Annals of Oncology最新文献

Background: The optimal duration of immune checkpoint blockade (ICB) in lung cancer remains undefined. Indefinite treatment in long-term responders increases healthcare burden, exposes patients to avoidable toxicities, and is not supported by any clinical and biological rationale or translational data. Prospective strategies to determine the optimal duration of immunotherapy in lung cancer are urgently needed.

Patients and methods: In this retrospective cohort study, 455 patients from 21 nNGM centers with ≥2 years of disease control on first-line ICB-based therapy were grouped into PET/CT-guided discontinuation (cohort A, n=126) or continued ICB without PET/CT (cohort B, n=329), and assessed for overall survival (OS). Matched pre- and post-ICB tumor samples from cohort A patients with persistent or progressive disease were analyzed by comprehensive genomic profiling, histological TIL quantification, and spatial transcriptomics to explore mechanisms of late resistance.

Results: After a median follow-up of 55 months, cohort A showed significantly longer OS (median not reached vs. 82 months; HR 0.35 [0.18-0.67], p = 0.002), despite substantially shorter treatment duration (27 vs. 45 months; p < 0.001). Discontinuation was either PET-driven (A) or resulted from immune-related toxicity, progression, or patients' choice (B). Systematic re-biopsies in cohort A revealed a high incidence of second primary lung cancers (SPLC, 28%). All progression events were managed exclusively with local (ablative) treatments in 53% (A) vs. 17% (B). Post-treatment tumors exhibited features of acquired resistance, whereas SPLC displayed characteristics of primary resistance, including low PD-L1 expression, low TMB, and immunologically cold tumor microenvironments.

Conclusions: A structured discontinuation strategy appears to provide a safe approach for long-term ICB responders, enabling earlier detection of resistance before generalized progression. A confirmatory prospective non-inferiority randomized trial within the nNGM is underway.

Background: The TROPION-Breast01 study (NCT05104866) demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review (BICR) with the trophoblast cell-surface antigen 2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in patients with previously treated, inoperable/metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this article, we report results from the final overall survival (OS) analysis.

Patients and methods: Patients with inoperable/metastatic HR-positive/HER2-negative breast cancer, who had disease progression on endocrine therapy and for whom endocrine therapy was unsuitable, and had received one to two prior lines of chemotherapy in the inoperable/metastatic setting were randomly assigned in a 1 : 1 ratio to Dato-DXd (6 mg/kg every 3 weeks) or ICC (eribulin/capecitabine/vinorelbine/gemcitabine). Dual primary endpoints were PFS by BICR and OS.

Results: At data cut-off, median follow-up was 22.8 months. OS for the Dato-DXd versus ICC arm did not reach statistical significance (hazard ratio 1.01, 95% confidence interval 0.83-1.22, P = 0.9445). Use of ADCs (trastuzumab deruxtecan and sacituzumab govitecan) as subsequent therapy was imbalanced: 12.3% in the Dato-DXd arm versus 24.0% in the ICC arm. Secondary efficacy endpoints (PFS by investigator assessment, objective response rate, duration of response, disease control rate at 12 weeks, time to first and second subsequent therapy or death, and time to second progression or death) continued to favor Dato-DXd at this final analysis. The overall safety profile of Dato-DXd remained favorable compared with ICC, and no new safety signals were observed with longer follow-up.

Conclusions: TROPION-Breast01 met its dual primary endpoint of PFS by BICR. While there was no statistically significant improvement in the dual primary endpoint of OS with Dato-DXd versus ICC, subsequent ADC treatment may have affected OS results. The totality of efficacy and safety data supports Dato-DXd as a new treatment option for patients with previously treated, inoperable/metastatic HR-positive/HER2-negative breast cancer.

Background: Addition of pembrolizumab to neoadjuvant chemotherapy (NACT) is a standard-of-care treatment in non-metastatic triple-negative breast cancer (TNBC). Trials employing reduced doses of immune checkpoint inhibitors have yielded encouraging activity in several tumor types. Whether low-dose pembrolizumab enhances pathological complete response when added to NACT in TNBC remains uncertain.

Patients and methods: A phase II, open-label, randomized controlled study was conducted at a tertiary cancer center in New Delhi, India. Eligible participants had previously untreated stage II-III TNBC and lacked access to standard-dose pembrolizumab. Patients were randomly assigned (1 : 1) to receive dose-dense NACT-four cycles of doxorubicin-cyclophosphamide followed by four cycles of paclitaxel with or without a low dose of pembrolizumab (50 mg every 6 weeks for three cycles). The primary endpoint was pathological complete response.

Results: Between February 2024 and February 2025, 157 patients were enrolled. Baseline characteristics were comparable between study arms. Surgery was completed in 152 patients. In the intention-to-treat population, pathological complete response was achieved in 53.8% [90% confidence interval (CI) 43.9% to 63.5%] of patients receiving low-dose pembrolizumab + NACT versus 40.5% (90% CI 31.1% to 50.4%) with NACT alone, corresponding to an absolute difference of 13.3% (90% CI 0.3% to 26.3%, one-sided P = 0.047). Among those who underwent surgery, the respective pathological complete response rates were 56.7% and 41.0% (absolute difference 15.7%, one-sided P = 0.031). Grade ≥3 toxicities occurred in 50% of patients in the low-dose pembrolizumab arm and in 59.5% in the control arm.

Conclusions: Addition of low-dose immunotherapy to NACT led to a statistically significant increase in pathological complete response rates, and the benefit appears to be numerically similar to that seen in the KEYNOTE-522 trial. In settings where access to the standard regimen is restricted, a low-dose approach may offer a feasible and cost-effective treatment option for patients with TNBC.

Background: Anti-epidermal growth factor receptor (EGFR) drug rechallenge could be of therapeutic value in a subgroup of refractory metastatic colorectal cancer (mCRC).

Patients and methods: The randomized phase II CAVE-2 GOIM trial compared two rechallenge regimens in RAS/BRAF wild-type mCRC (cetuximab monotherapy or in combination with avelumab). Patients were selected according to baseline plasma circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) by FoundationOne Liquid CDx. Primary endpoint was overall survival (OS).

Results: From August 2022 to December 2024, 156 out of 328 screened patients were randomly assigned in a 2 : 1 ratio to cetuximab plus avelumab (arm A, 104 patients) or cetuximab (arm B, 52 patients). Median progression-free survival (mPFS) was 5.3 months [95% confidence interval (CI) 4.3-6 months] in arm A versus 4.3 months (95% CI 3.5-5.5 months) in arm B [hazard ratio (HR) 0.78, 95% CI 0.55-1.10, P = 0.158]. Median OS (mOS) was 14.8 months (95% CI 12.1-18.3 months) in arm A versus 12.9 months (95% CI 11 months-not evaluable) in arm B (HR 1.00, 95% CI 0.65-1.52, P = 0.983). A pre-planned exploratory analysis evaluated the impact of genomic pathogenic variants on therapeutic efficacy in the EGFR pathway. In the whole study population, 124/156 patients had tumors without any genomic alteration in KRAS, NRAS, BRAF, EGFR extracellular domain, PIK3CA exon 20, MAP2K1, AKT1, MET, PTEN, and ERBB2 ('negative hyperselection'). These patients had significantly improved mPFS [5.35 months (95% CI 4.4-5.9 months) versus 3.65 months (95% CI 2.8-4.8 months); HR 0.62, 95% CI 0.42-0.92, P = 0.017] and mOS [15.0 months (95% CI 12.6-19.9 months) versus 11.1 months (95% CI 8.6-15.6 months); HR 0.61, 95% CI 0.39-0.97, P = 0.037] compared with patients having at least one pathogenic variant ('positive hyperselection'). Similarly, improved objective response rate, mPFS, and OS were observed for each treatment arm in patients with 'negative hyperselection'.

Conclusion: Addition of avelumab does not increase efficacy of cetuximab rechallenge. Liquid biopsy CGP identifies patients who benefit from anti-EGFR rechallenge supporting its implementation in the continuum of care of mCRC.

Background: Adding the pan-Akt serine/threonine kinase (AKT) inhibitor capivasertib to first-line paclitaxel in metastatic triple-negative breast cancer (TNBC) led to significantly longer progression-free survival (PFS) and overall survival (OS) versus placebo-paclitaxel in the phase II PAKT trial. CAPItello-290 was designed to further assess capivasertib-paclitaxel, including in patients with PIK3CA/AKT1/PTEN-altered tumours.

Patients and methods: Patients with previously untreated metastatic TNBC were randomised 1 : 1 to paclitaxel 80 mg/m² [day 1, weeks 1-3 (4-week cycle)] plus capivasertib 400 mg or placebo twice daily (days 2-5, weeks 1-3). PIK3CA/AKT1/PTEN alterations were analysed by retrospective central molecular testing. Dual primary endpoints were OS in the overall population and in patients with PIK3CA/AKT1/PTEN-altered tumours; investigator-assessed PFS was a key secondary endpoint.

Results: From July 2019 to February 2022, 812 patients were randomised; 30.7% of patients had PIK3CA/AKT1/PTEN tumour alterations. At final analysis [data cut-off (DCO) 18 March 2024], the median OS for the overall population was 17.7 and 18.0 months with capivasertib-paclitaxel and placebo-paclitaxel, respectively [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.78-1.08, P = 0.3239] and for patients with PIK3CA/AKT1/PTEN-altered tumours, it was 20.4 months in both arms (HR 1.05, 95% CI 0.77-1.43, P = 0.7602). At PFS DCO (25 May 2022), the median PFS in the overall population numerically favoured capivasertib-paclitaxel (5.6 versus 5.1 months placebo-paclitaxel; HR 0.72, 95% CI 0.61-0.84); this was also the case in patients with PIK3CA/AKT1/PTEN-altered tumours (7.5 versus 5.6 months placebo-paclitaxel; HR 0.70, 95% CI 0.52-0.95). The most frequent adverse event (AE) of grade ≥3 was diarrhoea [12.7% versus 0.7% placebo-paclitaxel (overall population)]. Capivasertib was discontinued due to AEs in 8.5% of patients (4.9% placebo-paclitaxel; overall population); AEs led to death in 4.2% of all patients.

Conclusions: Capivasertib-paclitaxel did not meet the prespecified boundary for improving OS in either population; PFS numerically favoured the combination, especially in PIK3CA/AKT1/PTEN-altered tumours. The safety of capivasertib-paclitaxel was generally manageable and consistent with prior studies.

Background: Germline alterations and smoking status in lung cancer could inform etiology and clinical decisions. We investigated the prevalence of germline alterations in predisposition genes across various lung cancer histologies in two large populations.

Patients and methods: Germline sequencing of 11 740 primary lung cancers was carried out with Tempus xT tumor-normal matched assay (DNA sequencing of 648 genes at an average coverage of 500×, normal specimens at 150× coverage, full transcriptome RNA sequencing). Pathogenic/likely pathogenic (P/LP) potential germline alterations in 46 genes were compared between smokers and never smokers; never smokers somatic EGFR altered (sEGFRalt) and wild type (sEGFRwt); non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) histologies; and NSCLC sEGFRalt and NSCLC sEGFRwt. P/LP variants were investigated in these 46 genes in 1330 patients with lung cancer from the UK Biobank by smoking status.

Results: Tempus sequencing revealed P/LP alterations in 4.8% of smokers and 5.8% of never smokers, with most alterations in MUTYH (1.3% versus 1.1%), ATM (0.7% versus 1.0%), BRCA2 (0.6% versus 0.9%), and EGFR (<0.1% versus 0.4%). Never smoker sEGFRalt (n = 549) and sEGFRwt (n = 1025) tumors had alterations in MUTYH (1.1% versus 1.1%), ATM (0.7% versus 1.1%), and EGFR (1.1% versus 0%). NSCLC and SCLC tumors had alterations in MUTYH (1.3% versus 0.3%), ATM (0.8% versus 0.3%), and BRCA2 (0.7% versus 0%). sEGFRalt and sEGFRwt NSCLC tumors had germline alterations in MUTYH (1.6% versus 1.3%), ATM (0.5% versus 0.8%), EGFR (1.3% versus 0%), and BRCA2 (0.8% versus 0.6%). UK Biobank patients had similar P/LP alterations: 4.3% of smokers and 5.1% of never smokers, with most germline alterations in ATM (0.8%), BRCA2 (0.79%), and MUTYH (0.62%) in smokers and MUTYH (1.5%) and CHEK2 (1.01%) in never smokers.

Conclusion: Similar distribution of P/LP potential germline alterations in lung cancer subtypes from distinct populations by smoking status suggests that increased next-generation germline sequencing may improve risk assessment.