Introduction
Lorlatinib, a 3rd generation ALK inhibitor, significantly improved progression-free survival compared to crizotinib in the CROWN Phase 3 study in patients with previously untreated advanced ALK-positive NSCLC. Improvement in global quality of life (QoL) was greater in patients receiving lorlatinib versus crizotinib. We present the detailed results of patient reported outcomes (PROs) from the CROWN Phase 3 study (NCT03052608).
Methods
Patients (n=296) with ALK+ NSCLC were randomized to lorlatinib or crizotinib. PROs were assessed using the EORTC QLQ-C30 and QLQ-LC13, and the EQ-5D-5L on the first day of each cycle (28 days) through end of treatment. Results of the current analysis are presented through cycle 18 to correspond with the median follow-up time. Longitudinal mean score changes from baseline were compared between treatment arms (≥10-point difference considered clinically meaningful). Time to treatment deterioration (TTD) in pain in chest, dyspnea and cough was compared between treatment arms using Kaplan–Meier methods. P-values are nominal and no adjustments for multiple comparisons were made.
Results
Completion rates were 100% at baseline and remained ≥96% through Cycle 18 in both treatment arms. There were no clinically meaningful or statistically significant differences between treatment arms in any functioning domain, with numerical improvements favoring lorlatinib in physical, role, emotional, and social functioning scales, and a numerical improvement favoring crizotinib for cognitive functioning (Table). There were statistically significant, but not clinically meaningful differences favoring lorlatinib in symptoms of fatigue, nausea and vomiting, insomnia, appetite loss, and constipation. For diarrhea there was both a clinically meaningful and statistically significant difference favoring lorlatinib. Lung cancer symptoms improved from baseline in both treatment arms, with clinically meaningful improvements in cough as early as cycle 2 and maintained through cycle 18. TTD in the composite endpoint of lung cancer symptoms (cough, dyspnea, or pain in chest) was similar between treatment arms (HR 1.09; 95% CI 0.82-1.44; 2-side P=0.5415). Median time to worsening of global QoL was 24.0 months for lorlatinib and 12.0 months for crizotinib (HR 0.92; 95% CI 0.65-1.29). Additional analyses are ongoing; analyses stratified by baseline brain metastasis and other variables will be presented.
Conclusion
TTD for lung cancer symptoms was comparable between treatment arms. Improvements in lung cancer symptoms were seen early and clinically meaningful improvements in cough were detected in lorlatinib patients. PROs support the improved PFS and are consistent with safety/tolerability of lorlatinib relative to crizotinib.
Tabled
1
| Change from baseline estimated mean difference (95% CI) | |
|---|---|
| Global QoL | 4.65 (1.14-8.16)d |
| Functional domaina | |
| Physical | 2.02 ( -1.01-5.05) |
| Role | 2.09 (-1.87-6.04) |
| Emotional | 2.58 (-0.06-5.22) |
| Cognitive | -3.18 (-6.47-0.12) |
| Social | 2.27 (-1.30-5.85) |
| Symptom scale/itemb | |
| Fatigue | -5.67 (-9.42- -1.92)d |
| Nausea and Vomiting | -7.86 (-9.86- -5.86)c |
| Pain | 1.16 (-2.49-4.82) |
| Dyspnea | 1.72 (-1.98-5.43) |
| Insomnia | -7.95 (-11.25- -4.64)c |
| Appetite Loss | -9.21 (-11.80- -6.62)c |
| Constipation | -4.93 (-9.07- -0.79)e |
| Diarrhea | -12.03 (-15.49- -8.58)c |
| Financial Difficulties | -1.04 (-4.90-2.82) |
a>0 favors lorlatinib; b<0 favors lorlatinib; cP<0.001; dP<0.01; eP<0.05.
Keywords
Lorlatinib; Phase 3 trial; Patient-reported outcomes
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