In the phase 3 IPATential150 trial, ipatasertib addition to abiraterone significantly reduced the risk of disease progression in men with metastatic castration-resistant prostate cancer (mCRPC) with PTEN loss on immunohistochemistry (IHC), but not in the intention-to-treat (ITT) population. Here we report the final overall survival (OS) analysis and present results for prespecified and exploratory biomarker analyses.

This study demonstrates the analytical and clinical validity of the approved (United States and Japan) plasma-based Guardant360 companion diagnostic (CDx) test for selecting patients with human epidermal growth factor receptor 2 (HER2 [ERBB2])-mutated (HER2m) non-small-cell lung cancer (NSCLC) for trastuzumab deruxtecan (T-DXd) treatment. Concordance between the Guardant360 CDx test and the plasma-based AVENIO ctDNA Expanded Kit Assay (AVENIO), as well as the tissue-based clinical trial assays (CTAs) was investigated. Clinical utility was assessed by comparing T-DXd clinical efficacy results of patients in DESTINY-Lung01/02 who tested positive for HER2 mutations using the Guardant360 CDx test to benchmark efficacy results from DESTINY-Lung01/02. Finally, concordance between the Guardant360 CDx test and the tissue-based Oncomine Dx Target (ODxT) test was explored. High concordance was observed between the Guardant360 CDx test versus AVENIO [positive percent agreement (PPA), 98.8%; negative percent agreement (NPA), 91.5%] and CTAs (DESTINY-Lung01 Cohort 2-PPA, 91.0%; NPA, 100%; DESTINY-Lung02 arm 1-PPA, 86.0%; NPA, 100%). Confirmed objective response rates were similar in patients with HER2m NSCLC identified by the Guardant360 CDx test and by CTAs. There was a high level of agreement between the Guardant360 CDx test and the ODxT test. The Guardant360 CDx test demonstrated analytical and clinical validity for identifying patients with HER2m NSCLC for T-DXd therapy; results support plasma-based testing when tissue-based testing is not feasible.

Mobocertinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets EGFR exon 20 insertion (ex20ins) mutations in non-small cell lung cancer (NSCLC). This open-label, phase III trial (EXCLAIM-2, ClinicalTrials.gov identifier: NCT04129502) compared mobocertinib versus platinum-based chemotherapy as first-line treatment of EGFR ex20ins+ advanced/metastatic NSCLC.

Patients who actively engage in their medical decision-making processes can experience better health outcomes. This exploratory study aimed to identify predictors of preferred and actual roles in decision-making in healthy women with BRCA1/2 pathogenic variants (PVs).

CheckMate 8HW prespecified dual primary endpoints, assessed in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient status: progression-free survival with nivolumab plus ipilimumab compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab compared with nivolumab alone, regardless of previous systemic treatment for metastatic disease. In our previous report, nivolumab plus ipilimumab showed superior progression-free survival versus chemotherapy in first-line microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the CheckMate 8HW trial. Here, we report results from the prespecified interim analysis for the other primary endpoint of progression-free survival for nivolumab plus ipilimumab versus nivolumab across all treatment lines.

Evaluation of the prognostic performance and clinical utility of the MammaPrint 70-gene signature in early-stage invasive lobular carcinoma (ILC) for whom such analyses in a randomized trial is awaited.

Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, 2.443; 95% confidence interval (CI): 1.403-4.253; 99.8% CI: 1.019-5.855; one-sided P = 0.0008). Median duration of response was 13.9 versus 11.1 months. At this first interim analysis of overall survival, the hazard ratio was 0.47 (95% CI: 0.318-0.691; repeated CI: 0.166-1.322). Serious adverse event rates were 37.7% versus 34.6%. The safety profiles were consistent with those known for each agent. BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC+mFOLFOX6 versus SOC in patients with BRAF V600E mCRC. ClinicalTrials.gov identifier: NCT04607421 .

Determine if molecular classification using mismatch repair (MMR) and p53 protein expression predicts recurrence-free survival (RFS) and overall survival (OS) in endometrial cancer (EC) patients treated with chemotherapy and radiation (CRT) versus chemotherapy (CT).

To investigate whether hormone receptor-positive, human epidermal growth factor receptor 2-low (HR+HER2-low) versus HR+HER2-zero early breast cancers have distinct genomic and clinical characteristics.

Some patients with chronic lymphocytic leukemia who develop progressive disease (PD) during covalent Bruton tyrosine kinase (BTK) inhibitor treatment acquire resistance mutations in BTK or PLCG2. Here, we report gene mutation data from paired baseline and PD peripheral blood samples from 52 patients (zanubrutinib, n = 24; ibrutinib, n = 28) who, at an early median follow-up of 25.7 months, progressed on zanubrutinib or ibrutinib treatment in ALPINE. No BTK mutations were observed at baseline; at PD, 8 patients (zanubrutinib, n = 5; ibrutinib, n = 3) acquired 17 BTK mutations, 82.4% (zanubrutinib, n = 11/14; ibrutinib, n = 3/3) at C481. Non-C481 mutations occurred in 12.5% (3/24) of zanubrutinib-treated patients (L528W: n = 2; cancer cell fraction [CCF] = 9.58% and 17.6%; A428D: n = 1; CCF = 37.03%). At baseline, 48 of 52 patients had ≥1 driver gene mutation(s), most frequently in NOTCH1 (n = 21), TP53 (n = 19), BRAF (n = 10), SF3B1 (n = 8), and ATM (n = 8). At PD, acquired mutations occurred in 1 zanubrutinib-treated patient (TP53, XPO1) and 5 ibrutinib-treated patients (TP53, n = 1 patient; SETD2, n = 1; SF3B1, n = 1; ASXL1, n = 2). Baseline driver gene mutations were not associated with development of BTK mutations, but patients with ≥2 baseline driver gene mutations were more likely to acquire BTK mutations at PD. The short treatment duration and a low BTK mutations incidence suggests that mechanisms other than BTK/PLCG2 mutations drive most early PD. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.

Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg-1 every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.54-0.81; P < 0.001) than the placebo group. The primary endpoint was met. The median progression-free survival was 7.0 months versus 5.3 months (HR 0.53, 95% CI 0.44-0.65). The median OS in patients with a PD-L1 combined positive score ≥5 was 15.3 months versus 10.9 months (HR 0.58, 95% CI 0.41-0.82). The objective response rate was 65.2% versus 48.9% with a median duration of response of 8.8 months versus 4.4 months. Grade ≥3 treatment-related adverse events occurred in 65.9% of the cadonilimab group and 53.6% of the placebo group, and the most common were decreased platelet count, decreased neutrophil count and anemia. Most of the immune-related adverse events were grade 1 or 2. No new safety signals were observed. Cadonilimab plus chemotherapy significantly improved OS with a manageable safety profile in patients with advanced G/GEJ adenocarcinoma. ClinicalTrials.gov registration: NCT05008783 .

Patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer (BC) have low pathological complete response (pCR) rates with neoadjuvant chemotherapy. A subset of ER+/HER2- BC contains dense lymphocytic infiltration. We hypothesized that addition of an anti-programmed death 1 agent may increase pCR rates in this BC subtype. We conducted a randomized, multicenter, double-blind phase 3 trial to investigate the benefit of adding nivolumab to neoadjuvant chemotherapy in patients with newly diagnosed, high-risk, grade 3 or 2 (ER 1 to ≤10%) ER+/HER2- primary BC. In total, 510 patients were randomized to receive anthracycline and taxane-based chemotherapy with either intravenous nivolumab or placebo. The primary endpoint of pCR was significantly higher in the nivolumab arm compared with placebo (24.5% versus 13.8%; P = 0.0021), with greater benefit observed in patients with programmed death ligand 1-positive tumors (VENTANA SP142 ≥1%: 44.3% versus 20.2% respectively). There were no new safety signals identified. Of the five deaths that occurred in the nivolumab arm, two were related to study drug toxicity; no deaths occurred in the placebo arm. Adding nivolumab to neoadjuvant chemotherapy significantly increased pCR rates in high-risk, early-stage ER+/HER2- BC, particularly among patients with higher stromal tumor-infiltrating lymphocyte levels or programmed death ligand 1 expression, suggesting a new treatment paradigm that emphasizes the role of immunotherapy and T cell immunosurveillance in luminal disease. Clinical trials.gov identifier: NCT04109066.

The role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in patients with lung squamous cell carcinoma (LSCC) is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC.

Lasofoxifene, a novel endocrine therapy (ET), showed antitumor activity versus fulvestrant in women with ESR1-mutated, metastatic breast cancer (mBC) that progressed on prior ET (phase 2, ELAINE 1 study). We investigated changes in genitourinary syndrome of menopause (GSM) vulvar-vaginal symptoms with lasofoxifene and how patient/disease characteristics affect baseline vulvar-vaginal symptoms in ELAINE 1.

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC.

The FOxTROT trial has reported advantages of neoadjuvant chemotherapy (NAC) in locally advanced colon cancer (LACC). In this article, we present results of the embedded randomised phase II trial testing the addition of panitumumab to neoadjuvant FOLFOX compared with FOLFOX alone in RAS and BRAF-wild-type (wt) patients and with biomarker hyperselection.

The randomized GeparOLA trial reported comparable pathologic complete response (pCR) rates with neoadjuvant treatment containing olaparib versus carboplatin. In this study, we evaluate the association between functional homologous recombination deficiency (HRD) by RAD51 foci and pCR and the potential of improving patient selection by combining RAD51 and stromal tumor-infiltrating lymphocytes.

Panitumumab (pan) plus chemotherapy is a preferred first-line therapy for unresectable RAS and BRAF wild type metastatic colorectal cancer (mCRC). Older patients may not be suitable for combination regimens. We investigated 2 lower intensity pan-containing regimens.

BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 ("MORPHO") was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

ERBB2 overexpression/amplification in RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC; human epidermal growth factor receptor 2 [HER2]-positive mCRC) appears to be associated with limited benefit from anti-EGFR antibodies and promising responses to dual-HER2 inhibition; however, comparative efficacy has not been investigated. We conducted a randomized phase II trial to evaluate efficacy and safety of dual-HER2 inhibition against standard-of-care anti-EGFR antibody-based therapy as second/third-line treatment in HER2-positive mCRC.