Although first-line alectinib is highly effective, outcomes in ALK-positive NSCLC remain variable.

Evidence from experimental and clinical studies suggests that anesthetic drugs may modulate tumor biology by influencing immune regulation, inflammation and intracellular calcium signaling. However, the extent to which sevoflurane or propofol alters calcium-related molecular expression in human breast cancer tissue remains unclear.

Tumor-informed circulating tumor DNA (ctDNA) enables detection of molecular residual disease (MRD) after curative resection of colorectal cancer (CRC), but whether early intervention improves outcomes remains uncertain. ALTAIR was a randomized, double-blind, phase 3 trial embedded in the CIRCULATE-Japan platform evaluating a post-adjuvant ctDNA surveillance strategy with treatment initiation upon molecular recurrence. Patients with resected stage 0-IV CRC who became ctDNA positive after completion of standard-of-care therapy and had no radiological evidence of disease were randomly assigned (1:1) to receive trifluridine/tipiracil (FTD/TPI) or placebo for 6 months. The primary endpoint was investigator-assessed disease-free survival (DFS). Between July 2020 and June 2023, 243 patients were randomized to FTD/TPI (n = 122) or placebo (n = 121). Median DFS was 9.30 months with FTD/TPI and 5.55 months with placebo (hazard ratio = 0.79, 95% confidence interval: 0.60-1.05, P = 0.107), and the primary endpoint was not met. FTD/TPI increased grade 3 or higher hematologic adverse events (73.0% versus 3.3%) without new safety signals. These findings indicate that post-adjuvant intervention with FTD/TPI did not significantly improve DFS in ctDNA-positive patients without radiological disease. ClinicalTrials.gov identifier: NCT04457297 .

Adjuvant chemotherapy provides limited benefit in unselected stage II colon cancer. Post-operative circulating tumour DNA (ctDNA) has higher prognostic value than classical clinical markers, with ctDNA positivity indicating an unfavourable outcome.

Cholangiocarcinoma is a rare cancer associated with poor prognosis. Pemigatinib was the first FGFR1-3 inhibitor approved for second-line therapy and beyond, on the basis of the phase II FIGHT-202 trial. Here, we assess efficacy and safety of first-line pemigatinib.

Selpercatinib, a highly selective, potent, and central nervous system-penetrant RET inhibitor, is approved for RET fusion-positive advanced or metastatic non-small-cell lung cancer (NSCLC). The efficacy and safety of selpercatinib in early-stage NSCLC are unknown.

Current therapies offer limited benefit for patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). Aberrant activation of the RAS pathway is the key driver of PDAC, with oncogenic RAS mutations present in more than 90% of cases. Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS.

A previous trial involving patients with metastatic prostate cancer that was resistant to androgen pathway modulation (formerly referred to as castration-resistant) showed that adding talazoparib to enzalutamide significantly improved imaging-based progression-free survival and overall survival, with the greatest benefit observed in the cohort with alterations in homologous recombination repair genes.

Encorafenib + cetuximab (EC) and mFOLFOX6 or irinotecan, leucovorin, and fluorouracil (FOLFIRI) is approved in several countries for BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on results from the BREAKWATER trial.

INAVO120 (NCT04191499) demonstrated significantly improved progression-free/overall survival with inavolisib plus palbociclib-fulvestrant versus placebo plus palbociclib-fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative, endocrine-resistant advanced breast cancer. We provide comprehensive analyses of key selected adverse events and their management.

Determine whether mismatch repair (MMR) and p53 expression predict recurrence-free survival (RFS) and overall survival (OS) in early-stage endometrial cancer (EC) patients treated with vaginal cuff brachytherapy plus chemotherapy (VCB/C) versus pelvic radiation therapy (RT).

We aimed to develop the mutational signature-based BioMarker (MSBM) to define homologous recombination deficiency (HRD) in newly diagnosed, advanced ovarian cancer and overcome limitations of genomic scar-based assays. We conducted a phase 2 trial (MSBM-OL) to evaluate the efficacy of olaparib maintenance monotherapy and to validate MSBM as a novel HRD biomarker. The MSBM was designed to integrate three whole-exome sequencing-derived features without using genomic scars: tumor-BRCA mutation status, Mutational Signature 3 similarity score > 0.5, or score > 0.25 without CCNE1 amplification. Among 170 patients with stage IIIC/IV high-grade ovarian carcinoma, 58 HRD-positive patients responding to platinum-doublet chemotherapy (without bevacizumab) were enrolled. Thirty-two were randomized 2:1 to olaparib or placebo, and 26 enrolled after switching to a single-arm study. The primary endpoint was progression-free survival (PFS), evaluated against a predefined median of 9 months. Of 170 patients, 169 were evaluable for HRD (99.5%) and 123 (72.4%) were HRD-positive by MSBM, including 21.1% with tumor-BRCA mutations. The olaparib arm (n = 45) showed a median PFS of 22.3 months, significantly exceeding the 9-month threshold (p < 0.001), meeting the primary endpoint. The placebo arm (n = 11) with a median PFS of 16.7 months was not powered for comparison. Grade ≥ 3 adverse events included anemia (25.5%) and neutropenia (12.8%). In a subset (n = 16), MSBM showed 81% concordance with myChoice CDx and correlated with genomic instability scores (R = 0.63). MSBM enables robust HRD evaluation from a whole-exome sequencing assay. Olaparib monotherapy demonstrated clinical benefit for first-line maintenance in HRD-positive ovarian cancer without bevacizumab.

Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data.

Checkpoint inhibitor immunotherapy (CPI) for BRAF mutant advanced melanoma first-line results in a better long-term survival compared to targeted therapy (TT), however TT induction may benefit poor prognosis groups. The parallel-arm, randomised phase II, multicentre, feasibility CAcTUS trial (Clinicaltrials.gov NCT03808441) randomised 21 patients to receive standard of care investigators choice TT or CPI, switching to the alternative upon progression (n = 10), or commencing TT and switching to CPI upon an ≥80% reduction of BRAF variant allele frequency (VAF) in circulating tumour DNA (ctDNA; n = 11). The study achieved its primary endpoints with 100% (95% confidence interval [CI]: 94-100%) of critical results provided within 7 days to inform a decision to switch and 100% of patients commencing TT achieving an ≥80% reduction of BRAF VAF (95% CI: 80-100%). Secondary outcomes included progression-free survival and overall survival. No new safety signals were observed for TT/CPI. Post-hoc analysis of clinical features, circulating cytokines and chemokines at ctDNA nadir following TT induction suggested a more favourable profile prior to CPI initiation. Longitudinal ctDNA dynamics revealed ctDNA provided an early signal of CPI benefit and that rechallenge with TT following CPI progression resulted in a further ctDNA response. These data support the utility of ctDNA to guide treatment decision-making within a clinically relevant timeframe to optimise treatment scheduling strategies.

Maintenance therapy is key in prolonging remission and improving quality of life for hormone receptor-positive (HR + ), HER-2 negative (HER2-) metastatic breast cancer (MBC), but optimal strategies remain debated. This multicenter, open-label, randomized phase 3 trial conducted across 22 hospitals in mainland China (ClinicalTrials.gov, NCT04263298; Chinadrugtrials.org.cn, ChiCTR-IIR-17014036) compared the efficacy and safety of fulvestrant versus capecitabine as maintenance therapy in HR + /HER2- MBC patients after achieving objective response or disease control following first-line chemotherapy. The primary end point was investigator-assessed progression-free survival (PFS). A total of 210 patients underwent randomization, with 105 assigned to each group. As of the data cutoff date on March 1, 2025, the median follow-up was 33.6 months (range 1.5-81.1). Median PFS favored fulvestrant compared with capecitabine (17.3 months [95% CI 12.7-23.3] vs. 9.0 months [95% CI 7.5-14.3]; hazard ratio 0.63, 95% CI 0.47-0.99; p = 0.003). Overall survival data were not yet mature. Grade ≥3 adverse events (AEs) occurred in three patients (2.9%) in the fulvestrant group and 11 (10.5%) in the capecitabine group. Treatment discontinuation due to AEs occurred in 0% and 7.6% of patients, respectively. Fulvestrant maintenance therapy significantly improves PFS compared to capecitabine in HR + /HER2- MBC patients achieving objective response or disease control following first-line chemotherapy, with a favorable safety profile.

This multi-institutional randomized phase II clinical trial (NCT03414684) investigated the efficacy and safety of carboplatin plus nivolumab compared to carboplatin in metastatic triple-negative breast cancer (mTNBC). The primary endpoint was progression-free survival (PFS) in a modified intention-to-treat (mITT) population of patients with chemotherapy-naïve (i.e., first-line) mTNBC. Secondary endpoints included overall survival (OS), confirmed objective response rate, confirmed clinical benefit rate, time to and duration of confirmed objective response, safety, and tolerability. Clinical outcomes were evaluated in the PD-L1-positive subgroup ( ≥ 1% immune cells; SP142 clone) per central review. Biospecimens were collected for correlative analyses. 75 patients were enrolled and treated between 2/2018-9/2020. Among the mITT population (n = 62), median PFS was 4.2 months with carboplatin plus nivolumab vs 5.5 months with carboplatin. Median OS did not significantly differ between arms (16.8 vs 11.1 months, respectively). In PD-L1-positive mTNBC patients (n = 24), median PFS was 8.3 vs 4.7 months; median OS was 17.6 vs 10.7 months. Grade ≥3 adverse events occurred in 56.8% of patients in the combination arm and 65.8% in the carboplatin arm. Carboplatin plus nivolumab did not significantly improve PFS compared to carboplatin in patients overall; however, a trend toward improved outcomes was observed in PD-L1-positive mTNBC patients. High mutational burden, interferon-gamma signaling, early circulating tumor DNA reduction, low baseline serum thymidine kinase activity, and urea cycle dysregulation in the microbiome emerged as potential predictors of response to immune checkpoint inhibitors with platinum.

BACKGROUNDThe relationship between molecular subgroups in clear-cell renal cell carcinoma (ccRCC) and metastatic tropism is poorly understood.METHODSWe analyzed over 5,000 metastatic sites from 305 treatment-naive ccRCC patients in the IMmotion150 phase II clinical trial, where patients were randomized to atezolizumab, atezolizumab/bevacizumab, or sunitinib.RESULTSAngiogenic tumors (clusters 1 and 2) had a higher rate of pancreatic (21% vs. 6.9%; P = 0.002) and lower absolute number of lymph node (2.5 vs. 4.2; P = 0.006) metastases. In contrast, proliferative tumors (clusters 4 and 5) exhibited a higher absolute number of lymph node metastases (5.5 vs. 3.5; P = 0.019). Patients with pancreatic metastases receiving sunitinib had higher odds of overall response (OR, 7.13; 95% CI, 1.81-28.07; P = 0.0049) and longer progression-free survival than those without pancreatic metastases (P = 0.02).CONCLUSIONccRCC metastatic tropism relates to molecular clusters that predict response to therapy for tumors that metastasize to the pancreas.TRIAL REGISTRATIONClinicalTrials.gov NCT01984242FUNDINGNIH grants R01CA154475 and P50CA196516.

In the PROpel study (ClinicalTrials.gov identifier: NCT03732820), olaparib plus abiraterone demonstrated statistically significant radiographic progression-free survival benefit versus placebo plus abiraterone in a first-line metastatic castration-resistant prostate cancer (mCRPC) population unselected by homologous recombination repair gene mutation (HRRm) status. From PROpel, we report exploratory biomarker analyses assessing HRRm and BRCA1 and/or BRCA2 (BRCAm) status using tumor tissue and plasma-derived circulating tumor (ct) DNA.

We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD]neg) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel-treated patients achieving MRDneg. Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRDneg. ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRDneg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.

Diffuse intrinsic pontine glioma (DIPG) is the pediatric tumor with the worst prognosis. BIOMEDE was a randomized phase 2 trial comparing the efficacy in terms of overall survival (OS) (primary endpoint) of epidermal growth factor receptor (EGFR) inhibitor erlotinib, mTOR inhibitor everolimus and multitargeted tyrosine kinase inhibitor dasatinib in combination with radiotherapy in patients with a biopsy-proven DIPG. Tumors were assessed centrally for immunohistochemical biomarkers (EGFR overexpression or PTEN loss) together with whole-exome and RNA sequencing. A cohort of 66 children with the same inclusion criteria and treated previously with temozolomide-based regimen was used to compare outcome. Treatment allocation was performed by randomization in 233 patients, designed so that a drug could not be allocated if the corresponding biomarker was absent: 36 received erlotinib, 102 received dasatinib and 95 received everolimus. The trial was ended for futility of the primary endpoint following the recommendations of the independent data monitoring committee: OS from biopsy was not different from the control cohort (median OS = 10.8 months (95% confidence interval (CI): 9.5-13.0)) in any of the three arms (median OS = 9.7 months (95% CI: 7.8-14.6) for erlotinib; 9.9 months (95% CI: 8.8-11.2) for dasatinib; and 11.9 months (95% CI: 10.7-14.2) for everolimus). Everolimus showed significantly less ocular, renal, skin and gastrointestinal side effects and treatment discontinuation for toxicity (secondary endpoint). TP53 mutations, frequently linked to multiple structural chromosomal aberrations, were the strongest predictor for poor survival in multivariate analysis (hazard ratio = 2.8 (95% CI: 1.9-4.2), P < 0.0001). Both mutations in and activation of the mTOR pathway were associated with a better response to everolimus. Four long-term survivors treated with an mTOR inhibitor were alive free of treatment over 6 years from diagnosis. With comprehensive tumor profiling, BIOMEDE validated prognostic biomarkers as well as informative theranostic biomarkers for future trials. ClinicalTrials.gov: NCT02233049 .