Resistance

Although ceritinib overcomes crizotinib resistance, patients eventually develop resistance to ceritinib as well. The median duration of response in the ASCEND-5 trial was 6.9 months (95% CI, 5.4-8.9 months) in the ceritinib arm compared with 8.3 months (95% CI, 3.5-not estimable) in the chemotherapy arm. Dr Shaw noted that across trials of patients with crizotinib-resistant disease, the median duration of response ranged from 6.9 to 10 months.

Second- and third-generation ALK inhibitors, including alectinib and brigatinib, are in development and have demonstrated efficacy after crizotinib failure in early phase clinical trials, but have not been evaluated after ceritinib failure. Another ALK inhibitor, ensartinib, is also being evaluated in this setting.

Conclusions

According to Dr Shaw, “This study definitively established ceritinib, and in general, next-generation ALK inhibitors, as the standard and preferred treatment for crizotinib-resistant patients.”

She also noted that trials of first-line alectinib showed greater efficacy and tolerability compared with crizotinib. Taken together with the studies of ceritinib, “the new standard of care for newly diagnosed, ALK-positive NSCLC patients should be a second-generation ALK inhibitor.”

Ongoing research aims to determine treatment options for those patients who fail first-line therapy with ceritinib or alectinib. “The NCI ALK Master Protocol is currently under development and will focus on the use of tumor and liquid biopsies in ALK-positive patients failing a next-generation inhibitor in order to match them to appropriate targeted treatments,” Dr Shaw said.

References

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  2. Maione P, Sacco PC, Sgambato A, Casaluce F, Rossi A, Gridelli C. Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application. Ther Adv Med Oncol. 2015;7:263-73. doi: 10.1177/1758834015595048
  3. Shaw AT, Kim TM, Crino 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. 2017 Jul;18(7):874-86. doi: 10.1016/S1470-2045(17)30339-X