Sequential treatment with alectinib in crizotinib-resistant non-small-cell lung cancer.

Dear Editor,

Alectinib is a highly selective, potent inhibitor of anaplastic lymphoma kinase (ALK). Phase 2 data suggest that alectinib elicits response in 46% with crizotinib-resistant disease,[1] making it a better alternative to chemotherapy. We describe a case of crizotinib-resistant ALK + non-small-cell lung cancer (NSCLC) and our experience with alectinib as third-line tyrosine kinase inhibitor (TKI) therapy.

A 47 year-old female was evaluated for cough in September 2014. Supraclavicular node biopsy confirmed lung cancer of adenosquamous histology and ALK was amplified on fluorescence in situ hybridization. Positron emission tomography–computed tomography (CT) and magnetic resonance imaging brain showed right-lobe lung lesion, nodal metastasis, and brain metastasis. She was started on crizotinib in October 2014. She had clinical and radiological response sustained until December 2015. Serial CT scan done thereafter showed gradual radiological progression at single disease site. Crizotinib was continued as she remained asymptomatic. In July 2016, ceritinib was started in view of a significant increase in radiological burden of disease.. There was clinical and radiological progression of disease within 2 months of therapy. She began chemotherapy with pemetrexed–carboplatin.

In June 2017, she had new-onset pleural effusion. Alectinib 300 mg twice daily was started as third-line TKI. There was clinical benefit with no reported toxicity on subsequent follow-up. By RECIST criteria, she had partial response at 2 months which was sustained until December 2017. She presented after 6 months of therapy with alectinib with worsening cough and breathlessness. CECET scan confirmed radiological progression [Figures 1–3]. Interestingly, she was never symptomatic for CNS disease despite failure of crizotinib and alectinib. She is presently planned for lorlatinib.

Figure 1

Contrast-enhanced computed tomography thorax: June 2017: before starting alectinib

Figure 3

Contrast-enhanced computed tomography thorax: December 2017 – after 6 months of therapy with alectinib: multiple new lesions and new-onset pleural effusion

Contrast-enhanced computed tomography thorax: August 2017 – after 2 months of treatment with alectinib: complete resolution of pleural effusion

This case highlights the utility of second-generation TKI in ALK-positive NSCLC, especially in crizotinib refractory NSCLC. She tolerated crizotinib with sustained clinical benefit of 14 months. Ceritinib, her subsequent line of therapy, failed to control disease with progression within 2 months of initiation. With this background, alectinib has shown remarkable active in controlling an innately resistant disease for more than 6 months with no reported toxicity. Acquired mutations in ALK gene and P-glycoprotein overexpression have been reported mechanisms of crizotinib and certinib resistance which are overcome by alectinib. As our patient was unwilling for repeat biopsy, we were unable to identify resistant pathways which may help us choose from third-generation TKI.[2] Two single-arm phase 2 studies (Shaw et al. and Ou et al.)[13] evaluating alectinib in crizotinib-resistant disease showed PFS of 8.1 and 8.9 months and duration of response of 13·5 and 11.2 months, respectively. However, our patient had a PFS of only 6 months with alectinib.

In conclusion, sequential ALK suppression despite progression on TKI is the key to managing patients with ALK + NSCLC. Despite a shorter PFS than reported in literature, our patient had response to alectinib after two prior lines of ALK inhibitors. Future research should be directed at identifying mechanisms of resistance to ALK inhibitors which can help us choose the most appropriate TKI for our patients.

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Conflicts of interest

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