Clinical Cancer Research最新文献

Purpose: EGFR-targeting monoclonal antibodies are essential for managing RAS WT metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunological and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.

Experimental design: We conducted a phase I/II trial in KRAS WT mCRC patients, combining panitumumab and CB-839, hypothesizing that dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B cell activation signature 'Bscore' and glutamine PET as potential treatment response biomarkers.

Results: The combination of panitumumab and CB-839 was tolerable with manageable side effects, including Grade 4 hypomagnesemia in four patients, a known panitumumab-related event. Two patients achieved partial response (PR), and five had stable disease (SD), with a 41% disease control rate (DCR). Median progression-free survival (PFS) and overall survival (OS) were 1.84 and 8.87 months, respectively. A positive correlation between 'Bscore' and lesion size reduction suggested its association with clinical benefit (PR and SD). Lower 'Bscore' correlated with greater tumor avidity for glutamine by PET, indicating B cell activation sensitivity to glutamine depletion.

Conclusions: The combination of CB-839 and panitumumab showed safety and promising preliminary responses, but the study closed early due to CB-839 development termination. The B cell activation signature 'Bscore' emerged as a potential biomarker for EGFR and glutaminase inhibition in mCRC, warranting further studies. These findings suggest opportunities to improve immune response and therapies in glutaminolysis-dependent tumors.

Purpose: We aimed to investigate the efficacy and safety of anlotinib as adjuvant targeted therapy for completely resected localized high-grade soft tissue sarcomas (STS).

Patients and methods: Patients with localized high-grade STS after complete resection were randomly assigned in a 1:1 ratio to receive either oral 12 mg anlotinib or placebo once daily on days 1-14 every 21 days as a cycle, with up to 6 cycles until disease relapse, unmanageable toxicity or death. The efficacy and safety were analyzed. This trial was the first trial exploring adjuvant targeted therapy for STS (NCT03951571).

Results: Between June 2019 and November 2023, 88 patients were randomly assigned to receive anlotinib (n=44) or placebo (n=44). With a median follow-up of 30.95 months, the 1-year and 2-year disease-free survival (DFS) rates were 88% and 77% in the anlotinib group, compared to 64% and 58% in the placebo group. Compared to patients treated with surgery alone, patients receiving adjuvant anlotinib combined with surgery had a reduced risk of disease recurrence (HR 0.47 [95% CI 0.22~1.00, P=0.0445]). Based on the tumor histology, the reduced risk of disease recurrence with anlotinib versus placebo was observed in patients with myxofibrosarcoma (HR 0.54 [95% CI 0.17~1.65], P=0.2698) and undifferentiated pleomorphic sarcoma (HR 0.58 [95% CI 0.12~2.87], P=0.4971). Four patients discontinued anlotinib, including two for proteinuria/hematuria (2/44, 5%) and two for poor healing of surgical wound (2/44, 5%).

Conclusions: Compared to surgery alone, adjuvant anlotinib following surgery reduces the incidence of disease relapse in localized high-grade STS, with acceptable toxicity.

Purpose: Identifying biomarkers of radiotherapy (RT) response is important for optimising the treatment of early breast cancer (BC). Here we tested the interaction between endothelial cell (EC) expression of phospho-Tyr397-FAK (pY397-FAK) and adjuvant-RT on clinical outcomes after breast-conserving surgery (BCS) within a randomised study. Preclinical data suggests an enhanced effect of RT with low EC_ pY397-FAK expression.

Methods: We analysed tissue microarrays (TMAs) from the SweBCG91-RT (stage I-II, lymph node-negative) BC cohort, consisting of 1,178 patients randomly assigned to receive either BCS alone or BCS plus adjuvant-RT. TMA sections were immunostained for pY397-FAK, CD31, α-smooth-muscle-actin (αSMA) and pan-cytokeratin (panCK). HALO analysis scored mean pY397-FAK intensity in CD31+ ECs, panCK+ tumour epithelial cells (TCs) and αSMA+ mural/stromal cells per core. For 822 patients, multivariable Cox regression analysis was performed for the primary and secondary 5-year endpoints, locoregional recurrence (LRR) and 'all recurrence', respectively, as dependent variables, and RT and EC_pY397-FAK as independent variables.

Results: EC_ pY397-FAK expression was not predictive for the primary endpoint, LRR (p=0.098), but the direction of the RT effect was in line with preclinical findings. For the secondary endpoint, all recurrence, there was a significant interaction (p=0.026) between EC_ pY397-FAK and RT. Without RT, higher EC_ pY397-FAK expression resulted in lower risk for all recurrence (HR 0.74 per SD, CI 95% 0.57-0.96, p=0.026).

Conclusion: Within the first 5-years post-BCS, patients with low EC_pY397-FAK expression derive greater benefit from RT than patients with high EC_pY397-FAK expression. However, without RT low EC_pY397-FAK expression is associated with a higher risk of recurrence.

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy in hormone receptor-positive metastatic breast cancer patients. However, their activity has been relatively underexplored in patients with metastatic triple-negative breast cancer (mTNBC).

Methods: We conducted a single-arm phase II study of abemaciclib monotherapy in patients with retinoblastoma-positive (Rb+) mTNBC. Patients were treated with abemaciclib 200 mg orally twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), disease control rate (DCR), and safety and tolerability.

Results: A total of 27 patients were enrolled before the trial was closed early due to slow accrual. Patients had received a median of 2 lines of systemic therapy in the metastatic setting prior to enrollment. After a median follow-up of 28.5 months, the ORR was 0%, the CBR was 14.8%, and the DCR was 22.2%. The median PFS was 1.94 months (95% confidence interval (CI):1.84-11.47), and the median OS was 8.44 months (95% CI:4.57-15.57). Median PFS and OS did not differ significantly based on AR and PD-L1 status. Pre-treatment gene expression profiling of tumor tissue provided some hypothesis-generating insights into biological features associated with clinical benefit in this study. The most common treatment-related adverse events of grade 2 or higher were diarrhea (40.7%), neutropenia (40.7%), anemia (29.6%), and nausea (29.6%).

Conclusions: Abemaciclib monotherapy did not show clinical activity in patients with pretreated Rb+ metastatic TNBC.

Purpose: Argininosuccinate Synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, like PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis.

Experimental design: The effects of ADI-PEG20 on cell cycle regulation, apoptosis, and Bcl-xL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions between Bcl-xL, Bax, and Bak. In vitro synergy was determined, and in vivo efficacy was modeled.

Results: Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell cycle progression but did not induce significant cell death. Bcl-xL was found to bind to Bax and Bak, preventing the initiation of apoptosis despite arginine starvation. Inhibition of Bcl-xL allowed proapoptotic Bax and Bak to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo.

Conclusions: The study identifies Bcl-xL as a key factor limiting the efficacy of arginine starvation therapies. Combining Bcl-xL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in Phase 1 clinical trials for ASS1-deficient cancers.

Purpose: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase I study evaluated the safety of targeting ROR1 with autologous T lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated the persistence, trafficking, and antitumor activity of CAR-T cells.

Patients and methods: Twenty-one patients with ROR1+ tumors received CAR-T cells at one of four dose levels: 3.3 × 105, 1 × 106, 3.3 × 106, and 1 × 107 cells/kg body weight, administered after lymphodepletion with cyclophosphamide/fludarabine or oxaliplatin/cyclophosphamide. Cohort A included patients with chronic lymphocytic leukemia (CLL, n = 3); cohort B included patients with triple-negative breast cancer (TNBC, n = 10) or non-small cell lung cancer (NSCLC, n = 8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion.

Results: Treatment was well tolerated, apart from one dose-limiting toxicity at dose level 4 in a patient with advanced NSCLC. Two of the three (67%) patients with CLL showed robust CAR-T-cell expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR-T cells expanded to variable levels and infiltrated tumors poorly and 1 of 18 patients (5.5%) achieved partial response by RECIST 1.1.

Conclusions: ROR1 CAR-T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations. See related commentary by Kobold, p. 437.

Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine (NE) prostate cancer (NEPC) occur in up to 15% to 20% of patients with castration-resistant prostate cancer (CRPC) as a mechanism of treatment resistance and are associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of NE lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions, making clinical trial design challenging. In this manuscript, we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and IHC markers with a priority for AR, NK3 homeobox 1, insulinoma-associated protein 1, synaptophysin, and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.

Purpose: The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02-positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1- and/or LAGE-1a-positive non-small cell lung cancer.

Patients and methods: Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non-small cell lung cancer.

Results: More than 2,500 patients were screened for target expression. In the multiarm study, 738 (45%) of 1,638 tested patients were HLA-A*02-positive. NY-ESO-1 and LAGE-1a testing was positive in 12% (62/525) and 4% (15/348) of tested patients, respectively. Forty-one patients positive for HLA-A*02 and antigen expression were screened in the single-arm study. Overall, 43 patients underwent leukapheresis and 18 received lete-cel across studies. Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AE) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not seem to increase toxicity over lete-cel alone. Limited antitumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell expansion in all patients.

Conclusions: Extensive HLA-A*02 and antigen expression testing was performed to identify potential participants. Lete-cel was generally well tolerated and had no unexpected AEs. Antitumor activity was observed in a limited number of patients.

Purpose: Datopotamab deruxtecan (Dato-DXd) is a humanized anti-trophoblast cell-surface antigen-2 (TROP2) IgG1 mAb linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCX) varying in TROP2 expression.

Experimental design: The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors postneoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines.

Results: Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival in 8 (73%) models, whereas IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged event-free survival in 3 (27%) models. TROP2 RNA and protein were significantly higher in Dato-DXd-sensitive models. In isogenic cell lines derived from Dato-DXd-resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the two Dato-DXd-sensitive BCXs but not in a Dato-DXd-resistant BCX. In Dato-DXd-sensitive models, antitumor activity was enhanced in combination with a PARP inhibitor, olaparib.

Conclusions: Dato-DXd is active in breast cancer models. Dato-DXd has TROP2-dependent and -independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.