Clinical Cancer Research最新文献

Background: While detection of circulating tumor DNA (ctDNA) weeks after surgery is linked to recurrence for other solid tumors, the optimal time point for ctDNA assessment as a prognostic biomarker following chemoradiation for anal cancer is undefined.

Methods: Patients with stages I-III anal cancer treated with chemoradiation between 12/2020-5/2024 were evaluated for HPV ctDNA status at baseline, at the end of chemoradiation, and during surveillance using a droplet digital HPV ctDNA PCR assay targeting HPV E6 and E7 oncogenes for 13 oncogenic HPV types. Median recurrence-free survival (RFS) according to HPV ctDNA status was estimated via Kaplan-Meier and compared using a log-rank test.

Results: Detection of HPV ctDNA at ≥3 months after chemoradiation was associated with recurrence (80% versus 2%; odds ratio 168, 95% CI 13.6-2080; p<.0001) and inferior RFS (4.9 months versus not reached (NR); hazard ratio (HR) 39.2, 95% CI 4.6-330; p<.0001) relative to HPV ctDNA-negative status. Sensitivity and specificity for recurrence according to HPV ctDNA detection were 89% and 95%, respectively, with positive and negative predictive values of 80% and 98%, respectively. Differences in RFS according to HPV ctDNA status were not observed at the end of treatment (median RFS NR for both; HR 1.6, 95% CI .35-7.4; p=.48).

Conclusions: With a novel, highly sensitive assay, detection of HPV ctDNA at least 3 months after chemoradiation was associated with unfavorable survival. Future clinical trials should incorporate this 3-month post-treatment time point to identify patients with HPV-positive anal cancer at elevated recurrence risk according to HPV ctDNA status.

Purpose: Receptor CUB-domain containing- protein 1 (CDCP1) was evaluated as a target for detection and treatment of breast cancer.

Experimental design: CDCP1 expression was assessed immunohistochemically in tumors from 423 patients (119 triple-negative breast cancer (TNBC); 75 HER2+; 229 ER+/HER2- including 228 primary tumors, 229 lymph node and 47 distant metastases). Cell cytotoxicity induced in vitro by a CDCP1-targeting antibody-drug conjugate (ADC), consisting of the human/mouse chimeric antibody ch10D7 and the microtubule disruptor monomethyl auristatin E (MMAE), was quantified, including in combination with HER2-targeting ADC T-DM1. Detection of CDCP1-expressing primary and metastatic xenografts in mice was examined by PET-CT imaging using 89zirconium-labelled ch10D7 (89Zr-ch10D7). The impact of ch10D7-MMAE on tumor burden and survival in vivo, including in combination with T-DM1, was quantified in cell line and patient-derived xenograft mouse models.

Results: CDCP1 is expressed predominantly on the surface of malignant cells of 70% of TNBCs, 80% of HER2+ tumors, and increases in ER+/HER2- tumors from 44.9% in primary tumors to 56.4% in lymph node metastases and 74.3% in distant metastases. PET-CT imaging with 89Zr-ch10D7 is effective for the detection of primary and metastatic CDCP1-expressing TNBCs in mice. ADC ch10D7-MMAE kills CDCP1-expressing cells in vitro and controls primary and metastatic TNBC xenografts in mice, conferring significant survival advantages over chemotherapy. It compares favorably to T-DM1 in vivo, and ch10D7-MMAE combined with T-DM1 showed the most potent efficacy, markedly reducing tumor burden of CDCP1+/HER2+ xenografts and prolonging mouse survival, compared with T-DM1 or ch10D7.

Conclusions: CDCP1-directed molecular imaging has potential to identify aggressive breast cancers for CDCP1-targeted treatment.

Background: Race/ethnicity may affect outcomes in metastatic breast cancer (MBC) due to biological and social determinants. We evaluated the impact of race/ethnicity on clinical, socioeconomic, and genomic characteristics, clinical trial participation, and receipt of genotype-matched therapy among patients with MBC.

Methods: A retrospective study of patients with MBC who underwent cell-free DNA testing (cfDNA, Guardant360â, 74 gene panel) between 11/2016 and 11/2020 was conducted. Receipt of genotype-matched therapy targeted at a cfDNA actionable mutation was determined. Pearson's chi-squared and Wilcoxon rank-sum tests were used to compare categorical and continuous variables between groups. Multivariable logistic regression was used to assess the association of race and receiving matched therapy.

Results: 425 patients with MBC and cfDNA results were identified (White: 369, Black: 27, Hispanic 15, and Asian 14). White patients traveled further for cancer care than other groups (p<0.001). White patients had the highest rates of commercial insurance, Black patients had the highest rates of state-supported insurance, and Asian patients had the highest uninsured rates (p<0.001). Clinical trial enrollment did not differ by race/ethnicity (p=0.34). The proportion of patients with ≥1 actionable mutation in cfDNA did not vary by race/ethnicity (p=0.18). The highest rates of matched therapy were observed in White patients (p<0.001). After multivariable logistic regression adjusting for subtype, commercial vs. other insurance, Charlson comorbidity index, and distance to center, White patients remained more likely to receive matched therapy (p=0.024).

Conclusions: Racial/ethnic minority patients were less likely to receive matched therapy. Further research is needed to identify barriers to precision medicine.

Background: We evaluated the non-cyclic dinucleotide stimulator of interferon genes agonist MK-2118 ± pembrolizumab in patients with advanced solid tumors or lymphomas.

Methods: This first-in-human study (NCT03249792) enrolled patients with refractory, advanced solid tumors or lymphomas. Patients received intratumoral (IT) MK-2118 100-20,000 µg (arm 1), IT MK-2118 900-15,000 µg plus intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W; arm 2), or subcutaneous (SC) MK-2118 5000-150,000 µg plus IV pembrolizumab 200 mg Q3W (arm 4); arm 3 (visceral injection of MK-2118) was not pursued. IT dosing used an accelerated titration design and modified toxicity probability interval method; SC dosing (arm 4) was started subsequent to arms 1 and 2. Primary objectives were safety/tolerability. MK-2118 pharmacokinetics were a secondary endpoint; objective responses and biomarkers were exploratory endpoints.

Results: 140 patients were enrolled (arm 1, n=27; arm 2, n=57; arm 4, n=56). Grade 3/4 treatment-related adverse events occurred in 22%, 23%, and 11% of patients, respectively, but no maximum tolerated dose was identified up to MK-2118 20,000, 15,000, and 150,000 µg across the 3 arms. Dose-dependent increases in MK-2118 systemic exposure were observed following IT and SC administration. Objective responses were seen in 0%, 6%, and 4% of patients, respectively. IT MK-2118 led to dose-dependent changes in STING-based blood RNA expression levels, interferon-gamma, interferon-gamma‒induced protein 10, and interleukin-6; SC MK-2118 did not generate dose-related immune responses.

Conclusion: IT MK-2118 ± pembrolizumab and SC MK-2118 plus pembrolizumab had manageable toxicity and limited antitumor activity. IT but not SC administration demonstrated systemic immune effects.

Purpose: Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on natural killer (NK) cells/macrophages and EGFR on tumor cells, redirecting antitumor activity towards tumors. The safety and tolerability of AFM24 was evaluated in this Phase 1/2a dose escalation/dose expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR.

Methods: The main objective in Phase 1 was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the observation period. Secondary endpoints included the incidence of treatment emergent adverse events and pharmacokinetics.

Results: In the dose escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14-720 mg). One patient experienced a DLT of Grade 3 infusion-related reaction (IRR). IRRs were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics were dose-proportional and CD16A receptor occupancy on NK cells approached saturation between 320-480 mg. Paired tumor biopsies demonstrated activation of innate and adaptive immune responses within the tumor. Best objective response was stable disease in 10/35 patients; four had stable disease for 4.3-7.1 months.

Conclusions: AFM24 was well tolerated with 480 mg established as the RP2D. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.