Atezolizumab intravenous (IV) is approved for the treatment of various solid tumours. To improve treatment convenience and healthcare efficiencies, a co-formulation of atezolizumab and recombinant human hyaluronidase PH20 was developed for subcutaneous (SC) use. Part 2 of IMscin001 (NCT03735121) was a randomised phase III, open-label, multicentre, non-inferiority study comparing the drug exposure of atezolizumab SC with atezolizumab IV. Eligible patients with locally advanced/metastatic non-small-cell lung cancer were randomised 2:1 to receive atezolizumab SC (1875 mg; n = 247) or IV (1200 mg; n = 124) every 3 weeks. The co-primary endpoints were Cycle 1 observed Ctrough and model-predicted area under the curve (AUC0-21 d). Secondary endpoints included steady-state exposure, efficacy, safety, and immunogenicity. Exposure following atezolizumab SC was then compared with historical atezolizumab IV values across approved indications. The study met both of its co-primary endpoints: Cycle 1 observed Ctrough (SC: 89 μg/mL [coefficient of variation (CV): 43%] versus IV: 85 μg/mL [CV: 33%]; geometric mean ratio (GMR), 1.05 [90% confidence interval [CI]: 0.88, 1.24]) and model-predicted AUC0-21 d (SC: 2907 μg•d/mL [CV: 32%] versus IV: 3328 μg•d/mL [CV: 20%]; GMR, 0.87 [90% CI: 0.83, 0.92]). Progression-free survival (hazard ratio [HR]: 1.08 [95% CI: 0.82, 1.41]), objective response rate (SC: 12% versus IV: 10%), and incidence of anti-atezolizumab antibodies (SC: 19.5% versus IV: 13.9%) were similar between arms. No new safety concerns were identified. Ctrough and AUC0-21 d for atezolizumab SC were consistent with the other approved atezolizumab IV indications. Compared with IV, atezolizumab SC demonstrated non-inferior drug exposure at Cycle 1. Efficacy, safety, and immunogenicity were similar between arms and consistent with the known profile for atezolizumab IV. Similar drug exposure and clinical outcomes following SC and IV administration support the use of atezolizumab SC as an alternative to atezolizumab IV.

In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status.Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis.After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms.Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.

Mismatch repair deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI are required for the design of future strategies further improving this therapy. We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-PD-1 +/- anti-CTLA-4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the IMMUNOMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was iPFS (progression-free survival by iRECIST). Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g., MSISensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites (HRC2 = 3.63; 95% CI [1.65-7.99] ; p = 1.4x10-3) and the expression of a set of 182 RNA markers with a non-epithelial TGFB-related desmoplastic orientation (HRC2 = 1.75 ; 95% CI [1.03-2.98] ; p = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with nonepithelial TGFB-related desmoplastic RNA markers.

HER2-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 antibody-drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from 9 different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were: (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the developed statements, including findings from the expert panel discussions, expert opinion and a summary of evidence supporting each statement.

Patritumab deruxtecan (HER3-DXd) is a HER3-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [ = -.8 × tumor cellularity (in %) + 1.3 × TILs (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer. Patients with previously untreated hormone receptor (HR)-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 mRNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score. Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P=.003). Among patients evaluable for clinical response (n=62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 vs +1.9). Change in CelTIL score was independent of baseline ERBB3 mRNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease. A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in HR-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.