Kiichiro Ninomiya

A suspected case of rocuronium–sugammadex complex-induced anaphylactic shock after cesarean section

An anaphylactic reaction during a cesarean section occurs rarely, and rocuronium is thought to be one of the common agents causing perioperative anaphylaxis. Here we report an anaphylactic shock after cesarean section that is suggested to be induced by the rocuronium–sugammadex complex. A 36-year-old primigravida underwent an elective cesarean section under general anesthesia due to placenta previa. While the operation was completed uneventfully, she developed anaphylactic shock following sugammadex administration. She was successfully managed with rapid treatments. Serum tryptase level was significantly elevated. Although sugammadex was first suspected to be the causative agent, the result of intradermal skin tests with sugammadex were negative. Surprisingly, a subsequent intradermal test with undiluted rocuronium caused the patient to fall into a state of shock. Furthermore, a later skin-prick test with pre-mixed rocuronium–sugammadex complex also revealed a strong positive reaction, and a test with only rocuronium showed negative. We finally concluded that the rocuronium–sugammadex complex is the causative agent in this case. To the best of our knowledge, this is the first report suggesting anaphylaxis caused by the rocuronium–sugammadex complex. This case highlights the importance of appropriate examinations to determinate the pathogenesis of anaphylaxis in order to establish risk reduction strategies.

Reappraisal of short-term low-volume hydration in cisplatin-based chemotherapy; hoping for it as a public domain

To the Editor: Although cisplatin-based chemotherapy is the standard care for advanced non-small-cell lung cancer (NSCLC) (1–3), nephrotoxicity is the most problematic adverse event. To avoid it, the classical longterm high-volume hydration (standard hydration; ≥4 l in half a day) has been indicated by the Japanese government. However, the hydration is substantially bothersome for both patients and medical staffs in terms of its administration, which complicates cisplatin use in the outpatient setting and potentially reduces patients’ quality of life. This method was clearly reflected by the clinical trial results and medical environment in the 1980s when cisplatin was approved. The development of serotonin antagonists and neurokinin-1-receptor antagonist in the subsequent quarter century has improved remarkably gastrointestinal toxicity induced by cisplatin, which could guarantee oral hydration. Nowadays, based on the western treatment guidelines including NCCN guidelines (4), the short-term low-volume hydration has become commonly used in daily clinical practices in Japan. At the same time, we have independently conducted a prospective trial, showing feasibility of short-term, low-volume hydration with 2.5-l intravenous and 1-l oral hydration within ∼4.5 h in cisplatin-based chemotherapy for advanced lung cancer (5) (Table 1). Indeed, there was no grade 2 or worse creatinine toxicity with the cumulative follow-up time for its assessment in the 46 patients of 4498 days. Any toxicity other than nephrotoxicity and efficacy, the secondary endpoints, was also acceptable (Table 2). Horinouchi et al. (6) reported almost identical safety and efficacy profiles (Table 1), with the only patient who had grade 2 elevation in creatinine (maximum value 1.7 mg/dl), had immediate improvement in creatinine levels and completed the planned cycles of chemotherapy.

A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non–Small Cell Lung Cancer

&NA; Trastuzumab emtansine (T‐DM1), an anti–erb‐b2 receptor tyrosine kinase 2 (HER2) antibody‐drug conjugate, has been shown to significantly improve survival in HER2‐positive breast cancer. We report a phase II trial of T‐DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years; male sex, 47%; performance status of 0 to 1, 80%; HER2 status IHC 3+, 33%; HER status IHC 2+/fluorescence in situ hybridization–positive, 20%; and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1–11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2–32.0). With a median follow‐up time of 9.2 months, the median progression‐free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment‐related deaths. T‐DM1 had a limited efficacy for HER2‐positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging; thus, additional molecular approaches are warranted.

Trastuzumab Emtansine in HER2+ Recurrent Metastatic Non–Small-Cell Lung Cancer: Study Protocol

Abstract The treatment outcome has been unsatisfactory for patients with non–small‐cell lung cancer (NSCLC) refractory to standard first‐line chemotherapy. Trastuzumab emtansine (T‐DM1), an anti‐HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T‐DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T‐DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T‐DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T‐DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T‐DM1 monotherapy is effective against HER2+ lung cancer.

Protocol Design for the Bench to Bed Trial in Alectinib-Refractory Non–Small-Cell Lung Cancer Patients Harboring the EML4-ALK Fusion Gene (ALRIGHT/OLCSG1405)

Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory non-small-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with non-small-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided α of 0.05, β of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK+ non-small-cell lung cancer even in the alectinib-refractory setting.

Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first‐line therapy for patients with EGFR‐mutated non–small‐cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression‐free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR‐TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR‐TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression‐free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial.

MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib

As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.

Clinical significance of repeat rebiopsy in detecting the EGFR T790M secondary mutation in patients with non-small cell lung cancer

Background Osimertinib is an essential drug to treat non-small-cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) T790M mutation, and rebiopsy is necessary to detect this mutation. However, the significance of repeat rebiopsy in NSCLC patients whose first rebiopsy was T790M-negative remains unclear. We used a retrospective cohort to clarify this issue. Methods We reviewed the medical records of patients with NSCLC harboring EGFR mutations who underwent EGFR tyrosine kinase inhibitor (TKI) treatment at Okayama University Hospital between January 2015 and January 2017. Results Of 102 patients with EGFR-mutant NSCLC, 55 underwent rebiopsy after acquired resistance to prior EGFR TKIs. Pre-existing activating EGFR mutations were found in all 55 rebiopsied samples. Of the 55 samples, 25 were T790M-positive (45%). Among the remaining 30 patients (T790M-negative on the first rebiopsy), 21 underwent additional rebiopsies following interval therapy. Of the 21 patients, 11 were T790M-positive on the second rebiopsy and 1 on the third. We also evaluated the efficacy of osimertinib in patients who needed a repeat rebiopsy to detect the T790M mutation. Osimertinib showed good activity with an objective response rate of 50%. Conclusions Repeat rebiopsy increases the ability to detect a secondary mutation (T790M) in EGFR.

Pembrolizumab for the first-line treatment of non-small cell lung cancer

ABSTRACT Introduction: Platinum-based chemotherapy had long played a role as standard therapy for the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors such as pembrolizumab, a monoclonal antibody that prevents programmed death protein 1 (PD-1) receptor, have brought a paradigm shift in this field. Areas covered: In this article, we review the relevant literatures and ongoing trials on the first-line treatment of pembrolizumab. Especially, in two pivotal phase III trials, KEYNOTE-024 and −189, both pembrolizumab monotherapy and combined pembrolizumab plus chemotherapy significantly prolonged overall survival (OS) compared to the existing platinum-based chemotherapy. Currently, multiple trials with combination therapy of pembrolizumab and other agents have been conducted, and further evidences are expected to be created. Expert opinion: Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway are essential drugs for advanced or recurrent NSCLC, among which pembrolizumab becomes one of the standards of care in the first-line of NSCLC. For further improvement in efficacy of pembrolizumab, it is necessary to clarify the identification of biomarkers exclusive to PD-L1 expression, predictive factors for patients who benefit most from the agent.

Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions

The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non‐small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2‐ROS1 and ABC‐20 harboring CD74‐ROS1, were used as cell line‐based resistance models. Crizotinib‐resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor‐receptor tyrosine kinase array and RNA sequence analysis by next‐generation sequencing. HCC78R cells showed upregulation of HB‐EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB‐EGF or EGF rendered HCC78 cells or ABC‐20 cells resistant to crizotinib. RNA sequence analysis by next‐generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR‐TKI or anti‐EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR‐TKI were more effective against HCC78R cells than monotherapy with an EGFR‐TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB‐EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR‐TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.