Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non–Small-Cell Lung Cancer

Abstract

Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)-assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion Alectinib showed good efficacy against CNS metastases, in addition to systemic activity, in crizotinib-refractory ALK-positive NSCLC.

How might treatment of ALK-positive non-small cell lung cancer change in the near future?

“…Alectinib is a very promising agent in this setting, since a preclinical study showed that it is not a substrate of P-glycoprotein (P-gp), a key efflux transporter that may impair drug penetration through the blood-brain barrier [18]. Consistently, a pooled analysis of crizotinib-pretreated patients with CNS metastases showed that alectinib provides a CNS-ORR of 64% in individuals with measurable CNS disease (n = 50) [19]. Importantly, other next-generation ALK-TKIs have shown a remarkable activity against CNS metastases, which is crucial in view of the fact that ALK-positive NSCLCs with CNS metastases usually experience a long survival, with median survival potentially exceeding 4 years [20].…”

Management of Brain Metastases from Solid Tumors

“…The disease control rate (DCR) was detected in 32 (64%) patients with measurable target brain lesions (PR = 22%) and in 37 (43%) patients without measurable target brain lesions (PR = 27%). In patients who underwent radiation therapy of BM (n = 95) before started alectinib therapy intracranial response rate (ICRR) was 35.8% versus 58.5% in patients (n = 41) who did not receive previously radiation therapy [39].…”

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

“…High RR and DCR were confirmed also stratifying patients according to previous radiotherapy. At the 2015 World Conference on Lung Cancer, a pooled analysis of CNS data from two phase II multicenter studies on patients previously treated with crizotinib (NP28761, NP28673) showed a complete RR of 22%, an ORR of 39% and a DCR of 85% in patients with CNS disease, irrespective of prior radiotherapy (111). The CNS response was sustained for a duration similar to the systemic response, suggesting that alectinib could provide an effective treatment for patients with ALK-positive NSCLC while actively targeting CNS metastases.…”