Puyuan Xing

Phase I Study and Biomarker Analysis of Pyrotinib, a Novel Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

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.

Clinical data from the real world: efficacy of Crizotinib in Chinese patients with advanced ALK-rearranged non-small cell lung cancer and brain metastases

Brain metastasis in non small cell lung cancer (NSCLC) patients is often considered as a terminal stage of advanced disease. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) for ALK-rearranged NSCLC patients. Herein, we conducted a retrospective study to explore how Crizotinib affects the control of brain metastases and the overall prognosis in advanced ALK-rearranged NSCLC patients with brain metastases in Chinese population. A total of 34 patients were enrolled, of whom 20 (58.8%) patients had baseline brain metastases before Crizotinib treatment. Among patients with brain metastases before Crizotinib, overall survival (OS) after brain metastases was significantly longer than that of patients with brain metastases after Crizotinib (median OS, not reached vs. 10.3 months, respectively, p = 0.001). There was also a significant difference in systemic progression-free survival (PFS) between patients developing brain metastases before and after Crizotinib treatment (21.2 months vs. 13.9 months, p = 0.003). In conclusion, ALK-rearranged NSCLC patients with brain metastases before Crizotinib may benefit more from Crizotinib than those developing brain metastases during Crizotinib treatment.

Comparison of gemcitabin, cisplatin, and dexamethasone (GDP), CHOP, and CHOPE in the first-line treatment of peripheral T-cell lymphomas

Objectives: Optimal chemotherapy regimen for peripheral T-cell lymphomas (PTCL) has not been fully defined. This study aimed to evaluate the optimal chemotherapy regimen in the first-line treatment for PTCL patients. Methods: Between 2003 and 2014, 93 consecutive patients with PTCL were enrolled in this study. Of 93 patients, 42 patients received CHOPE, 40 patients with CHOP, and 11 patients with GDP regimen. Results: Response could be evaluated in 88 of 93 patients at the end of primary treatment. The CR rate for patients received CHOP (n = 38), CHOPE (n = 39), and GDP (n = 11) were 28.9, 51.3, and 45.5%, respectively, (P = 0.132) with an ORR of 65.8, 76.9, and 90.9%, respectively, (P = 0.210). The median follow-up time was 17.1 (1.4–108.3) months. Median progression-free survival (PFS) in CHOP (n = 40), CHOPE (n = 42), and GDP (n = 11) groups were 6.0, 15.3, and 9.7 months (P = 0.094) with 1-year PFS of 35.0, 54.8, and 45.5%, respectively, (P = 0.078). One-year OS for patients received CHOP (n = 40), CHOPE (n = 42), and GDP (n = 11) were 65.0, 83.3, and 100%, respectively, (P = 0.013) (CHOP vs CHOPE, P = 0.030; CHOP vs GDP, P = 0.024; CHOPE vs GDP, P = 0.174). Conclusion: CHOPE has a trend to improve CR rate, 1-year PFS and OS compared with CHOP alone. GDP shows promising efficacy which worth further exploration in large cohort studies. Clinical experience presented in this study may serve as reference for future large cohort studies.

Response to crizotinib in advanced ALK-rearranged non-small cell lung cancers with different ALK-fusion variants

INTRODUCTION Anaplastic lymphoma kinase (ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. METHODS Among 96 ALK-rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants. RESULTS The median Progression-free survival (PFS) of the 96 ALK-rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4-ALK variants and non EML4-ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4-ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4-ALK variants. CONCLUSIONS Our results indicate prolonged PFS in patients with EML4-ALK variant 2.

Real world study of regimen containing bevacizumab as first-line therapy in Chinese patients with advanced non-small cell lung cancer: Bevacizumab as first-line for NSCLC

Large scale randomized controlled trials have demonstrated that the use of bevacizumab in addition to chemotherapy in patients with advanced non‐small cell lung cancer (NSCLC) conveys significant survival benefits. We explored the clinical impact of a first‐line regimen containing bevacizumab (B+) versus a non‐bevacizumab regimen (non‐B) in advanced non‐squamous NSCLC (NS‐NSCLC) patients in a real world setting.

The role of weekly nanoparticle albumin bound paclitaxel monotherapy as second line or later treatment for advanced NSCLC in China

For patients with pretreated advanced non-small cell lung cancer (NSCLC), more effective treatments are unmet. We conducted a study to explore the optimal treatment schedule of nanoparticle albumin bound paclitaxel (Nab-PTX) as a second line or later treatment for advanced NSCLC patients in China. Ninety-eight patients, who had experienced failure of prior treatment and received Nab-PTX monotherapy (130 mg/m2) on days 1, 8 of a 21-day cycle were included. The median progression-free survival (PFS) and overall survival (OS) were 4.34 months (95% confidence interval [CI] 3.508 to 5.165 months) and 11.73 months (95% CI 9.211 to 14.247 months), respectively. The objective responses rate (ORR) and disease control rate (DCR) were 22.4% and 74.5%. Prior treatment with taxane and line of therapy did not influence the efficacy of Nab-PTX. The main grade 3 to 4 toxicities were neutropenia (25.5%) and leukopenia (12.4%). Furthermore, 24 cases offered samples to assess secreted protein acidic and rich in cysteine (SPARC) expression. No statistical difference was observed in treatment efficacy between SPARC expression-negative and positive. The findings suggest that weekly Nab-PTX monotherapy is effective and well tolerated for patients with pretreated advanced NSCLC, regardless of prior taxane exposure or line of therapy.

Evaluation of calculating carboplatin dosage in carboplatin-pemetrexed therapy as the first-line therapy for Chinese patients with advanced lung adenocarcinoma: AUC of carboplatin

This study aims to explore the application of actual carboplatin in carboplatin plus pemetrexed regimen as first‐line treatment for advanced lung adenocarcinoma, and to determine the recommended dose of carboplatin for Chinese populations.

Heterogeneity-based, multiple mechanisms in the resistance to osimertinib (AZD9291): A case report: Heterogeneity-induced resistance to osimertinib

Osimertinib is a novel, irreversible, mutant‐selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting EGFR mutations and the EGFR T790 mutation. Here, we report a woman with EGFR‐mutated lung adenocarcinoma who, after 23‐month treatment with gefitinib, developed the EGFR T790M mutation, which converted the T790M status from positive to negative before osimertinib treatment and developed MET amplification, leading to rapid progression on osimertinib in two months. Subsequent treatment with crizotinib and c‐Met inhibitor plus gefitinib also failed to improve the clinical outcome, suggesting the potential existence of another resistance mechanism. Our findings revealed the underlying multiple and heterogeneous mechanisms in resistance to osimertinib, suggesting combination strategies should be considered post‐osimertinib progression.

Real world study of the continuation of bevacizumab beyond disease progression after first-line treatment containing bevacizumab in Chinese patients with advanced non-small cell lung cancer: Continuation of bevacizumab in NSCLC

Bevacizumab (Bev) plus platinum‐based chemotherapy is a standard first‐line treatment option for advanced non‐squamous non‐small cell lung cancer (NS‐NSCLC). We evaluated the efficacy and safety of continuing Bev in Chinese patients with advanced NS‐NSCLC progression after first‐line treatment containing Bev in a real‐world setting.

Therapeutic cancer vaccine: phase I clinical tolerance study of Hu-rhEGF-rP64k/Mont in patients with newly diagnosed advanced non-small cell lung cancer

BackgroundHu-rhEGF-rP64k/Mont is a biotechnology product for the treatment of advanced non-small cell lung cancer (NSCLC). The vaccine induces a neutralizing antibody-mediated immune response, against the normal circulating self-protein antigen epidermal growth factor (EGF), which prevents its binding to and activation of the EGF receptor, inhibiting the transduction of the signals that drive cancer cell proliferation, survival and spread. This phase I study aimed to evaluate the safety and the immunological response of Hu-rhEGF-rP64k vaccine in NSCLC patients.ResultsThe Hu-rhEGF-rP64k/Mont vaccine showed to be safe and well tolerated, with dizziness, injection-site reactions and tremors being the most commonly reported adverse event. No severe adverse events or death were related to the vaccination. Immune monitoring demonstrated the generation of anti-EGF antibody titers and as a consequence the patients exhibited a decrease in the EGF concentration. In 80% of the vaccinated patients stable disease was achieved.ConclusionHu-rhEGF-rP64k/Mont elicited a valuable immune response, with good safety profile assuring further clinical development of the vaccine in this population to further confirm the potential benefits on survival.Trial registrationChinese Clinical Trial Registry, ChiCTR-OID-17014048, date 2017/12/20 (retrospectively registered); Chinese Food and Drug Administration, CFDA 2009 L02105, date 2009/04/03; China Drug Trial, CTR20131039.