Whether fixed-duration acalabrutinib-venetoclax (with or without obinutuzumab) would result in better progression-free survival than chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia (CLL) is unknown.

This phase III trial aimed to compare ARX788, a site-specific, construct-homogeneous antibody-drug conjugate, with lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) who had progressed on one line of trastuzumab based regimen. Eligible patients were randomized (1:1) to receive ARX788 (1.5 mg/kg, IV, Q3W) or lapatinib plus capecitabine (LC: lapatinib 1250 mg QD; capecitabine 1000 mg/m2 BID, days 1-14, Q3W) and stratified by prior chemotherapy lines (0-1 versus >1) and visceral metastasis (yes versus no). The primary outcome was progression-free survival (PFS) assessed by a blinded independent central review (BICR). A total of 441 patients were randomly assigned to receive either ARX788 (n = 221) or LC (n = 220). The median PFS was 11.3 (95% confidence interval [CI], 8.4-13.8) months with ARX788 compared with 8.2 (95% CI, 6.9-8.7) months with LC, as per BICR (hazard ratio [HR] 0.64, p = 0.0006). Frequencies of treatment-related adverse events (TRAEs) of any grade were 98.6% and 99.1% for ARX788 and LC, respectively. Grade ≥3 TRAEs were 41.4% and 40.0%, respectively, the most common adverse events were blurred vision (12.3%), dry eye (9.1%), keratopathy (5.9%), and interstitial lung disease (ILD, 5.9%) with ARX788; hand-foot syndrome (18.1%) and hypokalemia (5.1%) with LC; all the hematological and gastrointestinal events of grade ≥3 with ARX788 were less than 3%. Six treatment-related deaths occurred, with three cases possibly related to ILD. ARX788 significantly improved PFS compared with LC in patients with HER2-positive ABC with a distinct toxicity profile, supporting it as a potential treatment option.

The GOSSAMER phase 2 study assessed the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib as maintenance therapy in patients with FLT3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML) in first complete remission without previous hematopoietic stem cell transplantation (HSCT).

We evaluate therapy-induced molecular heterogeneity in longitudinal samples from high-risk, hormone-receptor positive/HER2-negative breast cancer patients with residual tumor after neoadjuvant chemotherapy from the Penelope-B trial (NCT01864746; EudraCT 2013-001040-62). Intrinsic subtypes are prognostic in pre-therapeutic (Tx) samples (n = 629, p < 0.0001) and post-Tx residual tumors (n = 782, p < 0.0001). After neoadjuvant chemotherapy, a shift of intrinsic subtypes is observed from pre-Tx luminal (Lum) B to post-Tx LumA, with reverse transition back to LumB in metastases. In a combined analysis of 540 paired pre-Tx and post-Tx samples, we identify five adaptive clusters (AC-1-5) based on transcriptomic changes before and after neoadjuvant chemotherapy. These AC-subtypes are prognostic beyond classical intrinsic subtyping, categorizing patients into groups with excellent prognosis (AC-1 and AC-2), poor prognosis (AC-3 and AC-4), and very poor prognosis (AC-5, enriched for basal-like subtype). Our analysis provides a basis for an extended molecular classification of breast cancer patients and improved identification of high-risk patient populations.

This study aimed to compare the efficacy and safety of rezivertinib (BPI-7711) and gefitinib as first-line therapies in patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer (NSCLC).

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.

Liver metastases (LMs) are related to poor efficacy of immune checkpoint inhibitor (ICI)-containing therapies. In the AtezoTRIBE trial, Immunoscore-Immune-Checkpoint (immunoscore-IC) was a predictor of benefit from atezolizumab in mismatch repair-proficient (pMMR) metastatic colorectal cancer (mCRC).

Immunoscore (IS) and circulating tumor DNA (ctDNA) are two emerging technologies in improving prognostication and tailoring adjuvant treatments in patients resected from a stage III colon cancer (CC). Here, we analyzed the prognostic value of the two biomarkers in patients who participated in the randomized phase III IDEA-France and HORG trials.

The FIRE-4 study randomly assigned patients with first-line RAS wild-type (RASwt) metastatic colorectal cancer to either flourouracil (FU), folinic acid, and irinotecan (FOLFIRI) plus cetuximab until progression or intolerable toxicity (standard arm) or to FOLFIRI plus cetuximab followed by a switch maintenance treatment using FU plus bevacizumab (experimental arm). Here, we investigate the relevance of liquid biopsy (LB) RAS and BRAF testing compared with tissue-based analyses.

Research on social determinants of genetic testing uptake is limited, particularly among unaffected patients with inherited cancer susceptibility.

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.