Clinical Cancer Research最新文献

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood.

Experimental design: We applied targeted cell-free DNA sequencing to 126 mCRPC patients from three academic cancer centers, and separately performed genome-wide cell-free DNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome-positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 mCRPC patients, respectively, to develop and validate a stem-like signature, which we inferred from cell-free DNA.

Results: Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first-line ARSIs which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (p = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (p < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cell-free DNA revealed enrichment for stemness-associated transcription factors in lethal mCRPC patients. The resulting stemness signature was then validated in a completely held-out cohort of 80 mCRPC patients profiled by tumor RNA sequencing.

Conclusions: We analyzed a total of 220 mCRPC patients, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.

Despite emerging possibilities of molecular histopathologic characterization, multiparamateric magnetic resonance imaging (MTP) plays a key role in the diagnosis and classification of cerebral tumors. Imaging may also provide additional information about relevant histopathological features of these tumors.

Since 2011, the U.S. FDA has approved 30 new drugs for use in advanced non-small-cell lung cancer (NSCLC), mainly comprising tyrosine kinase inhibitors and immune checkpoint inhibitors. NSCLC with oncogene driver alterations is amenable to treatment with targeted drugs, usually small molecule inhibitors. In these cases, the demonstration of high overall response rates, coupled with a lasting duration of response, has allowed for accelerated approval in the U.S., based on single or multi-cohort trials. Confirmatory clinical evidence was subsequently provided through post-marketing trials. In NSCLC without such driver alterations, regulatory agencies in both the U.S. and the EU set clinical evidence expectations that foster the conduct of studies primarily focused on determining survival or event-free survival, based on randomized-controlled trial designs. This review analyzes the approval patterns of novel therapeutics for NSCLC with a focus on small molecule inhibitors that target driver alterations, as well as biologicals. The latter include monoclonal antibodies inhibiting immune checkpoints like PD-(L)1 or cell surface receptors, and antibody-drug conjugates, highly potent biologics linked to a cytotoxic compound. The differentiation of NSCLC into oncogene- and non-oncogene-addicted subtypes determines drug development strategies, the extent of the clinical development program, access to orphan drug development incentives, and regulatory approval strategies.

Purpose: Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy. We report the long-term efficacy and safety of pembrolizumab and cabozantinib and include a correlative biomarker analysis.

Patients and methods: This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. Primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, safety, and describe correlative biomarkers.

Results: With median follow-up of 22.4 months, median PFS was 12.8 months 2-year PFS of 32.6% (95%CI 18.8-56.3%) and median OS of 27.7 months,2-year OS of 54.7% (95%CI 38.9-76.8%). Median duration of response was 12.6 months, with 2-year rate of 38.5% (95%CI 30.8-81.8%). Long-term TRAEs included manageable hypothyroidism (5.5%) and grade 1 elevated AST and ALT (2.8%). Baseline tumor p-MET expression correlated with ORR (p=0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS (hazard ratio [HR]=5.27, p=0.030; HR =8.79, p=0.017; HR =6.87, p=0.040, respectively).

Conclusion: Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of increased CD8+, CD103+ and CSF1-R+ cell density in TIME deserve further evaluation in similar clinical settings.

Purpose: To identify predictive factors of nivolumab sensitivity, peripheral blood NKs and Tregs were evaluated in patients with metastatic renal cell carcinoma (mRCC) enrolled in the REVOLUTION trial.

Experimental design: 57 mRCCs being treated with nivolumab, as at least second-line of therapy (REV), and 62 healthy donors (HDs) were longitudinally evaluated (0-1-3-6-12 months) for peripheral NKs and Tregs, phenotype and function. Multivariable logistic regression were conducted to identify the independent predictors. The .632+ internal cross-validation was used to avoid overfitting. The best cut-off value based on three-months clinical-response was applied to progression-free survival (PFS) and overall survival (OS). Kaplan-Meier-curves for PFS and OS were produced.

Results: At pre-treatment, mRCCs displayed high frequency of NKp46+NKs, NKp30+NKs, KIR2DL1+NKs, KIR2DL2/DL3+NKs, and PD-1+NKs with reduced NK degranulation; as well as high frequency of Tregs, PD-1+Tregs, Helios+Tregs and ENTPD-1+Tregs. Responder patients (R), identified as a clinical response after three-months of treatment, presented at pre-treatment significantly low CD3+, high KIR2DL2/DL3+NKs, high PD-1+Tregs and high Helios+Tregs. Upon multivariate analysis, only KIR2DL2/DL3NKs and Helios+Tregs held as independent predictors of nivolumab responsiveness. The KIR2DL2/DL3+NKs >35.3% identified patients with longer OS while the Helios+Tregs >34.3% displayed significantly longer PFS. After 1-month of nivolumab, R patients showed low CD3+, high NKs, KIR2DL2/DL3+NKs and ICOS+Tregs. Among these subpopulations, CD3+ and KIR2DL2/DL3+NKs held as independent predictors of nivolumab efficacy. Low CD3+ (≤71%) significantly associated with longer PFS while high KIR2DL2/DL3+NKs (>23.3%) associated with both PFS and OS.

Conclusions: Pre-treatment evaluation of Helios+Tregs/KIR2DL2/DL3+NKs and one-month post-treatment CD3+/ KIR2DL2/DL3+NKs will predict nivolumab response in mRCCs.

Background: AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics (PK), and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory (R/R) hematologic malignancies.

Methods: In the monotherapy cohort (n=61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, on a 3-week cycle. In the combination cohort (n=17), patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) received escalating doses of AZD5991 and venetoclax on either a 3-week or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma PK and antitumor activity.

Results: The most common (≥30%) adverse events (AEs) were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred due to AEs: cardiac arrest, sepsis, tumor lysis syndrome (TLS), and acute respiratory failure; only TLS was related to AZD5991. Dose-limiting toxicities occurred in 5 patients. Three patients with MDS achieved an objective response: 1 marrow complete remission (mCR) without hematologic improvement, 1 partial remission with AZD5991 monotherapy, and 1 mCR with AZD5991+venetoclax. Asymptomatic elevations of troponin I or T were observed in 8 (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after cycle 1. There were no associations between elevated troponin and cardiovascular risk factors.

Conclusions: Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate.

Purpose: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICIs) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication.

Experimental design: We harnessed a variety of transcriptomic, spatial and functional assays to characterize the differential impact of neo-adjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to NACT-naïve HGSOC samples from 5 independent patient cohorts.

Results: We found neo-adjuvant chemotherapy (NACT)-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD-1+ CD8+ T cells over their ICI-insensitive TIM-3+PD-1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD-1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden.

Conclusion: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC.

Supramaximal resection beyond the contrast-enhancing tumor borders represents an emerging surgical strategy for patients with newly diagnosed glioblastoma. A recent study provides evidence detailing the interactive effects of more aggressive surgery with other clinical predictors of outcome, supporting guidance for surgical decision-making and informing clinical trialists about the need to stratify for extent of resection.

Purpose: HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data.

Experimental design: We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project. We analyzed paired genome and transcriptome data of tissue and genomic data of ctDNA collected pre- and postprogression in patients enrolled in the related trial, TRIUMPH, in ERBB2-amplified mCRC.

Results: In 155 patients with ERBB2-amplified solid tumors who received HER2-targeted therapy based on the SCRUM-Japan project, the objective response rate was 50%, 51%, and 35% in ERBB2 wild-type, variant of unknown significance, and pathogenic variant groups, respectively. In the paired genome and transcriptome data analyses in TRIUMPH, we identified the novel splicing-associated variant c.644-66_-2del in one of the 11 patients with paired whole-exome sequencing and whole-transcriptome sequencing data sets, which lacks the binding domain of pertuzumab, in progressed metastatic tumor as a variant with potential pathogenicity. The time-course ctDNA analysis detected c.644-66_-2del as an acquired variant.

Conclusions: This study highlighted the importance of ERBB2 genomic status when evaluating the efficacy of HER2-targeted therapies in ERBB2-amplified mCRC. The identification of a novel splicing-associated variant may provide insights into potential mechanisms of treatment resistance. Furthermore, we demonstrated the utility of ctDNA to follow the acquired genomic status of mCRC tumors.

Purpose: Histological transformation from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored.

Experimental design: We conducted whole transcriptome analysis of 59 regions of interest (ROIs) through the spatial profiling of FFPE tissues obtained from ten patients (lung adenocarcinoma, 22; combined SCLC/NSCLC, 7; t-SCLC, 30 ROIs). Transcriptomic profiles and differentially expressed genes (DEGs) were compared between pre- and post-transformed tumors.

Results: Following EGFR-TKI treatment, 93.7% (15/16) of transformed-SCLC (t-SCLC) components evolved into neuroendocrine-high subtypes (SCLC-A or SCLC-N). The transition to t-SCLC occurred regardless of EGFR-TKI treatment and EGFR mutational status, with a notable decrease in EGFR expression (P < 0.001) at both mRNA and protein levels. Pathway analysis revealed that gene overexpression was related to epigenetic alterations in t-SCLC. Interestingly, Histone deacetylase (HDAC) inhibitors restored EGFR expression in SNU-2962A cells and their organoid model. The synergistic effects of third-generation EGFR-TKI osimertinib and the HDAC inhibitor fimepinostat were validated in both in vitro and in vivo models.

Conclusions: Our study demonstrated most t-SCLC showed neuronal subtypes with low EGFR expression. DEGs analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.