Lorlatinib produces ‘unprecedented’ disease progression delay in ALK-positive lung cancer
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Key takeaways:
- Lorlatinib significantly improved PFS in adults with ALK-mutant advanced lung cancer compared with crizotinib.
- Researchers reported decreased risk for brain metastases among those treated with lorlatinib.
CHICAGO — Lorlatinib delivered never-before-seen PFS results in adults with anaplastic lymphoma kinase-positive non-small cell lung cancer, according to findings from a randomized phase 3 trial presented at ASCO Annual Meeting.
Lorlatinib (Lorbrena, Pfizer) also drastically delayed disease progression and development of brain metastases compared with crizotinib (Xalkori, Pfizer).
“In this 5-year analysis, the PFS observed with lorlatinib corresponds to the longest PFS ever reported in advanced NSCLC,” Benjamin J. Solomon, MBBS, FRACP, PhD, head of lung medical oncology at Peter MacCallum Cancer Center in Melbourne, Australia, said during a press briefing. “The systemic efficacy results coupled with prolonged intracranial efficacy from first-line lorlatinib treatment represent an unprecedented improvement in outcomes for patients with advanced ALK-positive NSCLC.”
The results are superior to any yet reported using an ALK-targeted tyrosine kinase inhibitor (TKI) as first-line therapy for individuals with non-small cell lung cancer who harbor ALK rearrangements, according to David R. Spigel, MD, chief scientific officer at Sarah Cannon Research Institute and subject matter expert for ASCO. “The PFS is outstanding. We have not seen anything close to this,” he said during the briefing. “Other great drugs that are available, including alectinib [Alecensa, Genentech] and brigatinib [Alunbrig, Takeda], have not reported durable PFS events of this magnitude.”
Background and methodology
Lung cancer causes more cancer-related deaths than any other type globally, according to background information Solomon shared during his presentation.
Roughly 5% of individuals with NSCLC adenocarcinoma have an ALK mutation, and they tend to be younger (median age, 50 years), never or lightly smoke, and get diagnosed at later stages.
Additionally, about 25% of those patients have brain metastases when diagnosed, and “progressive [central nervous system (CNS)] involvement remains a major concern,” Solomon said.
However, “Treatment for ALK-positive lung cancer has been transformed by the advent of targeted therapies directed at ALK,” he said.
Solomon and colleagues evaluated lorlatinib, a third-generation ALK-targeted TKI, against crizotinib as a front-line treatment in the CROWN trial.
Individuals had to have stage IIIB/IV ALK-positive NSCLC, no prior therapies for metastatic disease, and an ECOG score of 0 to 2 to be included in the trial.
Researchers randomly assigned study participants in a 1:1 ratio to either lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily).
The study included 296 individuals (149 in lorlatinib group; 147 in crizotinib).
Researchers evaluated PFS as the study’s primary endpoint.
The lorlatinib arm had a median follow-up of 60.2 months and the crizotinib cohort had a median follow-up of 55.1 months.
Results
Median PFS had not been reached in the lorlatinib cohort, whereas the crizotinib group had a median PFS of 9.1 months (HR = 0.19; 95% CI, 0.13-0.27).
The lorlatinib arm had a 5-year PFS rate of 60% compared with 8% for individuals who received crizotinib.
Researchers observed a PFS benefit across multiple subgroups, including based on whether study participants had brain metastases and their ethnicity (Asian or non-Asian), gender, age and smoking status.
For participants who had brain metastases entering the trial, median time to intracranial progression had not been reached in the lorlatinib arm compared with 7.2 months in the crizotinib cohort (HR = 0.03; 95% CI, 0.01-0.13). Those in the lorlatinib group had an 83% chance of being progression free.
For participants who did not have brain metastases entering the trial, median time to intracranial progression had not been reached in the lorlatinib arm compared with 23.9 months in the crizotinib cohort (HR = 0.05; 95% CI, 0.02-0.13). Those in the lorlatinib group had an 96% chance of being progression free compared with 27% in the crizotinib arm.
Only four patients in the lorlatinib cohort developed new brain metastases.
“These results speak to the ability of lorlatinib not only to prevent progression of the existing brain metastases, but to prevent or delay progression of new brain metastases,” Solomon said.
Grade 3 or worse adverse events occurred in 77% of patients in the lorlatinib arm (5% discontinued) and 57% in the crizotinib group (6% discontinued).
As of Oct. 31, 2023, 50% of patients in the lorlatinib arm continued to receive treatment compared with 5% in the crizotinib cohort.
“You don’t need a magnifying glass to see the difference here,” Julie R. Gralow, MD, FACP, FASCO, ASCO chief medical officer and executive vice president and press conference moderator, said during the briefing. “It’s just a profound difference between these two drugs.”
Comparison with other ALK inhibitors
Spigel noted use of crizotinib as a limitation of the study because the drug has been mostly phased out of use in the U.S., although clinicians in other countries still utilize it. Instead, they more often use second-generation inhibitors such as alectinib and brigatinib.
However, Spigel did not believe a trial comparing lorlatinib with either alectinib or brigatinib would have drastically changed the results.
Solomon specified that median PFS with alectinib had been 34.8 months and median PFS with brigatinib had been a little more than 30 months in previous trials.
“When we saw the alectinib and brigatinib results, we thought they were outstanding, and this is just better,” Spigel said.
“It’s just hard to believe that this would be worse head-to-head against those drugs,” he added. “You shouldn’t do cross-trial comparisons, but when you have somebody in front of you in clinic, it would be hard to ignore these results compared with those historical results.”
“Key features of lorlatinib are its CNS penetrants, but also its ability really to cover the mutations that cause resistance to other ALK inhibitors,” Solomon said of the differences in the drugs. “We did not see emergence of secondary mutations in the ALK kinase domain with lorlatinib, and I think this together with the CNS penetrants might really drive the benefit.”
When discussing whether lorlatinib should be prescribed prior to alectinib and brigatinib, Spigel said all three have different safety profiles, including lorlatinib having cholesterol and cognitive toxicities the others do not, but ultimately clinicians should decide which treatment offers their patients the best chance immediately.
“Patients don’t always make it to the next line of therapy, so should you use your best drug first, and I think that’s really what becomes the question when you have a patient in front of you,” Spigel said. “I want to give the best drug I can give up front that I can manage the best as well.”
Perspective
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Robert Chun-Hao Hsu, MD
Results of the CROWN study showed an impressive result, with the median PFS not reached in the lorlatinib arm after 5 years, along with median PFS of intracranial progression not being reached in the lorlatinib arm compared with 9.1 months in the crizotinib arm. Further, in patients without baseline brain metastasis in the lorlatinib arm, only four out of 114 patients developed brain progression, all within the first 16 months. With regard to safety, dose reduction occurring within the 16 months did not affect efficacy of the treatment. No new safety signals were seen, with 5% drug discontinuation in lorlatinib arm and 6% in the crizotinib arm.
Although a major shortcoming of this study is that there was a suboptimal control arm with patients receiving crizotinib instead of alectinib or brigatinib, these results put together make for very compelling evidence that lorlatinib should be the standard of care for first-line treatment of patients with metastatic ALK-positive NSCLC. For reference, the ALEX trial showed alectinib to have a median PFS of 34.8 months and the ALTA-1L trial showed brigatinib to have a median PFS of 30.8 months, and a phase 2 study evaluating patients with ALK-positive NSCLC treated with at least one prior second generation ALK TKI had ORR of 39.6% (95% CI, 31.4-48.2) and a median PFS of 6.6 months (95% CI, 5.4-7.4).
Further studies should focus on looking at dynamic ways to look at disease progression, particularly during the first 2 years when about 75% of the disease progression cases occur with lorlatinib.
References:
Camidge DR, et al. J Thorac Oncol. 2021;doi:10.1016/j.jtho.2021.07.035.
Mok T, et al. Ann Oncol. 2020;doi:10.1016/j.annonc.2020.04.478.
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Solomon BJ, et al. Abstract LBA8503. Presented at: ASCO Annual Meeting; May 31-June 4, 2024; Chicago.
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