Canadian perspectives: update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancer.

Barbara Melosky ,J Agulnik,W Morzycki,G Liu,Mustapha Tehfé ,Diana N Ionescu ,Randeep Sangha ,D Gwyn Bebb ,Mark Vincent ,Parneet Cheema ,Normand Blais ,Roula Albadine ,Ronald L Burkes ,Rosalyn A Juergens ,Ming‐Sound Tsao ,Zia Poonja ,Zhaolin Xu ,Charles Butts ,Alicia Chan ,Vera Hirsh ,Paul B Card

doi:10.3747/co.25.4379

Abstract

Inhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update. Clinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive nsclc. Randomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows:■ Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALK rearrangement.■ Treatment-naïve patients with ALK-positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially.■ Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially.■ Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially.■ Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy.■ Other systemic therapies should be exhausted before immunotherapy is considered. Multiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALK rearrangement.

Highlights

Lung cancer is the most common cause of cancer-related death in Canada (26%), with an estimated 28,600 new cases diagnosed in 20171
Improved responses in brain metastases were observed for all second- and /third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib
■■ Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALK rearrangement. ■■ Treatment-naïve patients with ALK-positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially. ■■ Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially. ■■ Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially. ■■ Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy. ■■ Other systemic therapies should be exhausted before immunotherapy is considered

Summary

Introduction

Lung cancer is the most common cause of cancer-related death in Canada (26%), with an estimated 28,600 new cases diagnosed in 20171. Results Randomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. To assess crizotinib in the first line, the pivotal phase iii profile 1014 trial randomized 343 treatment-naïve patients with advanced ALK-positive nonsquamous nsclc to receive either crizotinib or platinum–pemetrexed chemotherapy without pemetrexed maintenance[17].

Results

Conclusion