The case for publicly funding lorlatinib

Dear Editor, New Zealand Medical Journal,

The recent announcement that the third-generation epidermal growth factor receptor (EGFR) inhibitor, osimertinib, will be publicly funded in New Zealand is welcome news for patients and medical professionals alike.¹ By overcoming the EGFR T790M mutation in non-small cell lung cancer (NSCLC) that confers resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, survival times will be significantly increased.

The success of this third-generation EGFR inhibitor in clinical trials over earlier EGFR inhibitors erlotinib and gefitinib is impressive, with data from the FLAURA study indicating a hazard ratio (HR) for progression-free survival (PFS) of 0.45.² This, however, is eclipsed by the results for anaplastic lymphoma kinase (ALK) positive lung cancer patients treated by the third-generation ALK inhibitor lorlatinib. Although the Pharmac-funded second-generation ALK inhibitor alectinib has significantly improved median PFS compared with crizotinib, the first-generation ALK inhibitor, data from the CROWN study have shown the superiority of lorlatinib to both earlier drugs (Table 1).^3,4 Like alectinib, lorlatinib can overcome cancer mutations that afford resistance to crizotinib,⁵ and has superior efficacy in preventing and treating central nervous system (CNS) metastases.⁶

Lorlatinib both covers a greater range of ALK resistance mutations than alectinib and shows profound CNS penetration and efficacy against CNS metastases.⁵ In head-to-head trial, lorlatinib outperforms alectinib, but until recently there has not been a consensus on the use of lorlatinib as a first-line treatment for ALK-positive NSCLC.⁷ The main reason for this has been concerns with lorlatinib’s CNS effects.⁸ But dose reduction has been reported by oncologists to typically lead to amelioration or resolution of lorlatinib’s CNS effects, and now data from the CROWN trial have provided strong evidence that the superior efficacy of lorlatinib is retained in patients who have had a dose reduction.^9,10 This could improve confidence in a starting dose for lorlatinib below that of the current 100mg/day, and thereby moderate concerns with lorlatinib’s CNS toxicity. Given that liver toxicity occurs in a significant number of alectinib-treated patients, and that lorlatinib has been shown to be effective for a substantial number of patients with alectinib-resistant cancer, the case for adding lorlatinib to the publicly funded targeted treatments for lung cancer in New Zealand seems clear.

View Table 1.