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.

BACKGROUND:The clinical response to anti-programmed cell death 1 (PD-1) antibodies in patients with advanced gastric and gastroesophageal junction (GEJ) cancer in China has not been reported. METHODS: This study evaluated the efficacy and safety of SHR-1210, an anti-PD-1 antibody, in patients with advanced gastric/GEJ cancer in a phase 1 trial. The associations between candidate biomarkers (programmed death ligand 1 [PD-L1] expression, mismatch repair status, tumor mutation load, and lactate dehydrogenase [LDH] levels) and the efficacy of SHR-1210 were also explored. RESULTS: Thirty patients with recurrent or metastatic gastric/ GEJ adenocarcinoma who were refractory or intolerant to previous chemotherapy were enrolled between June 2, 2016, and June 8, 2017. Seven patients (23.3%) demonstrated objective responses, including 1 complete response. The objective response rates for patients with PD-L1-positive and PD-L1-negative tumors were 23.1% (3 of 13) and 26.7% (4 of 15), respectively (P = 1.000). Two treatment-related grade 3 or higher adverse events were reported: one was grade 3 pruritus, and the other (3.3%) was grade 5 interstitial lung disease. All 20 patients tested for the mismatch repair status had mismatch repair-proficient tumors, and the response rate was 30.0% (95% confidence interval, 11.9%-54.3%). Patients with a higher mutation load (4 of 10) tended to have better responses than those with fewer mutations (2 of 10), but the difference was not significant (P = .628). Patients with a >10% relative increase from the baseline LDH level were more likely to experience disease progression (90% [9 of 10]) than patients with a ≤10% change (40% [8 of 20]; P = .017). CONCLUSIONS: Anti-PD-1 antibody SHR-1210 shows encouraging efficacy in patients with advanced gastric/GEJ cancer in China, including mismatch repair-proficient subgroups. Cancer 2019;125:742-749.

Rationale: Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor alpha (ER-α), human epidermal growth factor receptor 2 (HER2) and progesterone receptor (PR) expression, but the effect of lacking the three factors on TNBC is unclear. Whether loss of the three factors contributes to deregulate genes that participate in the progress of TNBC remains unknown. Methods: We performed microRNA arrays and comprehensive analysis to screen for miRNAs that are transcriptionally regulated by ER-α, HER2 and PR. Functional assays and molecular mechanism studies were used to investigate the role of miR-4306 in TNBC. An orthotopic mouse model of TNBC was used to evaluate the therapeutic potential of a cholesterol-conjugated miR-4306 mimic. Results: We found that miR-4306 is transcriptionally regulated by ER-α, HER2 and PR, and the downregulation of miR-4306 in TNBC is caused by the loss of ER-α, HER2 and PR. Clinically, low miR-4306 expression is strongly associated with lymph node metastasis and poor survival for TNBC. Upregulation of miR-4306 greatly suppresses TNBC cell proliferation, migration and invasion and abrogates angiogenesis and lymphangiogenesis in vitro . According to in vivo models, miR-4306 overexpression considerably inhibits TNBC growth, lung metastasis, angiogenesis and lymph node metastasis. Mechanistic analyses indicate that miR-4306 directly targets SIX1/Cdc42/VEGFA to inactivate the signaling pathways mediated by SIX1/Cdc42/VEGFA. Finally, the orthotopic mouse model of TNBC reveals that miR-4306 mimic can be used for TNBC treatment in combination with cisplatin. Conclusions: Our findings suggest that miR-4306 acts as a tumor suppressor in TNBC and is a potential therapeutic target for TNBC treatment.

Background A small proportion of patients with advanced esophageal squamous cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors; however, reliable peripheral blood biomarkers for outcomes of anti‐PD‐1 immunotherapy in ESCC have not been identified. Methods The data of 43 patients in the ESCC cohort of a phase I trial at our center were retrospectively reviewed. All patients were administered intravenous camrelizumab (SHR‐1210), a novel anti‐PD‐1 antibody, at doses of 60 mg, 200 mg, or 400 mg (4‐week interval after first dose followed by a 2‐week schedule) until disease progression or intolerable toxicity. Associations between lactate dehydrogenase (LDH) and other peripheral blood biomarkers at baseline and the efficacy of camrelizumab were also investigated. Results After median follow‐up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression‐free and overall survival rates were 2.0 and 8.0 months, respectively. Patients with an elevated baseline LDH had lower tumor response rates ( P = 0.02) and shorter progression‐free ( P = 0.002) and overall ( P < 0.0001) survival than patients with normal LDH levels. An increase in LDH levels during treatment was significantly associated with disease progression. Multivariate Cox analysis identified LDH (hazard ratio [HR] 0.18), CRP (HR 0.27), the number of organs involved (HR 0.31), absolute monocyte count (HR 0.33), and Eastern Cooperative Oncology Group performance status (HR 0.36) as independent prognostic factors. Conclusions Serum LDH, which is readily available in routine clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients treated with anti‐PD‐1 therapy.