CHICAGO — The benefit observed with lorlatinib (Lorbrena) in 5-year follow-up data from the CROWN trial corresponds to the longest progression-free survival (PFS) reported for any targeted therapy in advanced non-small cell lung cancer (NSCLC), said study presenter Benjamin Solomon, MBBS, PhD, here at the 2024 American Society of Clinical Oncology (ASCO) annual meeting.
The third-generation ALK inhibitor from Pfizer was associated with a 72% improvement in PFS in patients with advanced anaplastic lymphoma kinase (ALK)-positive NSCLC, with 60% of patients remaining disease-free at 60 months, compared to the selective tyrosine kinase inhibitor crizotinib (Xalkori), also from Pfizer. Notably, lorlatinib was associated with a 92% reduction in intracranial progression as well.
These results, coupled with the absence of new safety signals, show that first-line lorlatinib provides an unprecedented improvement in outcomes for patients with ALK+ NSCLC, added Solomon, head of Lung Medical Oncology at the Peter MacCallum Cancer Centre in Melbourne, Australia, to a round of applause from meeting attendees.
Some experts noted, however, that crizotinib was a poor comparator drug because it is not a standard option for this patient population in the United States.
The research was simultaneously published in the Journal of Clinical Oncology.
Inside the CROWN Trial
Rearrangements of the ALK oncogene account for approximately 5% of NSCLC cases, with patients typically younger than those with other forms of the disease, who are light or never-smokers, and who have adenocarcinoma histology.
In 2018, the US Food and Drug Administration (FDA) approved lorlatinib for use in ALK+ metastatic NSCLC that has progressed on crizotinib and at least one other ALK inhibitor.
As previously reported by Medscape Medical News, an interim analysis of the ongoing phase 3 CROWN trial, presented at the 2020 European Society for Medical Oncology Virtual Congress, showed that first-line lorlatinib significantly prolonged PFS and reduced intracranial progression at 12 months compared to crizotinib.
CROWN included patients with stage IIIB/IV ALK+ NSCLC who had received no prior systemic treatment for metastatic disease. Patients with asymptomatic treated or untreated central nervous system (CNS) metastases were also allowed in the trial.
In total, 296 patients were randomized to lorlatinib (100 mg, once daily, n = 149) or crizotinib (250 mg twice daily, n = 147) with no crossover permitted between the treatment groups. The primary endpoint was PFS as assessed by blinded independent central review.
The primary endpoint evaluation was stopped after 3 years but the patients continued to be followed, Solomon said. In the current post hoc 5-year analysis, the median duration of follow-up was 60.2 months in the lorlatinib arm and 55.1 months in the crizotinib arm.
Even at this point, the median PFS had still not been reached with lorlatinib (95% CI, 64.3 months to "not reached") compared with 9.1 months with crizotinib (hazard ratio [HR] 0.19; 95% CI, 0.13 - 0.27). This translated to a five-year progression-free survival of 60% with lorlatinib vs 8% with crizotinib.
The PFS benefit with lorlatinib was seen across prespecified subgroups, including patients stratified by ethnic origin, sex, age, and smoking status, as well as by the presence of brain metastases.
Delving deeper into the data, Solomon reported that lorlatinib was associated with a benefit compared with crizotinib regardless of whether patients had brain metastases at baseline — HR 0.08 in those with brain metastases, HR 0.24 in those without.
The time to intracranial progression was markedly longer with lorlatinib, with the median not reached vs 16.4 months in the crizotinib group (HR, 0.06). Overall, at 5 years, 92% of patients assigned to lorlatinib were free of intracranial progression, compared with 21% of those treated with crizotinib.
Solomon also reported no new safety signals, although the rate of grade 3/4 adverse events was higher with lorlatinib, largely due to a higher incidence of grade 3/4 hypertriglyceridemia (25%), weight increase (23%), hypercholesterolemia (21%), and hypertension (12%). CNS adverse events were seen in 42% of patients who received lorlatinib, of which 86% were grade 1/2.
Although 23% of patients in the lorlatinib arm underwent dose reductions due to adverse events, Solomon reported that having a dose reduction in the first 16 weeks of treatment did not impact the efficacy of the drug.
Finally, lorlatinib was associated with a progression-free survival benefit over crizotinib in patients with poor prognostic biomarkers, such as the EML4-ALK fusion variant and TP53 mutation, and was not associated with emerging ALK mutations.
During the press conference, David R. Spigel, MD, chief scientific officer at the Sarah Cannon Research Institute, Nashville, Tennessee, who was not involved in the study, noted that the PFS seen in the study was "outstanding."
Jessica J. Lin, MD, Center for Thoracic Cancers, Massachusetts General Hospital, Harvard Medical School, Boston, also not involved in CROWN, said that the latest results cement lorlatinib's place in the first-line treatment landscape.
Asked how she would now treat a newly diagnosed metastatic ALK+ NSCLC presenting to the clinic, she said that treatment decisions will always need to be individualized, but lorlatinib would be her preferred initial therapy for most patients.
Inferior Comparator Drug
Despite the impressive findings, some experts questioned the trial design.
The trial compared the new agent to crizotinib, which is not often used in this setting in the US, as better drugs are available now, noted Spigel.
In fact, lorlatinib has not yet gone head-to-head with another modern, next-generation kinase inhibitor in a randomized controlled trial, Spigel cautioned.
A potentially more appropriate comparator drug may have been alectinib (Alecensa) — the standard of care in this population and approved in 2017 shortly after the CROWN trial started to accrue patients. Although alectinib and lorlatinib have not been compared head to head, in their respective trials against crizotinib, lorlatinib appears to have edged out alectinib at 24 months — 70% of patients were progression-free vs about 60% who received alectinib in a 2017 trial.
Nonetheless, the current results are "among the best we've ever seen," Spigel said. "The other impressive finding of this study is the prevention of progression or development of new CNS lesions, something that is quite awful for patients, and something we try desperately to prevent or treat for patients, as they live longer."
Still, there is more work to be done.
"We have to continue to refine our understanding of adverse events and optimal management strategies," and there's a need for subsequent treatment strategies to "rescue disease relapse and to elucidate the mechanisms of resistance to first-line lorlatinib," Lin added.
The study was funded by Pfizer.Solomon declares relationships with Amgen; AstraZeneca (Inst); BeiGene; Bristol-Myers Squibb (Inst); GlaxoSmithKline; GlaxoSmithKline (Inst); Janssen (Inst); Lilly; Merck Sharp & Dohme; Pfizer (Inst); Roche/Genentech (Inst); Takeda; Sanofi (Inst); UpToDate.Spigel declares relationships with many companies, including AbbVie (Inst); AstraZeneca (Inst); Bayer (Inst); Bristol-Myers Squibb (Inst); Janssen Oncology (Inst); Merck (Inst); Millennium (Inst); Novartis (Inst); Pfizer (Inst).Lin declares relationships with OncLive, Pfizer, AstraZeneca, Bayer, Bristol-Myers Squibb, among other companies.