Interviews

Intracranial Effects of Ceritinib in ALK-Positive NSCLC

lcIn an interview with Oncology Learning Network, Laura Q. M. Chow, MD, FRCPC, Professor and Associate Chair of Education, Department of Oncology, Dell Medical School, The University of Texas at Austin, discussed the background, findings, and clinical significance of the ASCEND-7 trial, which examined the intracranial effects of ceritinib in patients with ALK-positive nonsmall-cell lung cancer (NSCLC) and measurable baseline brain lesions.

What existing data led you and your co-investigators to conduct this research?

Crizotinib had demonstrated efficacy in patients with ALK-positive lung cancer, but many patients would have disease progress in the brain or in the primary site due to lack of activity, loss of activity, and resistance from decreased concentration or activity in the brain.

Early studies with ceritinib and other later-generation ALK inhibitors had demonstrated intracranial activity and reduction in lesions metastatic to the brain, but there was limited formal evaluation of the activity in the brain and no dedicated trial or trial design to evaluate this for targeted agents.

In both the ASCEND-4 and ASCEND-5 phase 3 studies, intracranial response evaluated by neuroradiologists was relatively similar to the extracranial response rate. Along with the efficacy results, preclinical data which suggested that ceritinib could have sufficient brain penetration provided the rationale to investigate ceritinib using a controlled study design as done in the ASCEND-7 study.

Even though other studies have reported intracranial brain activity, the ASCEND-7 study design is much cleaner as it included brain MRIs for all patients and only patients with active brain metastasis were included, which may not be the case with the other studies where inclusion criteria may not have been as strict.

Describe your study and its findings. Were any of the outcomes particularly surprising?

This is the first documented and designed study looking specifically at the brain activity and concentrations and penetration of a targeted agent in NSCLC. We found that there was indeed good activity, durable responses, and improvements in progression-free survival (PFS) in the disease in the brain and also the systemic extracranial disease in those who had progressed with prior crizotinib therapy, as well as in patients who were crizotinib-naïve.

There was activity and preliminary interesting activity in patients with leptomeningeal disease in the exploratory arm 5.

The ASCEND-7 study was designed to evaluate the efficacy and safety of oral ceritinib only in patients with ALK-positive NSCLC and active brain metastases. Across whole-body end points (overall response rate [ORR], time to tumor response [TTR], duration of response [DOR], and PFS), ceritinib activity was consistent with its known efficacy established in patients with ALK-positive NSCLC with or without brain metastases, crizotinib-pretreated or not.1-4

Ceritinib achieved fast, high, and durable intracranial response across all study arms. In many patients, responses were usually evident by 2 months of therapy. Patients who were naïve to a previous ALK inhibitor had higher intracranial response, and the intracranial disease control rate was high across all arms.

Compared with other second-generation ALK inhibitors, ceritinib achieved a similarly high intracranial disease control rate.

The ASCEND-7 study looks specifically at brain metastasis, and although responses have been reported with other second-generation ALK inhibitors, the eligibility criteria were not homogenous across studies.5-7

Furthermore, the safety profile in this population is consistent with the reported profile of ceritinib; no new or unexpected safety concerns were observed in this study. Adverse events were manageable and in line with the known toxicity profile with hepatic and gastrointestinal events

What are the possible real-world applications of these findings in clinical practice?

If we want to better understand the activity in the brain, we look to patients with measurable brain metastases. In these patients, the ORR was quite high and also closer to values observed in the extracranial domain.

In patients who had received prior ALK inhibitors, the ORR was 39.3% in arm 1 and 27.6 in arm 2; among patients who did not receive prior ALK inhibitors, the ORRs were 51.5% in arm 4 and 28.6% in arm 3 (which also had lower accrual).

Looking at patients with measurable and non-measurable brain metastasis, the ORR was 26.2% among those who had received prior radiotherapy and ALK inhibitors, and was about 20% in patients who had only received prior ALK inhibitors. Among patients who did not receive prior ALK inhibitors, arm 3 had low accrual and arm 4 had a response rate of 40.9%

Overall, the disease control rate with ceritinib across the board was quite high, ranging from 71.4% in arm 1 to 85% in arm 2; the extracranial ORR was relatively higher in patients who had received no prior ALK inhibitors.

The disease control rate intracranially was high across all arms. It is also important to note that in most cases, response was seen within 2 months and is similar to what is seen intracranially. Furthermore, paired CSF and plasma sampling showed that ceritinib penetrated the blood-brain barrier.

Overall, this was the first trial to formally study the activity of a targeted agent in the brain, and ceritinib was found to be active and led to responses in the brain and disease control rates in and outside of the brain.

Based on these data confirming the activity and penetration of ceritinib through the blood-brain barrier into the brain to elicit responses and improve disease control rates and progression-free survival, ceritinib would be ideally an excellent choice for use in patients in ALK-positive NSCLC as first-line therapy or preferential therapy in those who have brain metastases.

In fact, the European guidelines have now indicated that patients with brain metastases with ALK-positive NSCLC, provided they are asymptomatic and small, should likely consider targeted therapy up-front and assess responses to targeted therapy before pursuing radiation therapy upfront for brain metastases.

There were dose reductions and dose interruptions due to the gastrointestinal toxicities when patients were treated with ceritinib at 750 mg once daily. The dose adjustments and interruptions were in line with the rest of the ASCEND studies with a ceritinib 750 mg fasted dose. However, there are data that the 450-mg fed state dose is equivalent and much better tolerated and is an approved alternative dose.

From the pre-clinical data and ASCEND 8 study, it has been established from a pharmacokinetic perspective that the 450-mg fed state is equivalent to the 750-mg fasted dose and should have similar activity in the brain with much better tolerability and fewer gastrointestinal side effects.

Do you and your co-investigators intend to expand upon this research?

This study established the basis and the design for formally assessing the intracranial activity for all targeted therapies in NSCLC. This important study and its design will be essential for all future studies to assess the activity and formal intracranial activity of targeted agents in NSCLC.

There are plans to use this design to assess other targeted therapies and their effects on the central nervous system and brain.

References

1. Hida T, Satouchi M, Nakagawa K, et al. Ceritinib in patients with advanced, crizotinib-treated, anaplastic lymphoma kinase-rearranged NSCLC: Japanese subset. Jpn J Clin Oncol. 2017;47(7):618-624.

2. Costa DB, Shaw AT, Ou SH, et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol. 2015;33(17):1881-1888.

3. Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917-929.

4. Kiura K, Imamura F, Kagamu H, et al. Phase 3 study of ceritinib vs chemotherapy in ALK-rearranged NSCLC patients previously treated with chemotherapy and crizotinib (ASCEND-5): Japanese subset. Jpn J Clin Oncol. 2018;48(4):367-375.

5. Gadgeel SM, Shaw AT, Govindan R, et al. Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34(34):4079-4085.

6. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379(21):2027-2039.

7. Zhang Z, Guo H, Lu Y, Hao W, Han L. Anaplastic lymphoma kinase inhibitors in non-small cell lung cancer patients with brain metastases: a meta-analysis. J Thorac Dis. 2019;11(4):1397-1409.

Stay in the know.
OncNet Newsletter