6 kg/m2) were significantly associated with longer PFS (mPFS=3.8 vs 2.3 months and 3.7 vs 1.9 respectively). Patients with higher SFM and FBM had numerically but non-significantly longer (mOS=8.5 vs 7.7 months and 8.6 vs 6.4 months respectively). All anthropometric parameters were significantly associated with all-grade toxicity in the univariate but not in the multivariate analysis. None of the parameters were associated with grade 3-4 toxicity. Conclusions: In this large monocenter cohort, 3D measured high SFM and FBM were significantly associated with PFS. Automatic extraction of body composition parameters using AI may help in anticipating the benefits of ADCs in patients included in early-phase clinical trials. Citation Format: Matthieu Delaye, Littisha Lawrance, Younes Belkouchi, Felix Wirth, Pierre Decazes, Alexandre Bône, Kaïssa Ouali, Antoine Hollebecque, Cristina Smolenschi, Rastislav Bahleda, Anas Gazzah, Stéphane Champiat, François-Xavier Danlos, Clémence Hénon, Kristi Beshiri, Madona Sakkal, Aurélien Marabelle, Jean-Marie Michot, Vincent Ribrag, Claudia Parisi, Christophe Massard, Vincent Goldschmidt, Pierre Vera, Santiago Ponce-Aix, Nathalie Lassau, Samy Ammari, Capucine Baldini. Subcutaneous fat mass predicts progression-free survival in patients treated with antibody-drug-conjugates in early-phase clinical trials [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 6438.

Letter to the editor: Dexamethasone and overall survival and progression free survival in patients with newly diagnosed glioblastoma: a meta-analysis.

Letter to the editor: Dexamethasone and overall survival and progression free survival in patients with newly diagnosed glioblastoma: a meta-analysis.

Abstract 3279: MUC1 is necessary for the inflammatory memory response to osimertinib resistance in NSCLC cells

Abstract Emergence of resistance is an invariable outcome in cancer progression that may involve memory of cancer cells to treatment. The oncogenic MUC1-C protein confers pleotropic resistance of cancer cells to diverse cytotoxic and targeted agents by unclear mechanisms. We demonstrate that MUC1-C regulates the interferon (IFN) type I/II pathways in H1975 non-small cell lung cancer (NSCLC) cells selected for osimertinib resistance (H1975-OR). Targeting MUC1-C in H1975-OR cells suppressed STAT1 and inflammatory IFN signaling in association with reversing the osimertinib-resistant phenotype. Studies of H1975-OR cells selected for growth in the absence of osimertinib demonstrate that revertant H1975-RT cells retain MUC1-C-dependent memory necessary for recalling osimertinib resistance. Mechanistically, osimertinib treatment of H1975-RT cells activates the MUC1 gene at a (i) promoter-like signature (PLS) by MUC1-C and STAT1, and (ii) proximal enhancer-like signature (pELS) by PBAF and JUN/AP-1. Targeting MUC1-C in osimertinib-treated H1975-RT and MGH170 NSCLC MET-amplified cells isolated from a patient refractory to osimertinib treatment suppressed induction of STAT1 and downstream IFN-stimulated genes (ISGs) encoding MX1, OAS1 and ISG15. Targeting MUC1-C, STAT1, PBRM1/PBAF and JUN/AP-1 further confirmed their dependencies for reemergence of osimertinib resistance in H1975-RT and MGH170 cells. In support of these results, high MUC1-C protein expression analyzed by IHC is associated with shorter progression free survival for patients treated with osimertinib. These findings and the demonstration that MUC1-C is upregulated in NSCLC cells from patients refractory to osimertinib indicate that MUC1-C drives osimertinib resistance in NSCLC cells by promoting an inflammatory memory response. Citation Format: Naoki Haratake, Atrayee Bhattacharya, Ayako Nakashoji, Hiroki Ozawa, Mototsugu Shimokawa, Donald Kufe. MUC1 is necessary for the inflammatory memory response to osimertinib resistance in NSCLC cells [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 3279.

Abstract 5949: The clinical dual KRASG12C inhibitor FMC-376 has demonstrated potential as both a monotherapy and in combination for the treatment of patients with KRASG12C mutation positive NSCLC

Abstract KRAS, a membrane-associated guanosine triphosphatase (GTPase), is the most frequently mutated oncogene in cancer with activating mutations occurring in approximately 25% of NSCLC. Of these, KRASG12C occurs in approximately 14% of adenocarcinomas and in 0.5 to 4% of squamous NSCLCs. This mutation impairs GTPase activity and GTP-hydrolysis leading to an increase in the active, GTP-bound (ON), state. KRAS was long considered undruggable until the recent discovery of inhibitors that bind the GDP-bound, inactive (OFF) state of KRASG12C. The most clinically advanced of these first-generation molecules have demonstrated clinical response rates of 37-43% and 6 to 7-month progression-free survival in patients with KRASG12C positive NSCLC. While significant, a majority of cancers do not respond, and acquired resistance is common. FMC-376 is a next-generation dual inhibitor of both the ON and OFF states of KRASG12Cwith the potential to deliver improved outcomes as both a monotherapy and in combination, for patients with KRASG12C positive NSCLC. FMC-376 was discovered through the FrontierTM platform, which integrates chemoproteomics, machine-learning, and covalent fragment-based drug discovery. The potential for FMC-376 in the treatment of patients with KRASG12C mutant NSCLC has been assessed in a broad panel of NSCLC PDX models representing settings of sotorasib/adagrasib resistance, in a model of NSCLC CNS-metastasis and in combination with an immune checkpoint inhibitor. The dual ON + OFF state mechanism of action of FMC-376 is highly active across a panel of NSCLC CDX and PDX models, including those that carry co-mutations that are associated with both primary and acquired resistance to the OFF-state inhibitors adagrasib and sotorasib in NSCLC. These drivers of resistance include activating mutations of receptor tyrosine kinases (e.g. EGFR, MET, etc.), co-mutations including KEAP1 and adaptive resistance due to release of negative feedback control. Evaluation of FMC-376 in models where EGFR signaling is induced by EGF demonstrated rapid and durable target engagement in contrast to both sotorasib and adagrasib which show decreased effectiveness after EGF stimulation. As a result, FMC-376 is highly effective in NSCLC PDX models that have EGFR and MET upregulation. In addition, 27-42% of patients with KRASG12C positive NSCLC present with CNS metastasis. FMC-376 is highly active in an intracranial NSCLC model of CNS-metastasis, resulting in tumor regression. Furthermore, FMC-376 has demonstrated activity in combination with an anti-PD-1 mAb in a KRASG12C mutant mouse syngeneic tumor model. Together, these data demonstrate the potential of FMC-376, a next-generation clinical stage dual inhibitor of ON and OFF state KRASG12C, for the treatment of patients with KRASG12C mutant NSCLC as well as other KRASG12C positive tumors. Citation Format: Yan Wang, Allison Roberts, Philamer Calses, Richard M. Neve, Jocelyn Staunton, Kevin R. Webster. The clinical dual KRASG12C inhibitor FMC-376 has demonstrated potential as both a monotherapy and in combination for the treatment of patients with KRASG12C mutation positive 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 5949.

Abstract 5171: CD39, CD73 and CD38 as potential biomarkers for monitoring the response to mogamulizumab in Sézary syndrome

Abstract We demonstrated aberrant expression of CD39 or CD73 and low expression of CD38 in circulating and skin-homing CD4+ T cells in patients with Sézary syndrome (SS), an erythrodermic cutaneous T-cell lymphoma (CTCL) with a leukemic component. The anti-CCR4 monoclonal antibody Mogamulizumab (Moga) has been shown to increase progression-free survival in patients with advanced SS. Here, we longitudinally explored the modulation of the expression of CD39, CD73 and CD38 in circulating CD4+ T cells from SS patients under treatment with Moga. Eight patients with relapsed/refractory SS were included in the study and prospectively followed up for two years (median duration of treatment 9,5 months, range 5-28 months). Seven out of eight (87,5%) patients showed early complete response in the blood and partial (5/7, 71,4%) or near complete response (2/7, 28,6%) in the skin. One patient (12,5%) showed no blood or skin response to the treatment. Flow cytometry analysis highlighted that the clinical response was accompanied by a rapid and remarkable increase in CD38 expression in the residual circulating CD4+ T cells, as well as in CD8+ T cells. Moreover, in six patients carrying the homozygous G/G or heterozygous A/G ENTPD1 SNP rs10748643 genotypes, permissive to CD39 overexpression in T cells, the increased CD38 expression was paralleled by rapid reduction/loss of CD39. Notably, in one patient carrying the A/A genotype, characterized by low CD39 and high CD73 expression at the baseline, response to treatment was characterized by reduction of CD73 expression. The only one patient with A/A genotype who didn’t respond to Moga showed no modulation of CD38 or CD39 expression, while CD73 expression increased. Noteworthy, Moga increases the expression of CD38 in responding patients, and influences the expression of CD39 only in patients with the permissive CD39 genotypes (G/G; A/G), but not in those with the A/A genotype. Two patients showing initial response to Moga experienced skin progression during treatment, which was associated with a significant increase of CD39 and simultaneous decrease of CD38 in residual circulating CD4+ T cells, although there was no evidence of blood relapse. These preliminary results suggest that partial or complete responses to Moga is paralleled by reduced CD39 and/or CD73 expression and increased CD38 expression. Instead, an opposite modulation of these markers is associated with disease progression hinting at the potential clinical utility of CD38, CD39 and CD73 as markers to monitor patients' response to Moga therapy. Citation Format: Yuliya Yakymiv, Sara Marchisio, Erika Ortolan, Verdiana Pullano, Chiara Leso, Rebecca Senetta, Lorenzo Marega, Gabriele Roccuzzo, Pietro Quaglino, Ada Funaro. CD39, CD73 and CD38 as potential biomarkers for monitoring the response to mogamulizumab in Sézary syndrome [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 5171.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial

Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

Comparison of the prognostic value of lymph node yield, lymph node ratio, and number of lymph node metastases in patients with oral squamous cell carcinoma.

The aim of this study was to assess the prognostic significance of lymph node yield (LNY), lymph node ratio (LNR), and the number of lymph node metastases (LNMs) in patients affected by oral squamous cell carcinoma (OSCC). The study included patients who underwent surgical treatment for primary OSCC. Receiver operating characteristic curves were generated to determine the optimal threshold values. Kaplan-Meier curves were employed, along with the log-rank test, for the analysis of survival. To compare the performance in terms of model fit, we computed Akaike's information criterion (AIC). This study enrolled 429 patients. Prognostic thresholds were determined at 22 for LNY, 6.6% for LNR, and 3 for the number of LNMs. The log-rank test revealed a significant improvement in both overall survival and progression-free survival for patients with a LNR of ≤6.6% or a number of LNMs of ≤3 (p < 0.05). Interestingly, LNY did not demonstrate prognostic significance. The AIC analyses indicated that the number of LNMs is a superior prognostic indicator compared to LNY and LNR. Incorporating LNR or the number of LNMs into the TNM classification has the potential to improve the prognostic value, as in other types of cancers. Particularly, the inclusion of the number of LNMs should be contemplated for future N staging.