Many anticancer active pharmaceutical ingredients (APIs), such as paclitaxel (PTX), exhibit poor water solubility, which limits their bioavailability and necessitates the use of excipients. While biodegradable polymeric excipients combined with nanotechnology offer promising solutions, the high cost of polymers and APIs, along with the vast number of potential API-polymer combinations, poses significant challenges in developing effective drug delivery systems (DDS). This study explores the potential of API-polymer phase behavior modeling as part of the design of nanoparticle (NP)-based DDS for PTX using poly(lactide-co-glycolide) (PLGA) and poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-PEG) with varying molecular weights. The phase behavior of PTX-PLGA/PLGA-PEG systems, which reflects the compatibility of PTX with polymeric excipients, was predicted using the Conductor-like Screening Model for Real Solvents (COSMO-RS). To investigate the correlation between the predictions and experimental observations, PTX-PLGA and PEGylated PLGA NPs were prepared via an emulsion-solvent evaporation method with varying initial PTX amounts. The predicted trends in PTX solubility in polymeric excipients were then compared with key NP characteristics, such as drug loading, solid-state properties, and cytotoxicity in HeLa, SKOV-3, and MRC-5 cells. COSMO-RS predictions indicated limited PTX solubility in PLGA, which aligns with experimental observations, where the maximum amorphous PTX loading did not exceed 2 wt%, regardless of the polymer molecular weight. COSMO-RS modeling predicted higher compatibility of PTX with PEG, suggesting that incorporating PEG would enhance PTX loading in PEGylated NPs. This trend was corroborated by experimental findings, which showed increased drug loading capacity and slower PTX release from PEGylated NPs during cytotoxicity studies. These results highlight the potential of API-polymer modeling as a tool for tailoring polymeric carriers and optimizing API consumption in NP-based DDS development.

• Keywords
• COSMO-RS, Cell tests, Compatibility, Drug delivery systems, Nanoparticles, PLGA copolymers, Paclitaxel,
• MeSH
• Antineoplastic Agents, Phytogenic * chemistry   administration & dosage   pharmacology   MeSH
• Polylactic Acid-Polyglycolic Acid Copolymer * chemistry   MeSH
• Drug Delivery Systems MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Nanoparticles * chemistry   administration & dosage   MeSH
• Drug Carriers * chemistry   MeSH
• Paclitaxel * chemistry   administration & dosage   pharmacology   MeSH
• Polyethylene Glycols chemistry   MeSH
• Polyglactin 910 * chemistry   MeSH
• Excipients chemistry   MeSH
• Solubility MeSH
• Drug Liberation MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antineoplastic Agents, Phytogenic * MeSH
• Polylactic Acid-Polyglycolic Acid Copolymer * MeSH
• Drug Carriers * MeSH
• Paclitaxel * MeSH
• Polyethylene Glycols MeSH
• Polyglactin 910 * MeSH
• Excipients MeSH

PURPOSE: Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS: In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m2 and nab-paclitaxel 125 mg/m2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS: OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION: This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

• MeSH
• Adenocarcinoma * therapy   pathology   drug therapy   mortality   MeSH
• Albumins administration & dosage   adverse effects   MeSH
• Deoxycytidine analogs & derivatives   administration & dosage   adverse effects   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Gemcitabine MeSH
• Middle Aged MeSH
• Humans MeSH
• Pancreatic Neoplasms * pathology   therapy   drug therapy   mortality   MeSH
• Paclitaxel administration & dosage   adverse effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• 130-nm albumin-bound paclitaxel MeSH Browser
• Albumins MeSH
• Deoxycytidine MeSH
• Gemcitabine MeSH
• Paclitaxel MeSH

BACKGROUND: Current therapy for in-stent restenosis (ISR) is based on drug-eluting stents (DES) or drug-eluting balloon catheters. This prospective randomized study compared the efficacy of a novel sirolimus-eluting balloon (SEB) catheter to that of a paclitaxel-eluting balloon (PEB) catheter for the treatment of bare-metal stent (BMS-ISR) or DES-ISR. METHODS: A total of 145 patients with 158 BMS or DES-ISR lesions were randomly assigned to the treatment with either SEB or PEB. The in-segment late lumen loss at 12 months, the 12-month incidence of binary ISR, and major adverse cardiac events (cardiac death, nonfatal acute myocardial infarction, or target lesion revascularization) were compared between groups. RESULTS: The noninferiority of SEB compared with PEB in the treatment of BMS/DES-ISR with respect to late lumen loss was not demonstrated (Δlate lumen loss, -0.024 mm [95% CI, -0.277 to 0.229]; for a noninferiority margin of 0.20 mm), except in the post hoc subanalysis for the BMS-ISR group (-0.203 mm [95% CI, -0.584 to 0.178]). No significant differences in the incidence of repeated binary ISR (31.6% versus 30.4%, P=0.906) or 12-month major adverse cardiac events (31% for both; P>0.999) between the SEB and PEB groups were observed. CONCLUSIONS: The noninferiority of SEB relative to PEB in the treatment of BMS/DES-ISR with respect to late lumen loss was not confirmed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03667313.

• Keywords
• angioplasty, balloon, coronary, coronary restenosis, paclitaxel, sirolimus,
• MeSH
• Angioplasty, Balloon, Coronary * adverse effects   instrumentation   MeSH
• Coated Materials, Biocompatible * administration & dosage   MeSH
• Time Factors MeSH
• Cardiovascular Agents administration & dosage   adverse effects   MeSH
• Percutaneous Coronary Intervention * adverse effects   instrumentation   MeSH
• Coronary Restenosis * diagnostic imaging   therapy   mortality   etiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Coronary Artery Disease * diagnostic imaging   therapy   mortality   MeSH
• Paclitaxel * administration & dosage   adverse effects   MeSH
• Prospective Studies MeSH
• Prosthesis Design MeSH
• Risk Factors MeSH
• Aged MeSH
• Sirolimus * administration & dosage   adverse effects   MeSH
• Cardiac Catheters MeSH
• Drug-Eluting Stents adverse effects   MeSH
• Stents adverse effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Equivalence Trial MeSH
• Multicenter Study MeSH
• Comparative Study MeSH
• Names of Substances
• Coated Materials, Biocompatible * MeSH
• Cardiovascular Agents MeSH
• Paclitaxel * MeSH
• Sirolimus * MeSH

Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

• MeSH
• Deoxycytidine analogs & derivatives   administration & dosage   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Doxorubicin analogs & derivatives   administration & dosage   MeSH
• Phthalazines * therapeutic use   adverse effects   administration & dosage   MeSH
• Gemcitabine MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * drug therapy   MeSH
• Ovarian Neoplasms * drug therapy   genetics   mortality   pathology   MeSH
• Paclitaxel administration & dosage   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors * therapeutic use   adverse effects   MeSH
• Piperazines * therapeutic use   adverse effects   administration & dosage   MeSH
• Polyethylene Glycols administration & dosage   MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged MeSH
• Topotecan administration & dosage   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• BRCA1 protein, human MeSH Browser
• BRCA2 protein, human MeSH Browser
• Deoxycytidine MeSH
• Doxorubicin MeSH
• Phthalazines * MeSH
• Gemcitabine MeSH
• liposomal doxorubicin MeSH Browser
• olaparib MeSH Browser
• Paclitaxel MeSH
• Poly(ADP-ribose) Polymerase Inhibitors * MeSH
• Piperazines * MeSH
• Polyethylene Glycols MeSH
• BRCA1 Protein MeSH
• BRCA2 Protein MeSH
• Topotecan MeSH

PURPOSE: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression. The pivotal, phase 3 ENGOT-ov50/GOG-3029/INNOVATE-3 study evaluated efficacy and safety of TTFields therapy with paclitaxel (PTX) vs PTX in patients with platinum-resistant ovarian cancer (PROC). PATIENTS AND METHODS: Adult patients with PROC with ≤ 5 total prior lines of therapy (LOT), including ≤ 2 prior LOT for platinum-resistant disease, and ECOG PS of 0-1 were randomized 1:1 to receive TTFields (200 kHz; ≥ 18 h/day) + PTX (80 mg/m2 weekly) or PTX. Primary endpoint was overall survival (OS). Exploratory post-hoc analyses assessed OS in pegylated liposomal doxorubicin (PLD)-naive patients. RESULTS: Between March 2019 and November 2021, 558 patients (ECOG PS 0, 60.2 %; median [range] age, 62 [22-91] years) were assigned TTFields+PTX (n = 280) or PTX (n = 278). 24.4 % had 4 + prior LOT. Median OS was 12.2 months with TTFields+PTX vs 11.9 months with PTX (HR, 1.01; 95 % CI, 0.83-1.24; p = 0.89). Grade ≥ 3 adverse events (AEs) were similar between treatment groups. Grade 1/2 device-related skin AEs occurred in 83.6 % of patients receiving TTFields therapy. In exploratory post-hoc analysis in PLD-naive patients, median OS was 16 months with TTFields+PTX (n = 113) vs 11.7 months with PTX (n = 88; nominal HR, 0.67; 95 % CI, 0.49-0.94; p = 0.03). CONCLUSIONS: No new safety signals were identified. TTFields+PTX did not significantly improve OS compared with PTX in the intent-to-treat population. An exploratory post-hoc analysis suggests a potentially favorable benefit-risk profile for TTFields therapy in PLD-naive patients.

• Keywords
• Antineoplastic agents, Neoplasm drug resistance, Ovarian epithelial carcinoma, Ovarian neoplasm, Survival analysis,
• MeSH
• Drug Resistance, Neoplasm * MeSH
• Adult MeSH
• Doxorubicin analogs & derivatives   pharmacology   therapeutic use   MeSH
• Electric Stimulation Therapy * adverse effects   methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Ovarian Neoplasms * therapy   mortality   pathology   drug therapy   MeSH
• Paclitaxel * pharmacology   therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Doxorubicin MeSH
• Paclitaxel * MeSH

BACKGROUND: In the ARIEL4 trial of rucaparib versus standard-of-care chemotherapy in patients with relapsed BRCA-mutated ovarian carcinoma, the primary endpoint was met, showing improved investigator-assessed progression-free survival with rucaparib. Here, we present the final overall survival analysis of the trial and other post-progression outcomes. METHODS: This open-label, randomised, controlled phase 3 trial was done at 64 hospitals and cancer centres in 12 countries, including Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA. Eligible patients were women aged 18 or older with BRCA1 or BRCA2-mutated ovarian carcinoma and had received at least two previous chemotherapy regimens. Patients had to have evaluable disease as per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) criteria and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using an interactive response technology and block randomisation (block size of six) and stratified by progression-free interval after the most recent platinum-containing therapy to receive oral rucaparib (600 mg twice daily administered in 28-day cycles) or chemotherapy on the basis of platinum-sensitivity status. In the chemotherapy group, patients with platinum-resistant disease (progression-free interval ≥1 to <6 months) or partially platinum-sensitive disease (progression-free interval ≥6 to <12 months) received weekly paclitaxel (starting dose 60-80 mg/m2 on days 1, 8, and 15). Patients with fully platinum-sensitive disease (progression-free interval ≥12 months) received the investigator's choice of platinum-based chemotherapy (single-agent cisplatin or carboplatin, or platinum-doublet chemotherapy), in 21-day or 28-day cycles. The primary endpoint (previously reported) was investigator-assessed progression-free survival, assessed in the efficacy population (all randomly assigned patients with deleterious BRCA1 or BRCA2 mutations without reversion mutations) and in the intention-to-treat population (all randomly assigned patients). Overall survival was a prespecified secondary endpoint and was analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned study treatment. The cutoff date was April 10, 2022. This study is registered with ClinicalTrials.gov, NCT02855944; enrolment is complete and the study is closed. FINDINGS: Between March 1, 2017, and Sept 24, 2020, 349 eligible patients were randomly assigned to receive rucaparib (n=233) or chemotherapy (n=116). 332 (95%) of 349 patients were white and 17 (5%) patients were other or of unknown race. In the chemotherapy group, 80 (69%) of 116 patients crossed over to receive rucaparib. Median follow-up was 41·2 months (IQR 37·8-44·6). At data cutoff for this final analysis (April 10, 2022), 244 (70%) of 349 patients had died: 167 (72%) of 233 in the rucaparib group and 77 (66%) of 116 in the rucaparib group. Median overall survival was 19·4 months (95% CI 15·2-23·6) in the rucaparib group versus 25·4 months (21·4-27·6) in the chemotherapy group (hazard ratio 1·3 [95% CI 1·0-1·7], p=0·047). No new safety signals were observed, including during crossover to rucaparib. The most common grade 3-4 adverse events across treatment groups included anaemia or decreased haemoglobin (reported in 59 [25%] of 232 patients in the rucaparib group and seven [6%] of 113 in the chemotherapy group), and neutropenia or decreased neutrophil count (in 26 [11%] of 232 in the rucaparib group and 16 [14%] of 113 patients in the chemotherapy group). Serious adverse events were reported in 66 (28%) of 232 patients in the rucaparib group and 14 (12%) of 113 patients in the chemotherapy group. Ten treatment-related deaths were reported in the rucaparib group, two of which were linked to judged to be related to rucaparib (cardiac disorder and myelodysplastic syndrome), and one death related to treatment was reported in the chemotherapy group, with no specific cause linked to the treatment. INTERPRETATION: These data highlight the need for a better understanding of the most appropriate treatment for patients who have progressed on a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, and the optimal sequencing of chemotherapy and PARP inhibitors in advanced ovarian cancer. FUNDING: Clovis Oncology.

• MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Carcinoma, Ovarian Epithelial * drug therapy   genetics   mortality   MeSH
• Indoles * therapeutic use   adverse effects   administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * drug therapy   genetics   pathology   MeSH
• Mutation * MeSH
• Ovarian Neoplasms * drug therapy   genetics   pathology   mortality   MeSH
• Paclitaxel administration & dosage   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors * therapeutic use   adverse effects   MeSH
• BRCA1 Protein * genetics   MeSH
• BRCA2 Protein * genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH
• Names of Substances
• BRCA1 protein, human MeSH Browser
• BRCA2 protein, human MeSH Browser
• Indoles * MeSH
• Paclitaxel MeSH
• Poly(ADP-ribose) Polymerase Inhibitors * MeSH
• BRCA1 Protein * MeSH
• BRCA2 Protein * MeSH
• rucaparib MeSH Browser

Mismatch repair-deficient (dMMR) endometrial cancer (EC) is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877) in newly diagnosed, high-risk EC after surgery with curative intent. Patients were randomly assigned to pembrolizumab 200 mg or placebo (six cycles) plus carboplatin-paclitaxel (four to six cycles) once every 3 weeks, then pembrolizumab 400 mg or placebo once every 6 weeks (six cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary end point. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis on the basis of the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

• MeSH
• Chemotherapy, Adjuvant MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Antibodies, Monoclonal, Humanized * administration & dosage   adverse effects   therapeutic use   MeSH
• Carboplatin administration & dosage   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Endometrial Neoplasms * drug therapy   genetics   pathology   radiotherapy   MeSH
• DNA Mismatch Repair * MeSH
• Paclitaxel administration & dosage   adverse effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Antibodies, Monoclonal, Humanized * MeSH
• Carboplatin MeSH
• Paclitaxel MeSH
• pembrolizumab MeSH Browser

PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. RESULTS: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSIONS: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.

• MeSH
• CD8-Positive T-Lymphocytes * immunology   drug effects   MeSH
• Tertiary Lymphoid Structures * immunology   pathology   MeSH
• Hepatocyte Nuclear Factor 1-alpha * genetics   metabolism   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   pharmacology   MeSH
• Carboplatin administration & dosage   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Tumor Microenvironment * immunology   drug effects   MeSH
• Ovarian Neoplasms * drug therapy   immunology   pathology   MeSH
• Neoadjuvant Therapy methods   MeSH
• Paclitaxel administration & dosage   therapeutic use   pharmacology   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   pharmacology   MeSH
• Cystadenocarcinoma, Serous drug therapy   pathology   immunology   MeSH
• Endoplasmic Reticulum Stress drug effects   immunology   MeSH
• Lymphocytes, Tumor-Infiltrating immunology   drug effects   metabolism   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hepatocyte Nuclear Factor 1-alpha * MeSH
• Immune Checkpoint Inhibitors * MeSH
• Carboplatin MeSH
• Paclitaxel MeSH

OBJECTIVES: Part 1 of the RUBY trial (NCT03981796) demonstrated improved survival in patients with primary advanced or recurrent endometrial cancer (EC) treated with dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel. Here, we examine additional efficacy and safety data from patients with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) EC in the RUBY trial. METHODS: Patients were randomized 1:1 to dostarlimab 500 mg or placebo plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo every 6 weeks for up to 3 years. In the dMMR/MSI-H population of RUBY Part 1, analysis of progression-free survival by investigator assessment compared with blinded independent central review, sensitivity analyses of the source-verified population compared with the randomized population, and analysis of safety in this population were completed. RESULTS: In total, 118 patients with dMMR/MSI-H were enrolled in the RUBY trial (53, dostarlimab arm; 65, placebo arm). At the first interim analysis, a 72% reduction in the risk of progression or death (P < 0.0001) was seen with dostarlimab plus carboplatin-paclitaxel by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), which was consistent with blinded independent central review per RECIST v1.1. Likewise, sensitivity analyses of the source-verified dMMR/MSI-H population compared with the randomized dMMR/MSI-H population were consistent for progression-free survival and overall survival. Safety results seen in the dMMR/MSI-H population were similar to those previously reported for the overall population. CONCLUSIONS: All primary and secondary efficacy assessments demonstrate the consistent benefit of dostarlimab plus carboplatin-paclitaxel. The improvements seen in survival and the manageable safety profile support the favorable benefit-risk profile for dostarlimab plus carboplatin-paclitaxel in patients with dMMR/MSI-H primary advanced or recurrent EC.

• Keywords
• Dostarlimab plus chemotherapy, Endometrial cancer, Immunotherapy plus chemotherapy, Primary advanced or recurrent endometrial cancer, dMMR/MSI-H endometrial cancer,
• MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Carboplatin administration & dosage   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * drug therapy   genetics   MeSH
• Endometrial Neoplasms * drug therapy   genetics   pathology   MeSH
• Paclitaxel administration & dosage   adverse effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols * adverse effects   therapeutic use   administration & dosage   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• dostarlimab MeSH Browser
• Antibodies, Monoclonal, Humanized MeSH
• Carboplatin MeSH
• Paclitaxel MeSH

BACKGROUND/AIM: Inflammation-based prognostic scores have shown prognostic significance and have been associated with clinical outcomes in various types of cancer. Inflammation is known to promote tumor progression leading to reduced survival. In pancreatic cancer, systemic inflammation is common and contributes to its dismal prognosis. Although the prognosis of pancreatic cancer is improving with the introduction of new drugs, the prognostic indicators are still poorly understood. The present study aimed to evaluate inflammation-based prognostic scores in patients with metastatic pancreatic cancer receiving first-line chemotherapy. PATIENTS AND METHODS: A total of 43 patients with metastatic pancreatic cancer undergoing first-line chemotherapy (gemcitabine+nab-paclitaxel and mFOLFIRINOX) in our institution were analyzed. Baseline clinicopathological and pre-treatment laboratory data were collected. Survival was estimated using the Kaplan-Meier method and survival differences were evaluated using the log-rank test. RESULTS: In the whole cohort, we identified lymphocyte-to-monocyte ratio ≥3, systemic inflammatory response index <2.3, carcinoembryonic antigen <2.5, neutrophil-to-lymphocyte ratio <5, Memorial Sloane Kettering score <2, and prognostic index <2 as prognostic markers associated with improved overall survival in patients receiving first-line chemotherapy. CONCLUSION: The current analysis showed an association between inflammatory-based prognostic markers and overall survival in patients with metastatic pancreatic cancer treated in a real-world setting at a single institution.

• Keywords
• Metastatic pancreatic cancer, inflammation-based prognostic markers, overall survival, palliative chemotherapy, real-world data,
• MeSH
• Albumins administration & dosage   MeSH
• Deoxycytidine analogs & derivatives   administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Fluorouracil administration & dosage   therapeutic use   MeSH
• Gemcitabine MeSH
• Irinotecan administration & dosage   therapeutic use   MeSH
• Kaplan-Meier Estimate MeSH
• Leucovorin administration & dosage   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Pancreatic Neoplasms * drug therapy   mortality   pathology   MeSH
• Neutrophils pathology   MeSH
• Oxaliplatin administration & dosage   therapeutic use   MeSH
• Paclitaxel administration & dosage   MeSH
• Palliative Care * methods   MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Inflammation * pathology   drug therapy   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 130-nm albumin-bound paclitaxel MeSH Browser
• Albumins MeSH
• Deoxycytidine MeSH
• Fluorouracil MeSH
• folfirinox MeSH Browser
• Gemcitabine MeSH
• Irinotecan MeSH
• Leucovorin MeSH
• Oxaliplatin MeSH
• Paclitaxel MeSH