Promising interim results from the randomized phase III CROWN study presented at the ESMO Virtual Congress 2020 for lorlatinib indicate that this agent considerably increased progression-free survival (PFS) compared with crizotinib, validating the outcomes benefit of lorlatinib already seen in later-line ALK-positive non-small-cell lung cancer (NSCLC) settings (LBA2).

The presenter also noted that these results support the use of lorlatinib as a future first-line standard therapy approach for ALK-positive NSCLC. Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK inhibitor approved for patients previously treated with ALK TKIs. 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 randomized 1:1 to receive lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily); 291 actually received study treatment. Patients were categorized by presence of CNS metastases and ethnicity.

The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). At the data cutoff (March 20, 2020), the average 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). The use of lorlatinib resulted in 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 <.001). Average 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 observed with crizotinib (78.1% and 38.7%, respectively). The results of the BICR examination were validated by investigator-assessed PFS data.

Additionally, lorlatinib was also correlated with numerical enhancements 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 average 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 prevalence of grade 3/4 adverse events (AEs) was greater 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% vs. 9.2%).

In the presentation at ESMO 2020, presenter Dr. Solomon stated, “These results of the CROWN study support the use of lorlatinib as a highly effective first-line therapy for patients with advanced ALK-positive NSCLC. The CROWN study clearly establishes lorlatinib as another option among other first-line ALK inhibitors.”

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