A patient with ALK-positive lung adenocarcinoma who survived alectinib-refractory postoperative recurrence for 4 years by switching to ceritinib.

Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements are found in ~ 5% of patients with non-small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so-called ALK-positive NSCLC. In cases of tumor progression during treatment with second-generation ALK-TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third-generation ALK-TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second-generation ALK-TKIs. Here, we present a rare case of a 53-year-old Japanese woman, who had never smoked, with ALK-positive lung adenocarcinoma who survived alectinib-resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum-doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4-ALK rearrangement. Therefore, the patient started to take ALK-TKIs. Alectinib was the second ALK-TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second-generation ALK-TKI, switching to another second-generation ALK-TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK-TKI is best for each patient.

Matsumura Y ，Inomata S ，Yamaguchi H ，Mine H ，Takagi H ，Watanabe M ，Ozaki Y ，Yamaura T ，Fukuhara M ，Muto S ，Okabe N ，Hasegawa T ，Shio Y ，Suzuki H ... -  《-》

ALTA-2: Phase II study of brigatinib in patients with ALK-positive, advanced non-small-cell lung cancer who progressed on alectinib or ceritinib.

Kim ES ，Barlesi F ，Mok T ，Ahn MJ ，Shen J ，Zhang P ，Ou SI ... -  《-》

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Ge FJ ，Dai XY ，Qiu Y ，Liu XN ，Zeng CM ，Xu XY ，Chen YD ，Zhu H ，He QJ ，Gai RH ，Ma SL ，Chen XQ ，Yang B ... -  《-》

Clinical Efficacy of Alectinib in Patients with ALK-Rearranged Non-small Cell Lung Cancer After Ceritinib Failure.

Several second-generation inhibitors of anaplastic lymphoma kinase (ALK) have demonstrated potent activity in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Two of these agents, ceritinib, and alectinib, recently received approval for the treatment of ALK-rearranged NSCLC in Japan. The efficacy of treatment with a second-generation ALK inhibitor after failure with a different second-generation ALK inhibitor remains unclear. We present a series of eight patients with ALK-rearranged NSCLC treated with alectinib who experienced disease progression after ceritinib. Both crizotinib and ceritinib were administered to six patients, with four (29%) patients receiving crizotinib followed by ceritinib. Among the eight study patients, two (25%) had partial response, one (12%) stable disease, and five (63%) had progressive disease. The median progression-free survival was 3.6 months (95% confidence interval=0-7.1 months). The results of this study suggest that the second-generation ALK inhibitor alectinib has limited efficacy after initial treatment with the second-generation ALK inhibitor ceritinib.

Oya Y ，Yoshida T ，Kuroda H ，Shimizu J ，Horio Y ，Sakao Y ，Hida T ，Yatabe Y ... -  《-》

Efficacy of Ceritinib After Alectinib for ALK-positive Non-small Cell Lung Cancer.

Alectinib is a new standard treatment for treatment-naïve anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC); however, resistance ultimately develops in almost all patients, and data regarding the efficiency of ceritinib for such patients are insufficient. Patients with ALK-positive NSCLC treated at the Kyoto University Hospital from January 2012 to March 2017 were reviewed. Patients who were treated with ceritinib after alectinib were identified, and the efficacy of ceritinib after alectinib was retrospectively evaluated. There were 35 patients with ALK-positive NSCLC, nine of whom received ceritinib after alectinib. The overall response rate to ceritinib was 44%. It was 16% in patients who received ceritinib immediately after alectinib, and 100% in patients who received chemotherapy before ceritinib. The median progression-free survival for patients treated with ceritinib was 4.4 months (95% confidence interval(CI)=1.1-6.5 months). Ceritinib demonstrated a modest clinical benefit after failure of alectinib. Ceritinib may be a reasonable treatment option in this setting.

Yoshida H ，Kim YH ，Ozasa H ，Sakamori Y ，Tsuji T ，Nomizo T ，Yasuda Y ，Yamamoto T ，Ajimizu H ，Hirai T ... -  《-》