Onkologie 31. Jänner 2017
Emerging treatments in ALK-positive NSCLC: new options, but also new challenges
Treatment with the ALK tyrosine kinase inhibitor (TKI) crizotinib has been established as a standard first-line option in patients with ALK-rearranged advanced NSCLC. Before the advent of crizotinib, a platinum–pemetrexed doublet followed by pemetrexed maintenance was standard of care in non-squamous NSCLC. However, after an initial response to crizotinib, acquired resistance invariably develops due to multiple mechanisms, which can include secondary mutations in the ALK tyrosine kinase domain.
First-line ceritinib: ASCEND-4
Ceritinib demonstrated robust anti-tumour activity in crizotinib-naïve and crizotinib-refractory patients with ALK-positive advanced NSCLC in the single-arm phase I and II ASCEND trials (ASCEND-1–3) and in a randomised phase III study (ASCEND-5). The randomised, global, open-label, ASCEND-4 phase III study that was presented in the Presidential Symposium at the WCLC compared first-line ceritinib 750 mg/day with platinum and pemetrexed chemotherapy, followed by pemetrexed maintenance, in untreated patients . PFS by blinded independent radiological review was the primary endpoint. A total of 376 patients were enrolled in the study, with 189 randomised to ceritinib and 187 to chemotherapy. Approximately one third in each arm had brain metastases. Prior brain radiotherapy had been administered in 40 % of these patients.
Figure: Primary endpoint in ASCEND-4: PFS advantage with ceritinib over chemotherapy
According to patient-reported outcomes, the lung cancer symptom scores were significantly improved versus chemotherapy, and the time to definitive deterioration of lung-cancer-specific symptoms was prolonged. The safety profile of ceritinib was consistent with previous studies, with diarrhoea, nausea and liver enzyme elevations as the most common AEs. Management included dose adjustments or dose nterruptions/ delays, as well as concomitant medication.
J-ALEX: superiority of alectinib over crizotinib
In addition to ceritinib, alectinib is a standard option in the setting of progression on crizotinib treatment. The Japanese J-ALEX trial enrolled 207 patients who had received at most one prior line of chemotherapy. They were randomised to either first-line alectinib 300 mg BID (i.e., standard alectinib dose in Japan) or crizotinib 250 mg BID . Patients with treated or asymptomatic brain metastases were also included.
Updated analysis on CNS results obtained with alectinib
These data are supported by a pooled analysis of two phase II trials. The pivotal NP28761 and NP28673 studies investigated alectinib 600 mg BID after progression on crizotinib treatment. NP28761 was conducted in North America and NP28673 globally. The results demonstrated high response rates and durable responses [3, 4]. A pooled analysis of these two trials performed with the data cut-off on 27 April, 2015, yielded a CNS ORR of 64.0 % and a duration of CNS response of 10.8 months in patients with measurable CNS disease at baseline .
Brigatinib & lorlatinib
Likewise, the investigational next-generation ALK inhibitors brigatinib and lorlatinib have been shown to have pronounced activities, particularly in the CNS. An update from the pivotal randomised ALTA phase II trial that evaluated brigatinib at two doses (90 mg and 180 mg OD) in crizotinib-refractory patients demonstrated substantial efficacy and an acceptable safety profile in both arms . At brigatinib 180 mg, ORR was 54 % according to the Independent Review Committee, and OS probability at 1 year was 82 %. Median PFS obtained with 180 mg surpassed PFS in the 90 mg arm considerably (15.6 vs. 9.2 months, respectively; HR, 0.58). When treated with brigatinib 180 mg, patients with measurable brain metastases experienced an intracranial ORR of 67 %.
Treatment selection – the current perspective
The growing armamentarium in the field of ALK-targeted agents raises several questions with respect to patient selection and selection of ALK TKIs. “The observation that many crizotinib-resistant tumours remain ALK-dependent over time provides the rationale for sequential therapy,” noted Benjamin Solomon, MBBD, PhD, Peter MacCallum Cancer Centre, Melbourne, Australia . Retrospective analyses have suggested survival benefits with sequential ALK inhibitor therapies in ALK-positive NSCLC patients [11, 12].
1 De Castro G et al., First-line ceritinib versus chemotherapy in patients with ALK-rearranged (ALK+) NSCLC: a randomized, phase 3 study (ASCEND-4). WCLC 2016, PL03.07
© 2017 Springer-Verlag GmbH, Impressum