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BackgroundDostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab.MethodsGARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review.ResultsScreening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5–22.1) for cohort A1 and 11.5 months (IQR 11.0–25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1–2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab.ConclusionDostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile.Trial registration numberNCT02715284.

Recently, the development of immunotherapy through the immune checkpoint blockade led to long-lasting responses in several types of cancers that are refractory to conventional treatments, such as melanoma or non-small cell lung cancer. Immunotherapy has also demonstrated significant improvements in various other types of cancers. However, breast cancer remains one of the tumors that have not experienced the explosion of immunotherapy yet. Indeed, breast cancer was traditionally considered as being weakly immunogenic with a lower mutational load compared to other tumor types. In the last few years, anti-PD1/PD-L1 (Programmed death-ligand 1) agents have been evaluated in breast cancer, particularly in the triple negative subtype, with promising results observed when delivered as monotherapy or in combination with conventional treatments. In this review, we will report the results of the most recent studies evaluating immune checkpoint inhibitors in breast cancer. In addition, we will discuss the concomitant development of possible biomarkers, which is required for improving the selection of patients with the highest probability of benefiting from these agents.

Breast cancers (BC) associated with germline mutations of BRCA1/2 represent 3–5% of cases. BRCA1/2-associated BC have biological features leading to genomic instability and potential sensitivity to DNA damaging agents, including poly(ADP-ribose) polymerase (PARP) and platinum agents. In this review, we will summarize clinical trials of chemotherapy and PARP inhibitors (PARPi), alone or in combination, at the early or late stage of BRCA1/2-associated BC. We will also present the mechanisms of resistance to PARPi as well as the new therapeutic strategies of association with PARPi. Finally, we will discuss under which conditions the use of DNA damaging agents can be extended to the BRCA1/2-wild type population, the BRCAness concept.

Background Immunotherapy (IO) has become a standard of care for treating various types of metastatic cancers and has significantly improved clinical outcome. With the exception of metastatic melanoma in complete response for which treatment can be stopped at 6 months, these treatments are currently administered until either disease progression for some IO, 2 years for others, or unacceptable toxicity. However, a growing number of studies are reporting maintenance of response despite discontinuation of therapy. There is currently no evidence of a dose effect of IO in pharmacokinetic studies. Maintaining efficacy despite a reduction in treatment intensity by decreasing the frequency of administration in patients with highly selected metastatic cancer, is the hypothesis evaluated in the MOIO study. Method/design This non-inferiority, randomized phase III study aims to compare the standard regimen to a 3 monthly regimen of variousIO drugs in adult patients with metastatic cancer in partial (PR) or complete response (CR) after 6 months of standard IO dosing (except melanoma in CR). This is a French national study conducted in 36 centers. The main objective is to demonstrate that the efficacy of a three-monthly administration is not unacceptably less efficacious than a standard administration. Secondary objectives are cost-effectiveness, quality of life (QOL), anxiety, fear of relapse, response rate, overall survival and toxicity. After 6 months of standard IO, patients with partial or complete response will be randomized 1:1 between standard IO or a reduced intensity dose of IO, administered every 3 months. The randomization will be stratified on therapy line,, tumor type, IO type and response status. The primary endpoint is the hazard ratio of progression-free survival. With a planned study duration of 6 years, including 36 months enrolment time, 646 patients are planned to demonstrate with a statistical level of evidence of 5% that the reduced IO regimen is non-inferior to the standard IO regimen, with a relative non-inferiority margin set at 1.3. Discussion Should the hypothesis of non-inferiority with an IO reduced dose intensity be validated, alternate scheduling could preserve efficacy while being cost-effective and allowing a reduction of the toxicity, with an increase in patient’s QOL. Trial registration NCT05078047.

Background: Immune checkpoint inhibitors (ICIs) have shown efficacy in endometrial cancer (EC); however, their efficacy varies according to mismatch repair (MMR) status. Notably, even among patients with MMR-deficient (MMRd) or microsatellite instability-high (MSI-H) tumors, approximately one-third exhibit primary resistance to ICI monotherapy. Objectives: We aimed to characterize dissimilarities in the tumor immune microenvironment of ICI-treated MMRd/MSI-H versus MMR-proficient (MMRp)/microsatellite stable (MSS) EC, and to identify mechanisms of resistance. Design: Adults with histologically confirmed advanced or recurrent EC treated with ICIs in 6 French comprehensive cancer centers were included. Patients without available archival formalin-fixed paraffin-embedded primary tumor samples were excluded. Clinical data were collected retrospectively. Methods: Patients were classified as ICI-Responders or Non-Responders based on best objective response. A seven-color multi-immunofluorescence staining (CD20, CD4, CD8, FoxP3, CD68, CK, and DAPI) was performed on sections from archival formalin-fixed paraffin-embedded primary tumors. Cell densities and spatial proximity were analyzed using inForm software. T/B lymphoid aggregates (LA) and tertiary lymphoid structures (TLS) were separately quantified. Microsatellite status, presence of LA/TLS, and immune cell densities were correlated to response to treatment. Results: Twenty-one MMRd/MSI-H and 12 MMRp/MSS tumors were analyzed. We observed more MMRd/MSI-H tumors with LA/TLS compared to MMRp/MSS cases: 81% versus 17%, p ⩽ 0.001. There were more CD8+ T effector cells in the vicinity of B cells in MMRd/MSI-H tumors compared to MMRp/MSS tumors (1.26 (0–3.40) vs 0.49 (0–1.86), p = 0.017), suggesting cooperation between CD8+ T cells and B cells in MMRd/MSI-H tumors. No differences were shown in terms of the presence of LA/TLS and the subsequent response to ICI in EC (p = 0.400). Using a multivariate logistic regression model, we found that a low density of CD68+ tumor-associated macrophages (TAMs) in the stroma, was associated with response to ICI in EC (odds ratio = 11.67, 95% CI (1.69–237.45), p = 0.033) and showed good accuracy in predicting response to ICI in the whole cohort (AUC = 0.75, 95% CI (0.59–0.91)). Conclusion: We characterize the immune landscape in EC patients treated with ICIs. Distinct immune infiltrate patterns were observed in MMRd/MSI-H and MMRp/MSS tumors. A significant negative association between TAM density and ICI response was shown. Plain language summary Exploring immune cells and tumor macrophages in endometrial cancer: insights for immunotherapy success Immune checkpoint inhibitors (ICIs) are promising treatments for endometrial cancer (EC), particularly in patients with specific genetic profiles, such as mismatch repair-deficient or microsatellite instability-high (MMRd/MSI-H) tumors. However, these treatments do not work for everyone, and many patients with MMRd/MSI-H tumors show resistance to ICIs. This study analyzed differences in the immune environment of EC tumors with and without these genetic markers to understand why some patients respond better to ICIs. Tumor samples from 33 patients treated with ICIs were studied using advanced staining techniques to visualize immune cells. Researchers also measured the densities of various immune cells, including T cells, B cells, and tumor-associated macrophages (TAMs), and examined their interactions within the tumors. The study found that MMRd/MSI-H tumors had more immune structures, such as lymphoid aggregates and tertiary lymphoid structures, compared to other types of EC. These tumors also showed more collaboration between two types of immune cells: CD8+ T cells (which attack cancer cells) and B cells. However, the presence of these structures did not predict whether patients would respond to ICI treatment. Interestingly, the researchers discovered that a lower number of TAMs, which can suppress the immune response, was strongly linked to better responses to ICIs. This finding suggests that TAM density could serve as a potential biomarker to predict which patients might benefit most from this therapy. Overall, this study highlights differences in immune environments between EC tumor types and identifies TAMs as a potential target to improve ICI efficacy. This research may help refine treatment strategies and improve outcomes for patients with endometrial cancer.

Ovarian cancer (OC) is one of the most common cancers in women, with a high mortality rate. Most of published studies have been focused on Caucasian populations, with the need to explore biological features and clinical outcomes of patients from other ethnicities. We described clinical outcome (progression-free survival and overall survival) and biomarkers associated with survival in a cohort of patients with OC from Tunisia. Using immunohistochemistry, we assessed the expression of 14 proteins known to be altered in OC in a cohort of 198 patients. We explored the correlation between protein expression and copy number alteration (CNA) profiles. FIGO stage, menopausal status and mismatch repair deficiency were associated with survival. ERBB2 amplification was correlated with high ERBB2 expression (OR = 69.32, p  = 4.03 E-09), and high PDL1 expression was associated to CD274 amplification (OR = 4.97, p  = 5.79 E-2). We identified a correlation between survival and exposure to two CNA signatures (MAPK pathway and BRCA-related homologous recombination deficiency). Moreover, Gama-H2AX protein expression was correlated with exposure to a genomic signature associated with homologous recombination deficiency. We observed that OC clinical and pathological characteristics of these patients from Tunisia were similar to those of Caucasian patients. We identified frequent CNA in this population that need to be confirmed in other sets from Africa.

ECRG4/C2ORF40 is a potential tumor suppressor gene (TSG) recently identified in esophageal carcinoma. Its expression, gene copy number and prognostic value have never been explored in breast cancer. Using DNA microarray and array-based comparative genomic hybridization (aCGH), we examined ECRG4 mRNA expression and copy number alterations in 353 invasive breast cancer samples and normal breast (NB) samples. A meta-analysis was done on a large public retrospective gene expression dataset (n = 1,387) in search of correlations between ECRG4 expression and histo-clinical features including survival. ECRG4 was underexpressed in 94.3% of cancers when compared to NB. aCGH data revealed ECRG4 loss in 18% of tumors, suggesting that DNA loss is not the main mechanism of underexpression. Meta-analysis showed that ECRG4 expression was significantly higher in tumors displaying earlier stage, smaller size, negative axillary lymph node status, lower grade, and normal-like subtype. Higher expression was also associated with disease-free survival (DFS; HR = 0.84 [0.76-0.92], p = 0.0002) and overall survival (OS; HR = 0.72 [0.63-0.83], p = 5.0E-06). In multivariate analysis including the other histo-clinical prognostic features, ECRG4 expression remained the only prognostic factor for DFS and OS. Our data suggest that ECRG4 is a candidate TSG in breast cancer, the expression of which may help improve the prognostication. If functional analyses confirm this TSG role, restoring ECRG4 expression in the tumor may represent a promising therapeutic approach.

Endometrioid ovarian cancers (EOvC) are usually managed as serous tumors. In this study, we conducted a comprehensive molecular investigation to uncover the distinct biological characteristics of EOvC. This retrospective multicenter study involved patients from three European centers. We collected clinical data and formalin‐fixed paraffin‐embedded (FFPE) samples for analysis at the DNA level using panel‐based next‐generation sequencing and array‐comparative genomic hybridization. Additionally, we examined mRNA expression using NanoString nCounter® and protein expression through tissue microarray. We compared EOvC with other ovarian subtypes and uterine endometrioid tumors. Furthermore, we assessed the impact of molecular alterations on patient outcomes, including progression‐free survival (PFS) and overall survival (OS). Preliminary analysis of clinical data from 668 patients, including 86 (12.9%) EOvC, revealed more favorable prognosis for EOvC compared with serous ovarian carcinoma (5‐year OS of 60% versus 45%; P = 0.001) driven by diagnosis at an earlier stage. Immunohistochemistry and copy number alteration (CNA) profiles of 43 cases with clinical data and FFPE samples available indicated that EOvC protein expression and CNA profiles were more similar to endometrioid endometrial tumors than to serous ovarian carcinomas. EOvC exhibited specific alterations, such as lower rates of PTEN loss, mutations in DNA repair genes, and P53 abnormalities. Survival analysis showed that patients with tumors harboring loss of PTEN expression had worse outcomes (median PFS 19.6 months vs. not reached; P = 0.034). Gene expression profile analysis confirmed that EOvC differed from serous tumors. However, comparison to other rare subtypes of ovarian cancer suggested that the EOvC transcriptomic profile was close to that of ovarian clear cell carcinoma. Downregulation of genes involved in the PI3K pathway and DNA methylation was observed in EOvC. In conclusion, EOvC represents a distinct biological entity and should be regarded as such in the development of specific clinical approaches. We used tissue microarray, mRNA and DNA analyses to compare endometrioid ovarian cancer (EOvC) with serous ovarian cancer and endometrioid endometrial cancer. We observed that EovC exhibit specific protein, mRNA, and DNA profiles. PTEN expression was prognostic with shorter progression‐free survival in patients with PTEN loss. Our observations highlight the need to develop research programs dedicated to rare subtypes of ovarian cancer.

Background Carboplatin and paclitaxel (CP) have been the standard of care for advanced/recurrent endometrial cancer (EC) for many years. However, this chemotherapy combination shows limited efficacy and recurrences often occur in less than 12 months. ABTL0812 is a novel drug that selectively kill cancer cells by cytotoxic autophagy and has shown anticancer efficacy in preclinical models of EC in combination with CP. Methods ENDOLUNG was an open-label, phase 1/2 clinical trial designed to determine the safety and efficacy of Ibrilatazar (ABTL0812) with CP in patients with advanced/recurrent EC and non-irradiable stage III and IV squamous non-small cell lung cancer (sq-NSCLC). The phase 1 part consisted of a 3 + 3 de-escalation design followed by an expansion cohort with 12 patients. The primary endpoint was safety. ABTL0812 starting dose was 1300 mg tid combined with carboplatin at area under the curve (AUC) 5 and paclitaxel at 175 mg/m 2 both administered every 21 days for up to 8 cycles. The phase 2 part included a total of 51 patients. The primary endpoint was overall response rate (ORR) and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results During the phase 1 only one dose limiting toxicity (DLT), a grade 4 neutropenia, was observed in 1 out of 6 patients, thus no de-escalation was applied. One additional DLT, a grade 3 febrile neutropenia, was observed in the expansion cohort, thus the recommended phase 2 dose (RP2D) for ABTL0812 was established at 1300 mg tid. Most frequent hematological adverse events (AE) of the combination were neutropenia (52.9%), anemia (37.3%) and thrombocytopenia (19.6%). Nausea (66.7%), asthenia (66.7%), diarrhea (54.9%) and vomiting (54.9%) were the most frequent non-hematological adverse events (AEs). The combination of ABTL0812 plus CP showed an ORR of 65.8% (13.2% complete response and 52.6% partial response) with a median DOR of 7.4 months (95% CI: 6.3–10.8 months). Median PFS was 9.8 months (95% CI: 6.6–10.6) and median OS 23.6 months (95% CI 6.4-ND). Pharmacokinetic parameters were compatible with target engagement observed in preclinical studies, and blood pharmacodynamic biomarkers indicated sustained target regulation during, at least, 28 days after starting the treatment. Conclusions This study suggests that the combination of ABTL0812 with CP is safe and feasible with an encouraging activity in patients with advanced/recurrent EC. Our data warrant further confirmation in prospective randomized trials. Trial registration EU Clinical Trial Register, EudraCT number 2016-001352-21 and National Clinical Trials Number, NCT03366480. Registration on 19 September 2016. Highlights ABTL0812 is a novel drug in clinical development that kills tumor cells by cytotoxic autophagy. The recommended phase 1/2 dose of ABTL0812 in combination with paclitaxel/carboplatin is 1300 mg three times a day (tid) by the oral route. The combination of ABTL0812 plus carboplatin and paclitaxel (CP) in patients with advanced/recurrent EC suggests an improved benefit-to-risk ratio vs. CP alone and warrants further clinical evaluation.

Endometrial cancer (EC) can easily be cured when diagnosed at an early stage. However, advanced and metastatic EC is a common disease, affecting more than 15,000 patients per year in the United Sates. Only limited treatment options were available until recently, with a taxane–platinum combination as the gold standard in first-line setting and no efficient second-line chemotherapy or hormone therapy. EC can be split into four molecular subtypes, including hypermutated cases with POLE mutations and 25–30% harboring a microsatellite instability (MSI) phenotype with mismatch repair deficiency (dMMR). These tumors display a high load of frameshift mutations, leading to increased expression of neoantigens that can be targeted by the immune system, including (but not limited) to T-cell response. Recent data have demonstrated this impact of programmed death 1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors on chemo-resistant metastatic EC. The uncontrolled KEYNOTE-158 and GARNET trials have shown high response rates with pembrolizumab and dostarlimab in chemoresistant MSI-high tumors. Most responders experiment long responses that last more than one year. Similar, encouraging results were obtained for MMR proficient (MMRp) cases treated with a combination of pembrolizumab and the angiogenesis inhibitor lenvatinib. Approvals have, thus, been obtained or are underway for EC with immune checkpoint inhibitors (ICI) used as monotherapy, and in combination with antiangiogenic agents. Combinations with other targeted therapies are under evaluation and randomized studies are ongoing to explore the impact of ICI-chemotherapy triplets in first-line setting. We summarize in this review the current knowledge of the immune environment of EC, both for MMRd and MMRp tumors. We also detail the main clinical data regarding PD-1/PD-L1 inhibitors and discuss the next steps of development for immunotherapy, including various ICI-based combinations planned to limit resistance to immunotherapy.