Patients with ALK-positive non–small cell lung cancer (NSCLC) that was metastatic to the brain at baseline demonstrated whole-body, intracranial, and extracranial responses following treatment with ceritinib, according to findings from the phase II ASCEND-7 study presented by Chow et al at the European Society for Medical Oncology (ESMO) 2019 Congress (Abstract 1478O). Ceritinib was active in patients regardless of prior treatment that included brain radiotherapy and prior ALK inhibitor therapy, radiotherapy alone, or prior sole ALK inhibitor therapy, and was also active in patients receiving neither previous radiotherapy or ALK inhibitor treatment.

Laura Q. Chow, MD, FRCPC

Laura Q. Chow, MD, FRCPC, of Dell Medical School at The University of Texas at Austin, explained that the phase II trial was designed specifically to study the intracranial effects of ceritinib based upon the intracranial responses previously reported in patients with ALK-positive NSCLC with measurable baseline brain lesions participating in the ASCEND-1–4 studies.

Methods

ASCEND-7 enrolled patients with World Health Organization performance status 0 to 2 ALK-positive NSCLC confirmed by fluorescence in situ hybridization with newly diagnosed or progressive brain metastases. Patients were further required to have one or more extracranial measurable lesion according to RECIST v1.1. Patients pretreated with chemotherapy and/or crizotinib were allowed.

Forty-two patients previously treated with brain radiotherapy and an ALK inhibitor were assigned to arm 1 of the trial; 40 patients with prior ALK inhibitor only were assigned to arm 2; 12 patients with prior brain radiotherapy only were assigned to arm 3; and 44 patients not previously treated with brain radiotherapy or an ALK inhibitor were assigned to arm 4. 

The trial’s primary endpoint was investigator-assessed whole-body overall response rate (ORR), defined as complete response or partial response. A key secondary endpoint was investigator-assessed disease control rate (DCR), defined as complete response, partial response, or stable disease. Intracranial responses were evaluated according to modified RECIST v1.1 and extracranial responses by RECIST v1.1.

Findings

As of February 2019, all 138 patients in the trial had discontinued treatment.

The whole-body ORR was 35.7% (95% confidence interval [CI] = 21.6–52.0), 30.0% (95% CI = 16.6–46.5), 50.0% (95% CI = 21.1–78.9), and 59.1% (95% CI = 43.2–73.7) in arms 1, 2, 3, and 4, respectively.

The whole-body DCR was 66.7% (95% CI = 50.5–80.4), 82.5% (95% CI = 67.2–92.7), 66.7% (95% CI = 34.9–90.1), and 70.5% (95% CI = 54.8–83.2), respectively. In arms 1 through 4, whole-body response of either complete or partial response was observed in 15, 12, 6, and 26 patients, respectively. The duration of response in these patients was 10.8 (95% CI = 4.1–not estimable), 12.8 (95% CI = 3.7–17.3), not estimable (95% CI = 11.7–not estimable), and 9.2 months (95% CI = 7.3–23.9), respectively.

Median whole-body progression-free survival (PFS) was 7.2 (95% CI = 3.3–10.9), 5.6 (95 % CI = 3.6–9.2), not estimable (95% CI = 1.0–not estimable), and 7.9 months (95% CI = 5.5–9.4). Median overall survival across the respective arms was 24.0 months (95% CI = 12.6–not estimable), not estimable (95% CI = 16.2–not estimable), not estimable (95% CI = 1.0–not estimable), and not estimable (95% CI = 26.5–not estimable), in arms 1, 2, 3, and 4, respectively.

Evaluation of the intracranial response was done in 28, 29, 7, and 33 patients in the respective arms having measurable brain metastases at baseline and showed intracranial ORRs of 39.3%, 27.6%, 28.6%, and 51.5% in arms 1, 2, 3, and 4, and intracranial DCRs of 75.0%, 82.8%, 85.7%, and 75.8%, respectively. 

Patients in arms 1 through 4 also demonstrated extracranial responses following treatment: ORRs of 31.0%, 42.5%, 41.7%, and 61.4%, respectively. The extracranial DCRs were 69.0%, 92.5%, 66.7%, and 72.7%, respectively.

The most common all-grade adverse events occurring in more than 50% of patients across arms 1 to 4, regardless of causality, were: diarrhea, nausea, increased ALT, vomiting, increased AST, and decreased appetite. Most of these adverse events were grades 1 or 2.

The authors concluded, “Efficacy of ceritinib, either in patients with or without a prior exposure to crizotinib, as reported in other studies, is confirmed in this study where only patients with active brain metastases were eligible. Safety profile of ceritinib in these patients remain[s] consistent to what was reported earlier.”

Disclosure: ASCEND-7 was funded by Novartis. For full disclosures of the study authors, visit esmo.org.