First-line lorlatinib trumps crizotinib for advanced ALK+ lung cancer

The novel third-generation ALK* inhibitor lorlatinib outdid the first-generation inhibitor crizotinib as treatment for previously untreated advanced ALK+ non-small-cell lung cancer (NSCLC), according to the interim results of the CROWN trial.

“[In our study, participants] who received lorlatinib had significantly longer progression-free survival (PFS), a higher frequency of objective response (OR) and intracranial response (ICR), and better quality of life (QoL) than those who received crizotinib,” said the researchers.

“Although crizotinib was standard first-line therapy for advanced ALK+ NSCLC when CROWN was initiated in 2017, it has now been supplanted by more potent second-generation** ALK inhibitors,” they noted. However, the benefits of second-generation inhibitors are challenged by drug resistance and disease progression or recurrence. [Cancer Discov 2016;6:1118-1133; Clin Cancer Res 2014;20:5686-5696]

Lorlatinib maintains its potency against all known single ALK resistance mutations, has marked activity for tumours that progress despite use of other ALK inhibitors (first- or second-generation, or both), and has the potential to eliminate rare, pre-existing subclones that harbour ALK resistance mutations or prevent emergence of such resistant subclones among untreated individuals. [J Thorac Oncol 2019;14:1901-1911; Lancet Oncol 2018;19:1654-1667; J Clin Oncol 2019;37:1370-1379]

The study team saw 296 patients with locally advanced or metastatic ALK+ NSCLC who had not received previous systemic treatment. Participants were randomized 1:1 to receive either oral lorlatinib 100 mg daily or crizotinib 250 mg BID in 28-day cycles. [N Engl J Med 2020;383:2018-2029]

At 12 months, more lorlatinib vs crizotinib recipients were alive without disease progression (78 percent vs 39 percent; hazard ratio [HR] for disease progression or death, 0.28; p<0.001). “Although the length of follow-up does not allow determination of median PFS duration, [this] corresponds to a 72-percent lower risk of progression or death with lorlatinib vs crizotinib,” said the researchers.

Furthermore, more patients on lorlatinib vs crizotinib had an OR (76 percent vs 58 percent), with responses lasting at least 12 months in 70 percent of lorlatinib recipients, as opposed to only 27 percent of those on crizotinib.

Of those who had measurable CNS metastases at baseline (n=30), more patients on lorlatinib vs crizotinib had an ICR (82 percent vs 23 percent) and complete ICR (71 percent vs 8 percent).

At 12 months, cumulative incidence of CNS progression as first event was lower with lorlatinib vs crizotinib (3 percent vs 33 percent; HR, 0.06), with more patients alive without CNS*** progression in the former vs the latter arm (96 percent vs 60 percent; HR, 0.07). “[The lower rate of CNS progression] suggests that the prolonged PFS seen with lorlatinib may be due in part to the prevention of CNS metastases.”

“Lorlatinib was designed to cross the blood-brain barrier in order to achieve high exposures in the CNS,” they continued. “[Evidence shows that] lorlatinib had potent antitumour activity after failure of previous ALK inhibitors, [suggesting] that as first-line therapy, lorlatinib may be particularly effective in treating and preventing brain metastases.”

Grade 3/4 adverse event (AE) rate was higher with lorlatinib vs crizotinib (72 percent vs 56 percent), primarily due to elevated triglycerides, which is a recognized side effect of lorlatinib. “[Nonetheless, this is] usually asymptomatic and readily managed with lipid-lowering agents and dose modifications as needed,” they explained.

Any-grade cognitive (21 percent vs 6 percent) and mood effects (16 percent vs 5 percent) were also more frequent with lorlatinib vs crizotinib. However, these were largely low-grade and manageable through dose reduction and interruption. [Oncologist 2019;24:1103-1110; Adv Ther 2020;37:3019-3030] Weight gain was also more common with lorlatinib vs crizotinib (38 percent vs 13 percent), which the researchers attributed to increased appetite. “Both weight gain and cognitive and mood changes may be due to off-target inhibition of tropomyosin receptor kinase B in the CNS.”

Though not clinically significant, lorlatinib recipients reported greater overall improvement in global QoL compared with those on crizotinib (estimated mean difference, 4.65).

“Because of its efficacy and safety, lorlatinib is a standard treatment option for ALK+ patients in whom one or more ALK inhibitors have failed,” they added. The current findings support previous data and underpin the potential of lorlatinib in this patient setting.