Purpose This phase I study assessed the safety, tolerability, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Patients and Methods Pyrotinib was administered continuously, orally, once per day to patients who did not have prior exposure to tyrosine kinase inhibitors of HER2. Planned dose escalation was 80, 160, 240, 320, 400, and 480 mg. For pharmacokinetic analysis, timed blood samples were collected on day 1 and day 28. Next-generation sequencing was performed on circulating tumor DNA and genomic DNA from tumor samples. Results Thirty-eight patients were enrolled. The dose-limiting toxicity was grade 3 diarrhea, which occurred in two patients administered 480 mg of pyrotinib; thus, the maximum tolerated dose was 400 mg. Common pyrotinib-related adverse events included diarrhea (44.7% [17 of 38]), nausea (13.2% [five of 38]), oral ulceration (13.2% [five of 38]), asthenia (10.5% [four of 38]), and leukopenia (10.5% [four of 38]). The only grade 3 adverse event was diarrhea. Pharmacokinetic analyses indicated that pyrotinib exposure was dose dependent. The overall response rate was 50.0% (18 of 36), and the clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) was 61.1% (22 of 36). The median progression-free survival was 35.4 weeks (95% CI, 23.3 to 40.0 weeks). The overall response rate was 83.3% (10 of 12) in trastuzumab-naive patients and 33.3% (eight of 24) in trastuzumab-pretreated patients. Preliminary results suggest that PIK3CA and TP53 mutations in circulating tumor DNA ( P = .013) rather than in archival tumor tissues ( P = .474) may predict the efficacy of pyrotinib. Conclusion Continuous once-per-day pyrotinib was well tolerated and demonstrated promising antitumor activity in HER2-positive patients with metastatic breast cancer. The maximum tolerated dose was established as 400 mg. Diarrhea was the dose-limiting toxicity. The promising antitumor activity and acceptable tolerability of pyrotinib warrant its further evaluation in a phase II study.

The current management of advanced esophageal squamous cell carcinoma (ESCC) remains unsatisfactory. We investigated the safety, efficacy, and biomarkers of SHR-1210, an anti-PD-1 antibody, in patients with recurrent or metastatic ESCC. This study was part of a phase I trial in China. Patients with advanced ESCC who were refractory or intolerant to previous chemotherapy were enrolled. Eligible patients received intravenous SHR-1210 at a dose of 60 mg, with escalation to 200 and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between candidate biomarkers (PD-L1 and somatic mutation load) and the efficacy of SHR-1210 were also explored. Between May 11, 2016, and December 9, 2016, a total of 30 patients from one site in China were enrolled. Ten patients (33.3%) had an independently assessed objective response. Median progression-free survival was 3.6 months (95% CI, 0-7.2). Three (10.0%) treatment-related grade 3 adverse events were reported: two (6.7%) pneumonitis and one (3.3%) increased cardiac troponin I. No grade 4 or grade 5 treatment-related adverse events were reported. The exome sequencing and analysis showed that the mutational burden and the potential mutation-associated neoantigen count were associated with better responses. An objective response was more common in patients with PD-L1-positive tumors as defined by ≥5% staining (7 of 15 patients) than in those with PD-L1-negative tumors (1 of 9 patients). In this population of ESCC patients, SHR-1210 had a manageable safety profile and promising antitumor activity. .

Our results demonstrated a promising antitumour activity and a manageable safety profile of SHR-1210, displayed an explicit PK evidence of the feasibility of fixed dose, and established the foundation for further exploration.

Purpose: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2positive metastatic breast cancer (MBC).Patients and Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m 2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers.Results: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17 (60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose-limited toxicity was observed. Grade 3 treatment-related adverse events (AE) occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. The overall response rate (ORR) was 78.6% [95% confidence interval (CI): 59.0%-91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%-96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0-26.2 months). ORR was 70.6% (12/17) in trastuzumabpretreated patients and 90.9% (10/11) in trastuzumab-na€ ve patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared with none or one genetic alteration (median, 16.8 vs. 29.9 months, P ¼ 0.006).Conclusions: In a population largely na€ ve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC.

ObjectiveTo assess the association between PD-L1 expression and driver gene mutations in patients with non-small-cell lung cancer (NSCLC).MethodWe performed a meta-analysis of 26 studies (7541 patients) which were published from 2015 to 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated to describe the correlation. Subgroup analysis was performed based on population characteristics, types of PD-L1 antibodies and quality of individual studies.ResultsA lower frequency of PD-L1 positivity was observed in NSCLCs harboring EGFR mutation (OR: 0.64, 95% CI, 0.45–0.91, p = 0.014). A negative correlation was also found at 1% (OR: 0.35, 95% CI, 0.22–0.55, p = 0.000) and 50% (OR: 0.33, 95% CI, 0.14–0.81, p = 0.015) cutoff for PD-L1 positive, elderly age group (OR: 0.56, 95% CI, 0.35–0.89, p = 0.013), female dominant group (OR: 0.55, 95% CI, 0.29–0.94, p = 0.030) and smoker dominant group (OR: 0.52, 95% CI, 0.29–0.96, p = 0.035). No significant differences in PD-L1 expression were observed among patients with different ALK, BRAF, HER2, PIK3CA status and MET expression level. Higher level of PD-L1 was found in tumors with KRAS mutation (OR: 1.45, 95% CI, 1.18–1.80, p = 0.001). PD-L1 expression level was not significantly different between triple (EGFR/ALK/KRAS) wild type NSCLCs and those with EGFR/ALK/KRAS mutation.ConclusionsPD-L1 expression in EGFR mutated NSCLCs were lower than those in EGFR wild type NSCLCs, while tumors with KRAS mutation showed higher levels of PD-L1.