Onkologie 14. November 2016
Next-generation ALK inhibitors excel after crizotinib failure
ALK fusion-gene–positive lung cancer occurs in approximately 5 % of patients with advanced NSCLC . The ALK inhibitor crizotinib demonstrates significant initial efficacy in patients with ALK-positive advanced NSCLC.
Ceritinib is a next-generation ALK inhibitor with 20-fold greater potency than crizotinib . Anti-tumour effects of ceritinib in pre-treated patients were demonstrated in the ASCEND-1 and ASCEND-2 trials [3–5]. In ASCEND-2, ceritinib treatment promoted durable responses in an ALK-positive NSCLC population that had progressed on chemotherapy and crizotinib, including patients with brain metastases .
Ample benefits with ceritinib treatment
This ALK inhibitor therapy proved highly efficient, promoting statistically significant and clinically meaningful improvement in PFS according to the blinded independent review committee (BIRC; 5.4 vs. 1.6 months; HR, 0.49; p < 0.001). This effect was robust and consistent across a number of subgroups. Clinical benefit was further supported by ORR (39.1 % vs. 6.9 %) and DCR (76.5 % vs. 36.2 %). OS data were immature at the data cut-off. The safety profile matched the observations in prior ceritinib studies, which featured primarily diarrhoea, nausea, vomiting, and transaminase elevation.
Long-term follow-up of ASCEND-3: remarkable findings
Felip et al. presented the long-term follow-up of the global, phase II, single-arm, open-label ASCEND-3 study, which assessed ceritinib in 124 patients with metastatic ALK-positive NSCLC who had received no prior ALK inhibitor treatment . They were either chemotherapy-naïve (although only two patients) or had been treated with up to three lines of chemotherapy and had experienced progression during or after the last chemotherapy regimen. Asymptomatic or neurologically stable brain metastases at baseline were allowed. Forty percent of patients had brain lesions at study entry; local radiotherapy had been applied in 53.1 %. The primary endpoint was ORR according to the investigator.
After a median follow-up of 25.9 months, 48.4 % of patients remained on treatment. With regard to whole-body efficacy, the analysis yielded robust ORR findings of 67.7 % according to the investigator, and 63.7 % according to the BIRC (Table). Decreases in tumour burden from baseline occurred in 94.7 % of patients. Disease control was obtained in 90.3 % and 86.3 % according to the investigator and the BIRC, respectively. The study revealed remarkable results with regard to median PFS (16.6 and 18.4 months according to the investigator and the BIRC, respectively) and OS: at 24 months, 67.5 % of the patients were alive, and median OS had not been reached yet. Ceritinib also showed activity in patients with brain metastases. Those with CNS lesions at baseline achieved a whole-body ORR of 57.1 % and a median PFS of 10.8 months. Overall intracranial responses were obtained in 61.5 %.
Updated patient-reported outcomes at a follow-up of up to 29 cycles were consistent with those previously reported. The patients showed improvements in symptoms burden from baseline with a mean change in the overall Lung Cancer Symptom Scale score that ranged from -3.39 to -14.83. Quality of life was maintained on treatment.
Alectinib: update on pivotal data
The highly selective and potent oral ALK inhibitor alectinib has been approved by the FDA for the treatment of patients who have progressed on, or are intolerant to, crizotinib. Two pivotal phase II studies, the global NP28673 trial and the North American NP28761 trial, formed the basis of this approval [8–11]. They enrolled a total of 225 previously treated patients with locally advanced or metastatic ALK-positive NSCLC, who had progressed after prior crizotinib treatment. All patients received alectinib 600 mg orally twice daily.
An exploratory analysis assessed the time to response in both NP28673 and NP28761 . Determination of how rapidly patients can benefit from alectinib was rated as important for both symptomatic patients and patients at the point of developing symptoms, particularly within the CNS. In addition, rapidity of response is of relevance for those with active CNS disease, as an area of high unmet medical need. The findings showed that alectinib therapy can achieve a rapid response. Most patients in all populations showed a RECIST response by the first assessment (8 weeks in NP28673, and 6 weeks in NP28761). This also applied to time to CNS response in patients with measurable and/or non-measurable CNS disease at baseline, irrespective of prior radiotherapy. Further investigation into the early clinical benefit (<6 weeks) is warranted, to evaluate alectinib for initial treatment of CNS metastases, with the potential for sparing radiation therapy.
Substantial anti-tumour activity of brigatinib
An ongoing phase I/II, single-arm, multicenter dose-escalation, dose-expansion trial is evaluating the investigational next-generation ALK inhibitor brigatinib in patients with advanced malignancies, which includes 79 ALK-positive NSCLC patients. Ninety percent of them had received prior crizotinib therapy.
Figure: Overall survival obtained with brigatinib (ITT population)
1 Dearden S et al., Mutation incidence and coincidence in non small-cell lung cancer: metaanalyses by ethnicitiy and histology (mutMap).
© 2016 Springer-Verlag GmbH, Impressum
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