Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti-PD-L1, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer.

BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC). METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized. RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively. CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.

Long-term follow-up of efficacy and safety of selinexor maintenance treatment in patients with TP53wt advanced or recurrent endometrial cancer: A subgroup analysis of the ENGOT-EN5/GOG-3055/SIENDO study.

OBJECTIVE: To report long-term efficacy and safety of selinexor maintenance therapy in adults with TP53 wild-type (TP53wt) stage IV or recurrent endometrial cancer (EC) who achieved partial remission (PR) or complete remission (CR) following chemotherapy. METHODS: Analysis of the prespecified, exploratory subgroup of patients with TP53wt EC from the phase 3 SIENDO study was performed. Progression-free survival (PFS) benefit in patients with TP53wt EC and across other patient subgroups were exploratory endpoints. Safety and tolerability were also assessed. RESULTS: Of the 263 patients enrolled in the SIENDO trial, 113 patients had TP53wt EC; 70/113 (61.9%) had TP53wt/proficient mismatch repair (pMMR) EC, and 29/113 (25.7%) had TP53wt/deficient mismatch repair (dMMR) EC. As of April 1, 2024, the median PFS (mPFS) for TP53wt patients who received selinexor compared with placebo was 28.4 versus 5.2 months (36.8-month follow-up, HR 0.44; 95% CI 0.27-0.73). A benefit in mPFS was seen with selinexor versus placebo regardless of MMR status (patients with TP53wt/pMMR EC: 39.5 vs 4.9 months, HR 0.36; 95% CI 0.19-0.71; patients with TP53wt/dMMR EC: 13.1 vs 3.7 months, HR 0.49; 95% CI 0.18-1.34). Selinexor treatment was generally manageable, with no new safety signals identified. CONCLUSION: In the phase 3 SIENDO study, selinexor maintenance therapy showed a promising efficacy signal and a manageable safety profile in the prespecified subgroup of patients with TP53wt EC who achieved a PR or CR following chemotherapy. These results are being further evaluated in an ongoing randomized phase 3 trial (NCT05611931).

Immunotherapy Combined With Standard Therapies in Head and Neck Squamous Cell Carcinoma - A Meta-analysis.

Head and neck squamous cell carcinoma (HNSCC) is a deadly disease with a poor prognosis due to late diagnosis and limited treatment options. Immunotherapy (IT) is emerging as a promising approach, especially after the failure of standard of care therapies (STs). The objective of this systematic review and meta-analysis was to evaluate whether the addition of IT to STs improves outcomes for patients with HNSCC, including overall survival (OS), progression-free survival (PFS), and quality of life (QoL). This review employed the Population Intervention Comparison and Outcome (PICO) framework to identify relevant search terms in electronic databases, and also included supplementary hand searches. Six primary research articles were selected using the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) flow chart, and were critically appraised. Data extraction from these studies was conducted, and a meta-analysis was performed to aid in the generation of forest plots. The addition of IT to standard anticancer therapies was found to enhance patient outcomes, such as OS, PFS, and QoL. The toxicity profile of IT was acceptable, with minimal treatment-related deaths. The most frequently observed adverse events (AE) were related to the skin, followed by hematological toxicities. Based on our analysis, the addition of IT to STs is a suitable treatment option and is supported by current research. However, further studies are needed to investigate factors that influence treatment effectiveness and to develop optimal therapies. To achieve this, we recommend a comprehensive treatment approach that involves the multidisciplinary team (MDT) and patient assessment tools.

SEOM-GEICO clinical guideline on epithelial ovarian cancer (2023).

In recent years, the incorporation of new strategies to the therapeutic armamentarium has completely changed the outcomes of epithelial ovarian cancer (EOC). The identification of new predictive and prognostic biomarkers has also enabled the selection of those patients more likely to respond to targeted agents. Nevertheless, EOC is still a highly lethal disease and resistance to many of these new agents is common. The objective of this guideline is to summarize the most relevant strategies to manage EOC, to help the clinician throughout the challenging diagnostic and therapeutic processes and to provide evidence-based recommendations.