Cancer research communications最新文献

Purpose: AXL, a receptor tyrosine kinase related to oncogenic processes, is aberrantly expressed in various cancers and associated with treatment resistance. Enapotamab vedotin (EnaV), a novel anti-AXL human IgG1 and monomethyl auristatin E antibody-drug conjugate, demonstrated antitumor activity in preclinical models, including non-small cell lung cancer (NSCLC). This phase 1/2 study assessed the safety and preliminary efficacy of EnaV in solid tumors.

Patients and methods: This study comprised dose-escalation and dose-expansion phases; both phases investigated EnaV once every 3 weeks (Q3W) and EnaV on days 1, 8, and 15 of a 28-day cycle (3Q4W). Primary objectives determined the maximum tolerated dose (dose escalation) and safety (dose expansion). Pharmacokinetic profile, antitumor activity, and AXL expression were also assessed.

Results: During dose escalation, 32 patients received EnaV Q3W; 15 received EnaV 3Q4W. The maximum tolerated dose and recommended phase 2 dose were 2.2 mg/kg in Q3W and 1.0 mg/kg in 3Q4W schedules. In dose expansion, 189 patients received EnaV Q3W; 70 received EnaV 3Q4W. Common adverse events in dose expansion included fatigue, constipation, nausea, decreased appetite, and diarrhea. Overall response rates ranged from 4.5% to 12.5% with Q3W dose schedule and from 9.1% to 11.5% with 3Q4W dose schedule. Disease control rates for NSCLC cohorts were 40.9% to 50.0%. NSCLC subset analysis demonstrated correlation between radiomics signature and disease control. The relationship between clinical activity and AXL expression was not apparent.

Conclusions: EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued.

Significance: EnaV, an anti-AXL human IgG1 and monomethyl auristatin E antibody-drug conjugate, showed single-agent antitumor activity in preclinical models. This phase 1/2 study of EnaV demonstrated a manageable safety profile and antitumor activity in selected tumor types. Further studies exploring alternative targeting modalities, patient selection, and/or combinations are needed.

Tumor burden may have opposing influences on immunotherapy outcomes by enhancing neoantigen load or imposing barriers to immune responses. Whether tumor burden is a specific determinant of immunotherapy benefit or a general prognostic factor irrespective of drug mechanism remains ambiguous. We performed a post hoc individual patient-level data analysis of eight prospective trials, including patients with non-small cell lung cancer, hepatocellular carcinoma (HCC), bladder cancer, and renal cell carcinoma to determine the association between tumor burden and immunotherapy and conventional therapy efficacy. Objective response rates were higher among patients with low tumor burden treated with either atezolizumab or conventional therapies. Low tumor burden was also associated with improved progression-free survival in most cancer types and overall survival in all cancer types irrespective of treatment class. Tumor burden effects were dose-dependent across cancer types. An exception to this was in HCC, in which sorafenib treatment was uniquely associated with improved antitumor effects in high tumor burden cancers. Comparisons of outcomes within tumor burden strata showed that atezolizumab is superior to conventional therapy in improving overall survival but not progression-free survival in both high and low tumor burden patients compared with conventional therapies in non-small cell lung cancer, HCC, and bladder cancer. These findings demonstrate that tumor burden is a histology-agnostic and dose-related prognostic factor rather than an immunotherapy-specific predictive biomarker. Cross-treatment analyses suggest that surrogate endpoints may inadequately account for the detrimental impact of tumor burden, with implications for nonrandomized studies and early-phase trials, particularly in which variations in tumor burden exist in the underlying population.

Significance: Tumor burden is not a specific predictive marker of immunotherapy benefit but has substantial prognostic effects across cancer types and treatment classes. These results highlight the importance and broad applicability of tumor burden as stratification or selection markers in trial design, especially because surrogate endpoints do not wholly capture the detrimental effects of tumor burden on overall survival.

Purpose: In this preclinical human immune system patient-derived xenograft (HIS-PDX) model and phase II clinical trial, we assessed evorpacept (anti-CD47 engineered fusion protein with inactive Fc), cetuximab, and pembrolizumab (triple therapy) in microsatellite-stable (MSS) colorectal cancer.

Patients and methods: HIS BALB/c-Rag2nullIl2rγnullSirpαNOD mice with PDXs were treated with triple therapy or its components. Patients with refractory MSS colorectal cancer were treated with triple therapy in a safety run-in (stage 1) followed by expansion (stage 2, planned N = 42). The co-primary objectives were to determine the recommended dose of evorpacept and objective response rate (vs. historic control).

Results: In HIS-PDX mice, triple therapy decreased the growth of MSS colorectal cancer tumors and increased tumor-infiltrating CD8+ T cells. Sixteen patients were treated on the clinical trial across two evorpacept dose levels: N = 12 in stage 1 and N = 4 in stage 2. Trial enrollment was terminated early because of safety concerns (one treatment-related grade 5 event each of hemophagocytic lymphohistiocytosis and cytokine release syndrome). Otherwise, the adverse event profile was as expected. Among all patients, the objective response rate was 6.3%; formal hypothesis testing was not performed. The disease control rate was 12.5%, the median progression-free survival was 2.3 months, and the median overall survival was 10.9 months. Blood- and tumor-based clinical trial correlative analyses identified innate and adaptive immune system activation.

Conclusions: Whereas triple therapy demonstrated evidence of efficacy in refractory MSS colorectal cancer, safety concerns halted enrollment. Further investigation is necessary to determine the optimal use of CD47-targeted therapies in MSS colorectal cancer.

Significance: Evorpacept, cetuximab, and pembrolizumab demonstrated antitumor activity in a preclinical HIS-PDX model and clinical trial in refractory MSS colorectal cancer; however, immune-related adverse events prompted early termination of study enrollment. Evidence of innate and adaptive antitumor immune activation was identified. The role of SIRPα/CD47 blockade in the treatment of MSS colorectal cancer needs to be further elucidated in future trials.

Xevinapant is an orally bioavailable antagonist of select members of the inhibitor of apoptosis protein family. Despite promising phase II data, combining xevinapant with chemoradiotherapy (CRT) failed to improve outcomes in the phase III TrilynX trial when combined with CRT for locally advanced head and neck squamous cell cancer (SCCHN). In immunocompetent mouse models of SCCHN, xevinapant plus CRT maintained or improved locoregional control but in a CD8+ T cell-independent manner. On addition of xevinapant to CRT, the numbers of tumor-infiltrating cytotoxic CD8+ T cells and NK cells were reduced, with remaining CD8+ T cells characterized by PD-1hi CD38hi expression and Nr4a3 dynamics consistent with nonresponsiveness to antigenic restimulation. Furthermore, combination treatment significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute-phase proteins, and decreased levels of necroptosis mediator receptor-interacting protein kinase 3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumor-immune microenvironment, which may explain its lack of clinical benefit.

Significance: Despite hugely promising randomized phase II study data, combined CRT plus xevinapant failed in the TrilynX phase III clinical trial in locally advanced SCCHN. We show that adding xevinapant to chemoradiotherapy in vivo dysregulates antitumor lymphocyte function, acute-phase proteins, and cell death pathways, with net immunosuppressive effects on the tumor-immune microenvironment.

A fundamental limitation of HLA-A matched humanized mice (mHM), generated with donor hematopoietic stem and progenitor cells and bearing patient-derived xenografts, is that the fidelity of the interaction between the immune system and implanted tumors is limited by lack of thymic T-cell education. We created a model with patient-matched thymic and tumor tissue by using patient peripheral blood mononuclear cells reprogrammed into induced pluripotent stem cells to generate stem cell-derived thymic organoids (sTOs). When implanted in thymectomized mHM, which were subsequently engrafted with patient melanoma tissue (autologous, or mHMTA), sTOs expressed thymic tissue markers EPCAM, KRT5, and KRT8 and contained developing double-positive T cells. mHMTA had more activated HLA-DR+ T cells in their spleens. Tumor growth in mHMTA was significantly slower compared with mHM, and both tumor volume and viable melanoma content were significantly decreased in mHMTA. This was associated with an increase of intratumoral activated T cells in mHMTA. Whole-exome sequencing followed by intratumoral heterogeneity analysis identified seven candidate neoantigens that were selected against in the mHMTA model, suggesting more effective identification and T cell-driven tumor clearance. This study shows the feasibility of generating patient-specific, thymus-bearing mice and provides a promising new tool in immunology and immunotherapy development.

Significance: A humanized mouse xenograft model, in which T cells are educated in a patient-derived implanted thymic organoid autologous to the tumor, provides a more faithful and complete environment to study cancer immunity.

Purpose: The ataxia telangiectasia and Rad3-related kinase inhibitor elimusertib synergizes with cisplatin preclinically. We evaluated the clinical feasibility of combining elimusertib with cisplatin.

Patients and methods: Patients with advanced solid tumors who had received <300 mg/m2 of prior cisplatin, and for whom cisplatin-based treatment was deemed appropriate, were enrolled according to a standard 3 + 3 design, starting elimusertib at 20 mg orally twice daily on days 2 and 9, with cisplatin 60 mg/m2 intravenously on day 1 of a 21-day cycle. Primary objectives were the determination of the maximum tolerated dose and safety. Secondary objectives included the assessment of elimusertib pharmacokinetics and preliminary efficacy.

Results: Fifteen patients were enrolled. Dose level -2 (elimusertib 20 mg once on day 2 and cisplatin 30 mg/m2 on days 1 and 8) was deemed the maximum tolerated dose; dose-limiting toxicities (DLT) including creatinine increase, hypokalemia, febrile neutropenia, neutropenia, syncope, and thrombocytopenia, required dose de-escalation. Although the four patients with the highest elimusertib exposure all experienced hematologic DLTs within 1 week, they also received a higher day 1 cisplatin dose, precluding a definitive association of elimusertib exposure with DLT occurrence. Of 10 evaluable patients, one (10%) with clear-cell ovarian cancer had a partial response, whereas five (50%) had stable disease.

Conclusions: Cisplatin combined with elimusertib was associated with hematologic toxicity requiring significant dose de-escalation. Elimusertib pharmacokinetics was consistent with prior studies. Only modest activity was observed. Further clinical evaluation of elimusertib plus cisplatin is not warranted.

Significance: Preclinical data suggest synergy between cisplatin and the ataxia telangiectasia and Rad3-related inhibitor elimusertib, leading to this phase Ib trial in advanced solid tumors evaluating feasibility. The results do not support further examination of the combination due to DLTs observed in the absence of robust efficacy.

Gene fusions are a class of important oncogenic drivers, with many matched FDA-approved targeted therapies across multiple solid tumors. However, the prevalence of fusions varies considerably by cancer type and assay. Fusion detection is technically challenging, and studies have shown that RNA-based next-generation sequencing (NGS) can improve fusion detection rates when used in conjunction with DNA-based NGS. In this study, we performed a retrospective pan-cancer analysis of 67,278 patients receiving both RNA- and DNA-NGS in 43 distinct solid-tumor cancer types, including non-small cell lung cancer (18.6%), colorectal cancer (18.2%), and breast cancer (13.1%). In this cohort, 1,497 patients (2.2%) had at least one of nine fusions detected-each having an FDA-approved matched therapy in at least one indication. A total of 316 patients (21.1%) had a fusion detected (RET or NTRK1/2/3) with matched targeted therapy approved in all cancer indications. Concurrent RNA- and DNA-NGS increased the detection of driver gene fusions by 21% compared with DNA-NGS alone. Gene fusions were observed in a range of cancers beyond their approved cancer indications: of 1,501 fusions detected, 29% (n = 437) were detected outside of an FDA-approved indication. Finally, emerging fusion drivers with targets in drug development were found in an additional 218 patients, with combined RNA- and DNA-NGS increasing detection of these variants by 127%. Our findings support combined RNA-NGS and DNA-NGS to maximize detection of clinically actionable fusions with FDA-approved matched therapies and potentially actionable fusions in non-FDA-approved indications or those matched to therapies in clinical development.

Significance: This large, real-world pan-cancer study demonstrates that concurrent RNA- and DNA-based NGS significantly improves the detection of clinically actionable gene fusions compared with DNA-NGS alone. Our findings highlight the critical value of integrating RNA-NGS into routine molecular profiling to optimize the detection of driver gene fusions. Doing so may expand the population of patients eligible for matched targeted therapies or clinical trials, particularly in cancers with limited treatment options.

The randomized phase II MA.38 trial estimated the relative progression-free survival (PFS) associated with second-line endocrine therapy plus palbociclib administered on a 100 mg continuous daily dosing (CDD) schedule compared with the standard dose schedule (SDS) of 125 mg (days 1-21 of a 28-day cycle). A total of 180 patients were allocated 1:1 to protocol therapy. Molecular profiling was performed on the archival tissue and cell-free DNA (cfDNA) at enrollment, 3 months, and 6 months. The primary analysis for PFS demonstrated a similar outcome for the CDD versus SDS treatment strategy: HR = 0.93 (90% confidence interval, 0.66-1.30). Secondary efficacy measures for CDD versus SDS included the following: overall survival, HR = 1.07 (90% confidence interval, 0.67-1.69); response rate, 16.1% versus 18.0% (P = 0.66); median duration of response, 4.2 months (range, 2.8-13.9 months) versus 5.6 months (range, 2.4-13.9 months; P = 0.86); and clinical benefit rate, 53.2% versus 57.3% (P = 0.89). cfDNA profiling of the baseline enrollment sample prior to palbociclib commencement showed low tumor fraction (HR = 2.28; P = 9.9 × 10-6); higher short/long fragment length ratios (HR = 1.19; P = 0.049) and cfDNA variants in FGFR4 (HR = 3.65; P = 0.012) were prognostic and associated with inferior PFS. Variants in TP53 (HR = 2.48; P = 0.006) and ESR1 (HR = 3.42; P = 0.005) detected at 12 weeks on treatment were also associated with poor PFS. CDD palbociclib 100 mg dosing was not associated with improved efficacy compared with the standard intermittent 125 mg dosing schedule. Additionally, we identified prognostic biomarkers in alignment with prior research and demonstrated the value of cfDNA dynamics, including fragment length ratios and tumor fraction as a measure of treatment response.

Significance: A continuous 100 mg dosing schedule of palbociclib was tolerable but not associated with improved efficacy signals versus the standard intermittent 125 mg (days 1-21 of a 28-day cycle) schedule. Mutations detected in liquid biopsies and changes in cfDNA dynamics were linked to poor outcomes and may identify patients with treatment-resistant cancer.