Lung immune prognostic index is associated with clinical outcomes in recurrent or metastatic (R/M) nasopharyngeal carcinoma receiving immunotherapy: Results from the multicenter, single-arm, phase 2 study.

BACKGROUND: Immune-related biomarkers are linked to the outcomes of cancer immunotherapy. This study evaluates the baseline and longitudinal association between the lung immune prognostic index (LIPI) and immune checkpoint inhibitor outcomes in previously treated recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC) patients. METHODS: Data from 153 R/M NPC patients (median age = 49.00 years old) enrolled in a multicenter, single-arm, phase 2 study (NCT03848286) were analyzed. Pretreatment LIPI was classified into good and intermediate/poor (inter/poor) groups. Longitudinal LIPI variations were categorized into "Stable good", "Trend to increase", "Trend to decrease", and "Stable inter/poor". Primary and secondary outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). RESULTS: Pretreatment LIPI was significantly associated with OS (inter/poor vs. good: HR = 2.54, 95 % CI: 1.60-4.04, P < 0.001), PFS [inter/poor vs. good: hazard ratio (HR) = 2.18, 95 % CI: 1.47-3.23, P < 0.001], and DCR [inter/poor vs. good: odd ratio (OR) = 0.26, 95 % CI: 0.12-0.58, P < 0.001)]. Patients with persistently inter/poor LIPI status showed worse OS (HR = 3.25, 95 % CI: 1.84-5.74, P < 0.001), PFS (HR = 2.96, 95 % CI: 1.85-4.74, P < 0.001), and ORR (OR = 0.21, 95 % CI: 0.08-0.56, P < 0.001) compared to the persistently good subgroup. CONCLUSION: Pretreatment LIPI and its longitudinal variations may serve as potential biomarkers for predicting immune checkpoint inhibitor outcomes in R/M NPC patients.

Re-Evaluating PIN1 as a Therapeutic Target in Oncology Using Neutral Inhibitors and PROTACs.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) has emerged as a promising therapeutic target for cancer treatment. However, the current PIN1 inhibitors have shown limited efficacy in animal models, leaving the question of whether PIN1 is a proper oncologic target still unanswered. By screening a 1 trillion DNA-encoded library (DEL), we identified novel nonacidic compounds. Among resynthesized DEL compounds, DEL1067-56-469 (A0) is the most potent one (KD = 430 nM, IC50 = 420 nM). Further optimization of A0 resulted in compound C10 with much improved potency (KD = 25 nM, IC50 = 150 nM). As an alternative approach, C10 was then converted into proteolysis targeting chimeras (PROTACs) in order to achieve deeper downregulation of the PIN1 protein in cancer cell lines. Unfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated meaningful antiproliferation activity. In addition, siRNA knock-down experiments provided unfavorable evidence of PIN1 as an oncologic target. Our findings highlight the complexity of targeting PIN1 for cancer therapy.

Phase I study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours.

In this phase I study, the safety, pharmacokinetics, and antitumour activity of the HER2-targeted antibody-drug conjugate A166 were evaluated in patients with HER2-expressing advanced solid tumours. Patients with advanced solid tumours refractory to standard therapies received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8 or 6.0 mg/kg Q3W in a standard "3 + 3" design. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. Primary endpoints were assessment of the safety and tolerability of A166 and identification of the maximum tolerated dose or recommended phase II dose. In total, 81 patients were enroled and received A166 (n = 1 for 0.1 mg/kg; n = 3 for each of 0.3, 0.6, 1.2, 2.4 and 3.6 mg/kg doses; n = 27 for 4.8 mg/kg; n = 38 for 6.0 mg/kg). No dose-limiting toxicity or drug-related deaths occurred. The most common treatment-related adverse events at grade 3 or higher were corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), and peripheral sensory neuropathy (6.2%). The Cmax and area under the curve of Duo-5, its free payload, were approximately 0.1% and 0.2% of those of the ADC, respectively. For all assessable HER2-positive breast cancer patients enroled in the 4.8 mg/kg and 6.0 mg/kg cohorts, the corresponding ORRs were 73.9% (17/23) and 68.6% (24/35), respectively, and the median PFS was 12.3 and 9.4 months, respectively. A166 has a recommended phase II dose of 4.8 mg/kg Q3W, manageable toxicity, good stability in the circulation and promising antitumour activities in HER2-positive breast cancer patients.

Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study.

Background: KL-A167 is a fully humanized monoclonal antibody targeting programmed cell death-ligand 1. This phase 2 study aimed to evaluate the efficacy and safety of KL-A167 in Chinese patients with previously treated recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Methods: This was a multicentre, single-arm, phase 2 study of KL-A167 in R/M NPC (KL167-2-05-CTP) (NCT03848286), conducted at 42 hospitals across the People's Republic of China. Eligible patients had histologically confirmed non-keratinising R/M NPC, and had failed at least two lines of chemotherapy. Patients received KL-A167 900mg intravenously once every 2 weeks until confirmed disease progression, intolerable toxicity, or withdrawal of informed consent. The primary endpoint was objective response rate (ORR) assessed by the independent review committee (IRC) according to RECIST v1.1. Findings: Between Feb 26th, 2019 and Jan 13th, 2021, 153 patients were treated. Totally, 132 patients entered full analysis set (FAS) and were evaluated for the efficacy. As of data cutoff date on Jul 13th, 2021, the median follow-up time was 21.7 months (95%CI 19.8-22.5). For FAS population, the IRC-assessed ORR was 26.5% (95%CI 19.2-34.9%), and disease control rate (DCR) was 56.8% (95%CI 47.9-65.4%). Median progression-free survival (PFS) was 2.8 months (95%CI 1.5-4.1) . Median duration of response was 12.4 months (95%CI 6.8-16.5), and median overall survival (OS) was 16.2 months (95%CI 13.4-21.3). When using the cutoff of 1000 copies/ml, 5000 copies/ml and 10,000 copies/ml for plasma EBV DNA titer, baseline low plasma EBV DNA was consistently related with better DCR, PFS and OS. Dynamic change of plasma EBV DNA was significantly associated with ORR and PFS. Among 153 patients, treatment related-adverse events (TRAEs) occurred in 73.2% of patients, and grade ≥3 TRAEs were in 15.0% of patients. No TRAE leading to death was reported. Conclusion: In this study, KL-A167 showed promising efficacy and an acceptable safety profile in patients with previously treated R/M NPC. Baseline plasma EBV DNA copy number might be a potentially useful prognostic biomarker for KL-A167 treatment, and post-treatment EBV DNA decrease might be correlated with better response to KL-A167. Funding: Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd., China National Major Project for New Drug Innovation (2017ZX09304015).