CROWN Trial Supports Lorlatinib as a Future First-line Standard Treatment in ALK-positive Non-small Cell Lung Cancer

In a planned interim analysis of the CROWN trial, presented at today’s Presidential Symposium at ESMO Virtual Congress 2020, lorlatinib significantly improved progression-free survival (PFS) compared with crizotinib, thereby confirming the outcomes benefit of lorlatinib already seen in later-line ALK+ non-small-cell lung cancer (NSCLC) settings (LBA2). These results look set to secure the drug a place as a standard first-line treatment approach.

The phase III, open-label trial involved 296 previously untreated patients with ALK+ stage IIIB/IV NSCLC – enrolled across 104 study sites in 23 countries – who were randomised 1:1 to receive lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily); 291 actually received study treatment. Patients were stratified by presence of CNS metastases and ethnicity. The primary endpoint was PFS by blinded independent central review (BICR).

At the data cut-off (20 March 2020), the median follow-up for PFS by BICR was 18.3 months (95% confidence interval [CI] 16.4–20.1) for lorlatinib (n=149) and 14.8 months (95% CI 12.8–18.4) for crizotinib (n=147).

Lorlatinib led to a 72% improvement in PFS by BICR compared with crizotinib (hazard ratio [HR] 0.28; 95% CI 0.191–0.413; stratified one-sided p<0.001). Median PFS times for lorlatinib and crizotinib were not estimable (NE) and 9.3 months (95% CI 7.6–11.1), respectively. The median 12-month PFS rate by BICR with lorlatinib was twice that seen with crizotinib (78.1% and 38.7%, respectively). The results of the BICR analysis were supported by investigator-assessed PFS data.

Lorlatinib was also associated with numerical improvements in best overall response (BOR) rate by BICR. Three-quarters (n=113 [76%]) of patients receiving lorlatinib achieved a complete response (CR) (n=4) or a partial response (PR) (n=109). This compared with a 58% BOR rate for crizotinib, with no CRs and 85 PRs. The median duration of response (DOR) among responders receiving lorlatinib was NE, compared with 11.0 months (95% CI 9.0–12.9) for those receiving crizotinib.

The numerical BOR benefit of lorlatinib over crizotinib extended to the 30 patients who had measurable brain metastases. Fourteen of 17 patients (82%) receiving lorlatinib had a CR (n=12) or a PR (n=2) compared with 3 of 13 (23%) patients (1 CR and 2 PR) receiving crizotinib. The intracranial DOR in responders was NE with lorlatinib and ranged from 9.4 to 11.1 months with crizotinib.

The incidence of grade 3/4 adverse events (AEs) was higher with lorlatinib (72.5%) than crizotinib (55.6%), with the majority of AEs in the lorlatinib arm being laboratory abnormalities (mainly lipid abnormalities). However, fewer patients receiving lorlatinib, compared with crizotinib, experienced AEs leading to treatment discontinuation (6.7% versus 9.2%). 

Abstract and session details

ESMO 2020 Highlights on 1st line lorlatinib for ALK+ NSCLC: The CROWN Study

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