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CHICAGO -- Five-year results from a phase III trial had experts gushing over lorlatinib's (Lorbrena) progression-free survival (PFS) benefit in ALK-positive non-small cell lung cancer (NSCLC).

In the first-line CROWN trial, median PFS at 5 years per blinded independent central review was not reached with the third-generation ALK inhibitor as compared with 9.1 months with crizotinib (Xalkori; HR 0.19, 95% CI 0.13-0.27). Five-year PFS rates landed at 60% with lorlatinib versus 8% with crizotinib, the first drug approved for ALK-positive NSCLC more than a decade ago.

"These results represent the most significant progression-free survival benefit that has been reported in ALK-positive lung cancer to date," said Benjamin Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, who presented the findings at a press briefing in advance of the American Society of Clinical Oncology (ASCO) annual meeting.

ASCO discussant David R. Spigel, MD, chief scientific officer at the Sarah Cannon Research Institute in Nashville, Tennessee, noted that "these are the best results we have seen so far with the use of an ALK tyrosine kinase inhibitor in the first-line treatment of patients with ALK-rearranged non-small cell lung cancer."

"The progression-free survival is outstanding," he added. "We have not seen anything close to this in other great drugs that are available, including alectinib (Alecensa) and brigatinib (Alunbrig)."

Overall survival results were immature at the time of this analysis.

Interim results of the CROWN trial were first reported in 2020, and showed that treatment with lorlatinib, a third-generation ALK tyrosine kinase inhibitor (TKI), reduced the risk of disease progression or death by 72% for patients with untreated advanced ALK-positive NSCLC compared with crizotinib (HR 0.28, 95% CI 0.19-0.41, P<0.001).

Solomon also reported that lorlatinib showed superior PFS across patient subgroups and irrespective of the presence or absence of baseline brain metastases.

The hazard ratio in favor of lorlatinib compared with crizotinib for patients with baseline brain metastases was 0.08 (95% CI 0.04-0.19), and was 0.24 (95% CI 0.16-0.36) for those without brain metastases at baseline. Median PFS was not reached with lorlatinib in either arm, and was 6 months and 10.8 months with crizotinib, respectively. Five-year PFS rates were 53% with lorlatinib and not estimable with crizotinib in those with baseline brain metastases, and 63% and 10%, respectively, in those without baseline brain metastases.

Median time to intracranial progression was longer with lorlatinib in both patients with and without baseline brain metastases.

In 114 patients without baseline brain metastases in the lorlatinib arm, only four developed brain progression, occurring within the first 16 months of treatment.

These results are "the other impressive finding of this study," said Spigel, adding that the development or progression of central nervous system lesions "is something that is quite awful for patients, and something we try desperately to prevent or treat for patients as they live longer -- [to] not have progression in the brain be the reason for so-called failure."

Julie Gralow, MD, chief medical officer and executive vice president of ASCO, who moderated the press briefing, said that while crizotinib has been replaced by second-generation ALK TKIs, "you don't need a magnifying glass to see the ... profound difference between the two drugs."

The PFS results are "just unheard of," she added.

Spigel agreed, noting that "we just don't see results like that in oncology that often. Much less in non-small cell lung cancers. These are among the best results we have seen in advanced disease in any setting."

When asked to compare lorlatinib with brigatinib and alectinib -- the second-generation ALK TKIs used in clinical practice alongside lorlatinib -- Solomon cautioned against comparing drugs across trials, pointing out that all three are "very good drugs." However, he did note that the median PFS with alectinib was 34.8 months, and just over 30 months with brigatinib.

The PFS with lorlatinib is "really something quite different," he said.

Spigel added that "when we saw the alectinib and brigatinib results, we thought they were outstanding, and this is just better. It is hard to believe [lorlatinib] would be worse head-to-head against those drugs. You shouldn't do cross-trial comparisons, but when you have someone in front of you in clinic, it would be hard to ignore these results compared with those historical results."

CROWN was a comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who had received no previous systemic treatment for metastatic disease. The researchers noted that patients with ALK-positive NSCLC tended to be younger, never or light smokers, and were often diagnosed with late-stage disease. Around 25% of patients have brain metastases at baseline, and progressive central nervous system involvement is a major concern.

In this study, central nervous system metastases at baseline were present in 26% of patients in the lorlatinib group and 27% in the crizotinib group.

Grade 3 and 4 adverse events (AEs) occurred in 77% of patients in the lorlatinib group compared with 57% of those in the crizotinib group, while treatment-related AEs leading to treatment discontinuation occurred in 5% and 6% of patients, respectively.

Spigel cautioned that a possible limitation to the study was that crizotinib is not used as frequently in the U.S. as in other parts of the world.

"An outstanding drug in its time, but other drugs are available now," he said. "And it's not good to compare studies -- we have not had a randomized controlled trial of lorlatinib versus another next generation TKI -- but these results are among the best we've ever seen."

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