Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).

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DR recruited patients and collected the data. SL did the data analysis. All authors contributed to data interpretation, as well as critical review, revision, and approval of the report. Data sharingQualified researchers can request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and statistical analysis plan) that support the methods and findings reported in this report. Individual anonymised participant data will be made available once the indication has been approved by a regulatory body, if there is legal authority to share the data and there is not a reasonable likelihood of participant re-identification. Requests should be submitted on the Regeneron website.

SUMMARY Background ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALKi) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALKi than crizotinib in vitro, crosses the blood-brain barrier in vivo and shows clinical responses in crizotinib-resistant disease. Here, we assessed whole-body and intracranial activity of ceritinib in both ALK-pretreated and ALKi-naïve patients with ALK-rearranged NSCLC. Methods The primary objective (to determine the maximum tolerated dose of ceritinib) of this first-in-human, phase I, open-label ASCEND-1 trial has been reported previously. In the analysis reported here, antitumour efficacy of ceritinib was evaluated in all patients with ALK-rearranged NSCLC (n=246) treated with ceritinib at the recommended dose of 750 mg/day. Additionally, as patients with untreated or locally treated neurologically stable brain metastases at baseline were permitted in this study, intracranial efficacy was retrospectively confirmed by independent neuroradiologists for 94 patients with baseline brain metastases and at least one post-baseline MRI/CT tumour assessment. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516. Findings Median follow-up at the time of this report was 11 1 months (interquartile range 6·7–15·2). Patients were mainly heavily pretreated (105/246 [42·7%] at least three prior regimens). The overall response rate was 72·3% (60/83; 95% confidence interval [CI] 61·4–81·6) for ALKi-naïve (n=83) and 56·4% (92/163; 95% CI 48·5–64·2) for ALKi-pretreated (n=163) patients. Median progression-free survival in ALKi-naïve and ALKi-pretreated patients was 18·4 (95% CI 11·1-non-estimable) and 6·9 (95% CI 5·6–8·7) months, respectively. Brain metastases by investigator assessment were reported at study entry in 124 patients. Of these, 94 (n=19 ALKi-naïve and n=75 ALKi-pretreated) were included in the retrospective analysis; intracranial disease control rate was 78·9% (15/19; 95% CI 54·4– 93·9) in ALKi-naïve patients and 65·3% (49/75; 95% CI 53·5–76·0) in ALKi-pretreated patients. Of the 94 patients included in the retrospective analysis, 11 had measurable brain lesions and no prior radiotherapy to the brain: 6 of these achieved a partial intracranial response. Safety was evaluated for all 246 patients with ALK-rearranged NSCLC. Serious adverse events were recorded for 117 (47·6%) patients. The most common grade 3/4 laboratory abnormalities were increased alanine aminotransferase and increased aspartate aminotransferase, occurring in 73 (29·7%) and 25 (10·2%) patients, respectively. The most common grade 3/4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6.1%) patients. Two on-treatment deaths in the study were considered to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of mult...