Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase−Positive Non–Small Cell Lung Cancer

Abstract

an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC).OBJECTIVE To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor. DESIGN, SETTING, AND PARTICIPANTS This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC. INTERVENTIONS Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily. MAIN OUTCOMES AND MEASURESThe primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC.RESULTS A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P < .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P < .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC.

Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study

“…Indeed, the median PFS with first-line treatment using second-generation ALK inhibitors including alectinib exceeds 2 years. 2 , 3 , 4 Whereas four patients (36%) in this study discontinued bevacizumab early due to treatment-related AEs, seven patients (63.6%) overall discontinued bevacizumab early due to either treatment-related AEs, per investigator discretion, or per patient preference, after a median of 9 cycles of bevacizumab (range, 4-48). Long-term addition of an agent that must be administered i.v.…”

“… 1 Several randomized phase II trials have since demonstrated, however, that more potent and central nervous system (CNS)-active second-generation ALK TKIs (alectinib, brigatinib, and ensartinib) are superior to crizotinib in the first-line setting. 2 , 3 , 4 Alectinib in particular has been commonly used on the basis of the phase III global ALEX trial, which demonstrated significantly prolonged progression-free survival (PFS) compared with crizotinib with a median PFS of 25.7 months versus 10.4 months (by independent review committee assessment). 2 Despite this efficacy, drug resistance develops, and disease progression is inevitable in most patients.…”

Current Insights on the Treatment of Anaplastic Lymphoma Kinase-Positive Metastatic Non-Small Cell Lung Cancer: Focus on Brigatinib

“…Recently, also ensartinib, a novel second-generation ALK inhibitor, was demonstrated to be an effective option in the first-line setting, showing significant longer PFS (25.8 months vs 12.7 months, HR, 0.51, p < 0.001) and a higher rate of intracranial response (63.6% vs 21.1%) than crizotinib in phase III eXalt3 study. 42 However, the optimal treatment sequence of ALK inhibitors remains a matter to debate.…”

Management of Oligoprogression in Patients with Metastatic NSCLC Harboring ALK Rearrangements

“…However, as is well known, new generation ALK TKI selection and sequencing is still challenging because of the absence of head-to-head comparisons. In fact, second and third generation ALK TKIs, with an approximately 50% reduction in the risk of progression or death compared with crizotinib and with an impressive intracranial activity, overcame a first-line crizotinib approach (Table 3) [4,28,35,40,41,46,48].…”

“…In the absence of direct comparative trials, selection requires a comprehensive evaluation of drug systemic activity, CNS efficacy, drug interaction, safety and tolerability. Each ALK inhibitor has, indeed, its own unique side-effect profile with potential specific toxicities: diarrhea, nausea, and emesis with ceritinib; constipation and myalgias with alectinib; early-onset pneumonitis with brigatinib; rash, transaminase elevation, pruritus and nausea with ensartinib, altered lipid levels, cognitive and mood effects with lorlatinib [4,28,35,40,41,46,48].…”