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This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC. Immune checkpoint blockade could improve the complete cytoreduction rate with standard-of-care neoadjuvant chemotherapy (NACT) in patients with ovarian cancer. Here the authors report the results of a randomized phase II trial of NACT alone or in combination with pembrolizumab (anti-PD1) in patients with advanced high-grade serous carcinoma.

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

Background Efficacy of 2nd line treatment in advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma remains limited with no identified strong predictor of treatment efficacy. We evaluated the prognostic value of circulating tumor DNA (ctDNA) in predicting the efficacy of immune checkpoint inhibitors (ICI) plus chemotherapy in the randomized PRODIGE 59-FFCD 1707-DURIGAST trial. Methods ctDNA was evaluated before treatment (baseline) and at 4 weeks (before the third cycle of treatment, C3) using droplet-digital PCR assays based on the detection of CpG methylation. Results Progression-free survival (PFS) and overall survival (OS) were shorter in patients with a high (>1.1 ng/mL) versus low (<1.1 ng/mL) ctDNA concentration at baseline (2.3 vs. 5.8 months; HR = 2.19; 95% CI, 1.09–4.41; p  = 0.03 and 4.5 vs. 12.9 months; HR = 2.73; 95% CI, 1.29–5.75; p  < 0.01), respectively, after adjustment for identified prognostic variables. Patients with a ctDNA decrease ≤75% between baseline and C3 versus a ctDNA decrease >75% had a worse objective response rate ( p  = 0.007), shorter PFS (2.2 vs. 7.4 months, HR = 1.90; 95% CI, 1.03–3.51; p = 0.04) and OS (6.6 vs 16.0 months; HR = 2.18; 95% CI, 1.09–4.37; p  = 0.03). Conclusions An early decrease in ctDNA concentration is a strong predictor of the therapeutic efficacy of ICI plus chemotherapy in advanced gastric/GEJ adenocarcinoma. Clinical Trial Information NCT03959293 (DURIGAST). Plain language summary Some patients with advanced gastric cancer receive immunotherapy (treatments that help one’s own immune system recognize and attack cancer cells) in addition to other treatments. We measured circulating tumor DNA (ctDNA) in patient’s blood samples and looked at associations with treatment outcome. We found that survival was shorter in patients receiving immunotherapy plus chemotherapy, when the levels of ctDNA in the blood were high at the start of treatment and when they did not decrease over time. Our results suggest that ctDNA could be used as a predictor of how well this specific treatment will work in advanced gastric cancer patients. Tougeron et al. evaluate the prognostic value of circulating tumor DNA (ctDNA) in predicting the efficacy of immune checkpoint inhibitors (ICI) plus chemotherapy in advanced gastric adenocarcinoma. An early decrease in ctDNA concentration is associated with a worse objective response rate, shorter progression free survival and overall survival.

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

BackgroundManagement of patients with recurrent endometrial cancer after failure of platinum therapy remains an important clinical challenge. Tumors characterized by abnormalities in DNA repair are associated with high numbers of neoantigens, making immunotherapy a promising approach. Retifanlimab (INCMGA00012) is an investigational humanized immunoglobulin G4 monoclonal antibody against PD-1. In the dose escalation and tumor expansion portions of the POD1UM-101 phase 1 study, retifanlimab monotherapy demonstrated acceptable tolerability and durable clinical activity in multiple advanced tumor types, including pretreated endometrial cancer. Here we present interim clinical activity and safety data from a preplanned futility assessment in patients with microsatellite instability-high (MSI-H) recurrent endometrial cancer.MethodsPatients eligible for this cohort had histologically proven, unresectable recurrent endometrial cancer that was MSI-H or deficient mismatch repair (dMMR) based on local testing (either by PCR or IHC), ECOG performance status (PS) ≤1, disease progression during or following ≤5 prior systemic treatments, measurable disease per RECIST v1.1, and no prior treatment with immune checkpoint inhibitors. The primary endpoint is safety (using CTCAE v4.03 grading). Confirmed best overall response rate and duration of response were evaluated by RECIST v1.1 (investigator’s assessment). Retifanlimab 500 mg Q4W was administered up to 2 years.ResultsAs of April 7, 2020, 44 patients who received at least 1 dose of retifanlimab were assessed for safety, including 24 patients who were fully assessable for the planned futility analysis. Median age was 63 (49–86) years, 45.5% had an ECOG PS of 1, and 97.7% had adenocarcinoma (1 had missing histology data at cut-off). Of the 44 patients treated, all but 1 were pretreated with at least 1 prior platinum-based chemotherapy, 72.7% were treated with radiotherapy, and 90.9% underwent surgery. Median drug exposure was 1.9 (0.03–11.1) months. Eight patients (18.2%) experienced Grade (G) 3/4 AEs regardless of causality with anemia being the leading event (n=3, 6.8%). Two patients (4.5%) had immune-related AEs (n=1 each: dry mouth [G3] and myositis [G3]); both patients discontinued study treatment because of the event. No treatment-related deaths occurred. Confirmed responses (7 PR, 1 CR) per RECIST v1.1 were observed, supporting study continuation. Median duration of response was not reached, as no confirmed responders had disease progression or died at time of this analysis.ConclusionsRetifanlimab was generally well tolerated with preliminary evidence of encouraging antitumor activity in MSI-H pretreated advanced endometrial cancer. Enrollment is ongoing.AcknowledgementsThis study is sponsored by Incyte Corporation (Wilmington, DE).Trial RegistrationNCT03059823, EudraCT 2017-000865-63Ethics ApprovalThe study was approved by institutional review boards or independent ethics committees of participating institutions.Consentn/a

Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy. We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival. A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P = 0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects. In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.).

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

Cabazitaxel, a next-generation taxane, retains its efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress on new androgen receptor (AR)-targeted agents such as abiraterone acetate or enzalutamide. These findings are reinforced by in vitro preclinical data confirming cross-resistance between abiraterone and enzalutamide, but not between cabazitaxel and AR-targeted agents.

Introduction/BackgroundThe GOG 240 trial established bevacizumab plus chemotherapy as standard first-line therapy for metastatic (stage IVB), persistent or recurrent cervical cancer (R/M CC). The investigator-initiated open-label randomised phase 3 BEATcc trial (NCT03556839) evaluated atezolizumab (anti-PD-L1) combined with this standard regimen, irrespective of PD-L1 status.MethodologyPatients with previously untreated measurable R/M CC not amenable to curative surgery/radiation were randomised 1:1 to standard therapy (cisplatin 50 mg/m2 or carboplatin AUC5, paclitaxel 175 mg/m2 and bevacizumab 15 mg/kg) with or without atezolizumab (1200 mg day 1 every 3 weeks). Cycles were repeated until disease progression or unacceptable toxicity. Stratification factors were prior concomitant chemoradiation (yes/no), histology (squamous cell carcinoma/adenocarcinoma) and platinum agent (cisplatin/carboplatin). Dual primary endpoints were investigator-assessed progression-free survival (PFS) per RECIST v1.1 and overall survival (OS) in the intent-to-treat population. Secondary endpoints included objective response rate (ORR), duration of response (DoR), time to first subsequent therapy (TFST), PFS2 and safety.ResultsBetween October 2018 and August 2021, 410 patients were randomised. At the data cut-off (median follow-up 32.9 months), median treatment duration was 12.7 vs 8.5 months in the atezolizumab vs standard arms, respectively; treatment was ongoing in 23% vs 7%, respectively. Both PFS and interim OS were statistically significantly improved with the addition of atezolizumab to bevacizumab and chemotherapy; secondary endpoints showed consistent results (figure 1), with ORRs of 84% (95% CI 79–89%) with atezolizumab vs 72% (95% CI 66–78%) with standard therapy. Grade ≥3 adverse events (any cause) occurred in 79% vs 75% of the atezolizumab and standard arms, respectively. Safety profiles were as expected with atezolizumab, bevacizumab and platinum-based chemotherapy.Abstract 427 Figure 1ConclusionCombining atezolizumab with first-line bevacizumab added to chemotherapy for R/M CC significantly improved all efficacy outcomes. Atezolizumab combined with bevacizumab and platinum-based chemotherapy should be considered a new first-line treatment option for patients with R/M CC.DisclosuresStudy drug and funding for this investigator-initiated study are provided by F. Hoffmann-La Roche.AO reports honoraria/consultation fees from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, Exelisis, EMD Serono, F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, iTeos Therapeutics, MSD de España, Mersana Therapeutics, Novocure, OncXerna Therapeutics, PharmaMar, Regeneron, Shattuck Labs, Seagen and Sutro Biopharma; travel/accommodation from AstraZeneca, PharmaMar and Roche. Coauthor disclosures are provided separately.

Cabazitaxel, a next-generation taxane, retains its efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress on new androgen receptor (AR)-targeted agents such as abiraterone acetate or enzalutamide. These findings are reinforced by in vitro preclinical data confirming cross-resistance between abiraterone and enzalutamide, but not between cabazitaxel and AR-targeted agents.