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 presented from the phase II ASCEND-7 study at the ESMO Congress 2019 in Barcelona, Spain.
Ceritinib was active in patients regardless of prior treatment that included brain radiotherapy and prior ALK inhibitor therapy, radiotherapy alone, prior sole ALK inhibitor therapy, as well as in patients receiving neither previous radiotherapy or ALK inhibitor treatment.
Laura Q. Chow, Department of Oncology, Dell Medical School, University of Texas at Austin, Texas, USA explained that the phase II ASCEND-7 trial (NCT02336451) 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 to 5 studies.
ASCEND-7 enrolled patients with WHO performance status 0 to 2, ALK-positive NSCLC, confirmed by FISH, 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 pre-treated with chemotherapy and/or crizotinib were allowed.
Forty-two patients previously treated with brain radiotherapy and an ALK inhibitor were assigned to arm 1, 40 patients with prior ALK inhibitor only to arm 2, 12 patients with prior brain radiotherapy only to arm 3, and 44 patients not previously treated with brain radiotherapy or an ALK inhibitor were placed in arm 4.
The investigator-assessed whole body overall response rate (ORR), defined as complete response (CR) or partial response (PR) served as the primary endpoint and a key secondary endpoint was investigator-assessed disease control rate (DCR), defined as CR, PR or stable disease (SD). Intracranial responses were evaluated according to modified RECIST v1.1 and extracranial responses by RECIST v1.1.
High rates of whole body response observed across all four arms
As of 6 February 2019, all 138 patients 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) across arms 1 through 4, respectively.
As for the secondary endpoint, 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 CR or PR was observed in 15, 12, 6, and 26 patients, respectively. The duration of response (DoR) in these patients was 10.8 (95% CI, 4.1, not estimable [NE]), 12.8 (95% CI, 3.7, 17.3), NE (95% CI, 11.7, NE), and 9.2 months (95% CI, 7.3, 23.9), respectively. In the respective arms, the estimated 6-month event-free probability (EFP) was 64.6% (95% CI, 34.7, 83.5), 74.1% (95% CI, 39.1, 90.9), 100% (95% CI, 100, 100), and 72.7% (95% CI, 51.1, 86.0).
Median whole body progression-free survival (PFS) was 7.2 (95% CI, 3.3, 10.9), 5.6 (95 % CI, 3.6, 9.2), NE (95% CI, 1.0, NE), and 7.9 months (95% CI, 5.5, 9.4). The estimated 6-month EFP for PFS was 58.7% (95% CI, 41.6, 72.4), 44.7% (95% CI, 28.5, 59.5), 66.7% (95% CI, 33.7, 86.0), and 63.4% (95% CI, 46.8, 76.1), respectively. Median overall survival across the respective arms was 24.0 months (95% CI, 12.6, NE), NE (95% CI, 16.2, NE), NE (95% CI, 1.0, NE), and NE (95% CI, 26.5, NE), and the 12-month EFP was 67.4% (95% CI, 50.4, 79.6), 72.9% (95% CI, 55.5, 84.5), 75.0% (95% CI, 40.8, 91.2), and 77.9% (95% CI, 61.8, 87.9), respectively.
Evaluation of the intracranial response showed the majority of patients achieving at least disease control
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% (95% CI, 21.5, 59.4), 27.6% (95% CI, 12.7, 47.2), 28.6% (95% CI, 3.7, 71.0), and 51.5% (95% CI, 33.5, 69.2) and intracranial DCRs of 75.0% (95% CI, 55.1, 89.3), 82.8% (95% CI, 64.2, 94.2), 85.7% (95% CI, 42.1, 99.6), and 75.8% (95% CI, 57.7, 88.9), respectively.
In the 11, 8, 2, and 17 patients included in the DoR analysis, the DoR was 9.2 (95% CI, 3.7, NE), 10.1 (95% CI, 3.8, 17.3), NE, and 7.5 months (95% CI, 5.6, 11.2), respectively.
Patients in arms 1 through 4 also demonstrated extracranial responses following treatment: ORR 31.0% (95% CI, 17.6, 47.1), 42.5% (95% CI, 27.0, 59.1), 41.7% (95% CI, 15.2, 72.3), and 61.4% (95% CI, 45.5, 75.6). The DCRs were 69.0% (95% CI, 52.9, 82.4), 92.5% (95% CI, 79.6, 98.4), 66.7% (95% CI, 34.9, 90.1), and 72.7% (95% CI, 57.2, 85.0), respectively.
The most common all grade adverse events (AEs) occurring in more than 50% of patients across arms 1 to 4 regardless of causality were diarrhoea, nausea, ALT increased, vomiting, AST increased, decreased appetite; most of these AEs were grades 1 or 2.
Conclusions
According to the authors, the efficacy of ceritinib in patients with and without prior exposure to crizotinib, as reported in other studies, was confirmed in this study that enrolled only patients with active brain metastases. They pointed out that the safety profile of ceritinib in these patients was consistent to that reported earlier.
Disclosure
This study was funded by Novartis Pharmaceuticals Corporation.
Reference
1478O - Chow LQ, Barlesi F, Bertino EM, et al. Results of the ASCEND-7 phase II study evaluating ALK inhibitor (ALKi) ceritinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) metastatic to the brain.