First-Line Lorlatinib Improves Survival and Metastasis in Advanced ALK-Positive Lung Cancer

Early treatment with the anaplastic lymphoma kinase (ALK)-inhibitor lorlatinib reduced cancer progression and death in patients with ALK-positive non-small-cell lung cancer (NSCLC), according to a study published in the New England Journal of Medicine.

Around 5% of NSCLC cases are ALK-positive. These cases tend to be particularly aggressive, with uncontrolled proliferation of cancer cells. ALK-positive patients are also at high risk for developing brain metastasis.

First and second generation ALK inhibitors have been in development since 2008, but patients still face high rates of relapse and metastatic spread. Lorlatinib is a third generation ALK-inhibitor that has been approved for ALK-positive patients whose cancer has progressed after taking older-generation inhibitors.

Researchers from Massachusetts General Hospital conducted a randomized, phase III trial comparing lorlatinib with crizotinib, the current standard of care, as a first-line treatment for metastatic disease. The study enrolled 296 patients with advanced ALK-positive NSCLC with no previous systemic treatment for metastasis. Patients were randomized 1:1 to either lorlatinib or crizotinib. The primary end point was progression-free survival (PFS) and secondary end points included objective response and intracranial response.

At 12 months, PFS for patients who received lorlatinib was 78% (95% confidence interval [CI], 70-84) compared with 39% (95% CI, 30-48) in the crizotinib group. An objective response was achieved in 76% (95% CI, 68-83) of the lorlatinib group and 58% (95% CI, 49-66) of the crizotinib group.

Among patients with measurable brain metastases, 82% (95% CI, 57-96) and 23% (95% CI, 5-54), respectively, had an intracranial response, and 71% of the patients treated with lorlatinib achieved an intracranial complete response.

Common adverse events (AE) with lorlatinib include hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events than crizotinib (72% vs. 56%). Discontinuation of treatment because of AEs occurred in 7% and 9% of patients, respectively.

“Among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels,” the researchers concluded.

#OncoAlert Available @NEJM, results from the phase III CROWN trial of lorlatinib versus crizotinib as first line treatment for #ALK NSCLC. Initially presented at virtual #ESMO20, lorlatinib had a significantly better PFS (HR 0.28) #LCSM https://t.co/wbTETjJ0ZE

— Stephen V Liu (@StephenVLiu) November 19, 2020

Just Out?at @NEJM ?
CROWN ? Study

interim analysis among patients w/previously untreated advanced #ALK ➕ #NSCLC #LungCancer

✅lorlatinib had a significantly longer PFS & higher frequency of intracranial response Vs. crizotinib#OncoAlert ? #LCSM https://t.co/aPC1m11g8M pic.twitter.com/DtcwbwfZ4B

— Gil Morgan (@weoncologists) November 19, 2020