Lorlatinib: Another First-Line Option for ALK-Positive NSCLC?

M. Alexander Otto

September 23, 2020

First-line lorlatinib significantly prolonged progression-free survival (PFS) when compared with crizotinib in advanced ALK-positive non–small cell lung cancer (NSCLC), according to an interim analysis of the phase 3 CROWN trial.

Lorlatinib also produced a higher overall and intracranial response rate, prolonging progression to CNS disease.

These findings "support the use of lorlatinib as a highly effective first-line therapy for patients with advanced ALK-positive NSCLC," said Benjamin Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne.

"The CROWN study clearly establishes lorlatinib as another option" among other first-line ALK inhibitors, Dr. Solomon said when presenting the findings at the European Society for Medical Oncology Virtual Congress 2020.

"We now have multiple options for first-line treatment of patients with ALK-positive lung cancer," noted study discussant Christine Lovly, MD, PhD, a medical oncologist and associate professor at Vanderbilt University Medical Center in Nashville, Tenn.

The question now, she said, is how to choose among these options. The drugs have all bested crizotinib in trials but haven't gone head to head against one another.

Lorlatinib and CROWN

Lorlatinib is currently approved in the United States to treat ALK-positive metastatic NSCLC that has progressed on crizotinib and at least one other ALK inhibitor. Lorlatinib was granted accelerated approval for this indication based on response rate and duration.

The CROWN study was intended to support the conversion to full approval, according to Pfizer, which is developing both lorlatinib and crizotinib. Pfizer also plans to use the results of CROWN to seek a first-line indication for lorlatinib in NSCLC.

CROWN enrolled 296 patients with stage IIIB/IV ALK-positive NSCLC who had received no prior systemic treatment. Patients with asymptomatic treated or untreated CNS metastases were eligible.

There were 149 patients randomized to lorlatinib at 100 mg daily and 147 randomized to crizotinib at 250 mg twice daily. Five patients in the crizotinib arm were included in the analysis but were not treated, Dr. Solomon said.

The median age was 61 years in the lorlatinib arm and 56 years in the crizotinib arm. Nearly all patients were White (48% in the lorlatinib arm and 49% in the crizotinib arm) or Asian (44% in both arms). A majority of patients were women (56% in the lorlatinib arm and 62% in the crizotinib arm), and more than half said they never smoked (54% in the lorlatinib arm and 64% in the crizotinib arm).

Response and PFS

According to blinded independent central review, the objective response rate was 76% with lorlatinib (113/149) and 58% with crizotinib (85/147). There were four complete responses with lorlatinib and none with crizotinib.

Among patients who had measurable or nonmeasurable brain metastases at baseline, the intracranial ORR was 66% with lorlatinib (25/38) and 20% (8/40) with crizotinib. In patients with only measurable brain metastases at baseline, the intracranial ORR was 82% with lorlatinib (14/17) and 23% with crizotinib (3/13).

The 12-month PFS rate was 78% in the lorlatinib arm and 39% in the crizotinib arm. The median PFS was 9.3 months in the crizotinib arm but was not reached in the lorlatinib arm, which "corresponded to a 72% reduction in the risk of death or progression [hazard ratio, 0.21; P < .001]," Dr. Solomon said.

"[T]he PFS for alectinib in the first line is approximately 3 years," Dr. Lovly noted. "We anxiously await additional data for lorlatinib to see how long the PFS will be."

The median time to intracranial progression was 16.6 months in the crizotinib arm but was not reached in the lorlatinib arm (HR, 0.07; P < .001).

"These data indicate the ability of lorlatinib not only to delay the progression of existing brain metastases, but also to prevent the development of new brain metastases," Dr. Solomon said.

Dr. Lovly noted that the efficacy of lorlatinib in the brain is "quite compelling," but other ALK inhibitors have demonstrated similar results.

As for overall survival, the data are still immature. The median overall survival was not reached with lorlatinib or crizotinib (HR, 0.72).


Dr. Solomon noted that lorlatinib "does have a different toxicity profile, compared to other ALK inhibitors." Specifically, lorlatinib is associated with hypercholesterolemia and hypertriglyceridemia, which have not been seen with other ALK inhibitors.

Lorlatinib is also associated with neurocognitive problems, including inattention, memory impairment, and mild confusion. Mood effects include emotional lability – "someone watching a movie might burst into tears when they wouldn't have otherwise," Dr. Solomon said – as well as anxiety and depression.

"So it's important to tell not just the patient but their family about these things so that they identify when [the events] happen," Dr. Solomon said. "That's key because [the events are] completely reversible when you stop the drug. With dose interruption, those effects will resolve."

Other adverse events that were more common with lorlatinib (a 10% or greater difference in frequency from crizotinib) included edema, weight gain, and peripheral neuropathy. Diarrhea, nausea, fatigue, vision disorders, constipation, and increased liver enzymes were more common with crizotinib. Grade 3-4 adverse events led to discontinuation in fewer than 10% of patients in each arm.

The study was funded by Pfizer, and the investigators included employees. Dr. Solomon is an adviser for Pfizer and other companies, and Dr. Lovly's industry ties included being both an advisor and speaker for Pfizer.


SOURCE: Solomon B et al. ESMO 2020, Abstract LBA2.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.


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