Second-Line Ceritinib Best For ALK-rearranged NSCLC After Crizotinib

Second-line anaplastic lymphoma kinase inhibitor therapy offers better progression-free survival than docetaxel or pemetrexed for patients who progress after crizotinib therapy

medwireNews: ASCEND-5 trial findings indicate that progression-free survival (PFS) is longer in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) who are given a second ALK inhibitor after crizotinib failure than those given chemotherapy.

“The results presented here show that patients derive significant clinical benefit from more potent ALK inhibition after failure of crizotinib, and establish ceritinib as a more efficacious treatment option than chemotherapy in this patient population”, say Alice Shaw, from Massachusetts General Hospital in Boston, USA, and co-workers.

After a median of 16.5 months, PFS judged by a masked independent review committee (IRC) was a median of 5.4 months for the 115 patients who were assigned to receive open-label ceritinib 750 mg/day fasted in 21-day cycles. This compared with 1.6 months for the 116 patients assigned to receive an investigator’s choice of docetaxel or pemetrexed, giving a significant hazard ratio of 0.49 in favour of the ALK inhibitor.

And pre-planned interim PFS analysis indicated that the benefit for ceritinib was “consistent across patient subgroups”, including age, gender, race, smoking status, and the presence or absence of brain metastases, the authors report in The Lancet Oncology.

The overall response rate by IRC was 39.1% for the ceritinib group versus 6.9% for the chemotherapy patients, while disease control was achieved in a corresponding 76.5% and 36.2% of patients.

“Responses in both groups were rapid and durable”, the authors say, lasting a median of 6.9 and 8.3 months, respectively. Median time to deterioration of WHO performance status was 14.2 months with ceritinib versus 7.8 months with chemotherapy.

Investigator-assessed overall survival was a comparable 18.1 versus 20.1 months.

Treatment-related serious adverse events affected 11% of both trial arms. Patients given ceritinib had higher rates than those given chemotherapy of grade 3–4 elevations of alanine aminotransferase (21 vs 1%), gamma glutamyltransferase (21 vs 1%) and aspartate aminotransferase (14 vs 1%).

“Although GI [gastrointestinal] toxicity and transaminitis were common with ceritinib at the starting dose, these adverse events were usually manageable”, Alice Shaw et al write, explaining that the GI symptoms were more common than with chemotherapy but were “predominantly grade 1–2” and treated with supportive care and dose modification.

Specifically, one or more dose reductions were required by 61% of the patients given ceritinib, 18% of the pemetrexed-treated patients and 26% of those using docetaxel. Adverse events resulted in treatment discontinuation in a comparable 5% and 7% of the ceritinib and combined chemotherapy groups, respectively.

Of the two deaths occurring in the ceritinib arm that were not a result of disease progression, neither were considered to be treatment-related.

Reference

Shaw AT, Kim TM, Crinò L, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol; Advance online publication 8 June 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30339-X

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