Phase 3 CROWN Study Shows Longest PFS Ever Reported in Advanced NSCLC

The median progression-free survival (PFS) of patients receiving lorlatinib in the phase 3 CROWN study has yet to be reached with 5 years of follow-up, which corresponds to “the longest PFS ever reported” in advanced non-small cell lung cancer (NSCLC), according to study investigators.

Lead study author Benjamin Solomon, MBBS, PhD, who is head of Lung Medical Oncology at Peter MacCallum Cancer Center, presented long-term efficacy and safety outcomes from the CROWN study during an oral abstract session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

Lorlatinib is a brain-penetrant, third-generation ALK tyrosine kinase inhibitor (TKI) that previously showed improved PFS and intracranial (IC) activity compared with crizotinib in the phase 3 CROWN study, which included 296 patients with treatment-naïve, advanced ALK-positive NSCLC.

Dr. Solomon explained the context and importance of the 5-year follow-up data from the phase 3 CROWN study.

“Despite significant advancements with newer generation ALK TKIs, the majority of patients treated with second-generation ALK TKIs will have progression of their disease within 3 years. Lorlatinib is the only ALK TKI that has reported 5-year PFS, and even after this time, the majority of patients continue to have their disease controlled, including control of disease in the brain,” Dr. Solomon said in a statement provided by the society. “To our knowledge, these results are unprecedented for any TKI in patients with metastatic NSCLC.”

Study investigators randomized patients 1:1 to receive lorlatinib 100 mg once daily (n=149) or crizotinib 250 mg twice daily (n=147). As of October 31, 2023, 50% of the patients randomized to receive lorlatinib were still receiving the treatment, compared with 5% of those who were randomized to receive crizotinib.

The post hoc analysis presented at the 2024 ASCO® Annual Meeting included investigator-assessed efficacy outcomes, safety, and biomarker analyses, but “formal statistical testing was not performed,” according to the study investigators.

With a median 60.2 months of follow-up for PFS in patients receiving lorlatinib and a median follow-up of 55.1 months in patients receiving crizotinib, the median PFS was not reached with lorlatinib (95% CI, 64.3 to not reached) and was 9.1 months with crizotinib (95% CI, 7.4-10.9; hazard ratio, 0.19; 95% CI, 0.13-0.27). The 5-year PFS was 60% in patients receiving lorlatinib, compared with 8% in those receiving crizotinib.

“These long-term data results are off the charts, and this study confirms the outstanding durable efficacy of lorlatinib as a first-line choice for patients with ALK-positive NSCLC,” David R. Spigel, MD, chief scientific officer, of the Sarah Cannon Research Institute, said in a statement provided by the society. “However, it will be important to compare this treatment option [with] more commonly used ALK TKIs than crizotinib. Still, these findings report some of the best outcomes ever observed for an ALK TKI.”

Among patients who did not have brain metastases at baseline and received lorlatinib, 4 of 114 (3.5%) developed brain progression that occurred within the first 16 months of treatment. More than three-quarters (77%) of patients receiving lorlatinib had grade 3-4 adverse events (AEs), compared with 57% of patients receiving crizotinib. However, the rates of treatment-related AEs that led to treatment discontinuation were similar between the lorlatinib and crizotinib arms, at 5% and 6%, respectively.

“The most common AEs were edema, which is swelling due to fluid trapped in tissues, high cholesterol, and elevated levels of lipids, or hyperlipidemia,” according to a news release from the society. “The AEs that caused patients to stop treatment included cognitive effects, hyperlipidemia, and heart problems.”

The safety profile was “consistent with that observed in prior analyses,” according to the study investigators. In addition, no emerging new ALK mutations were detected in circulating tumor DNA collected at the end of lorlatinib treatment (n=31).

The study investigators concluded the abstract by reflecting on the implications of the study results and how these outcomes may shape the treatment landscape for advanced ALK-positive NSCLC.

“After 5 years of follow up, the median PFS in the lorlatinib arm has yet to be reached, corresponding to the longest PFS ever reported in advanced NSCLC,” Dr. Solomon and colleagues concluded. “Coupled with prolonged IC efficacy and absence of new safety signals, these results indicate an unprecedented improvement in outcomes for [patients] with advanced ALK-positive NSCLC.”

Reference

Solomon BJ, Liu G, Felip E, et al. Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study. Presented at the 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024, Chicago, Illinois.