QoL, Efficacy Data Support Use of Frontline Lorlatinib as New Standard in ALK+ NSCLC


February 2, 2021 - The time to treatment deterioration for symptoms such as cough, dyspnea, and pain in the chest was found to be comparable between treatment-naïve patients with ALK-positive non–small cell lung cancer who received lorlatinib versus crizotinib.

The time to treatment deterioration (TTD) for symptoms such as cough, dyspnea, and pain in the chest was found to be comparable between treatment-naïve patients with ALK-positive non–small cell lung cancer (NSCLC) who received lorlatinib (Lorbrena) versus crizotinib (Xalkori), according to patient-reported outcomes (PROs) data from the phase 3 CROWN trial (NCT03052608) presented during the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer (WCLC).1

Although no clinically meaningful differences were observed between the 2 arms in any EORTC QLQ-C30 functioning domain, improvements in physical, role, emotional, and social functioning scales were found to favor lorlatinib. Improvements in the cognitive functioning scale were found to favor crizotinib.

Moreover, several lung cancer symptoms, such as fatigue, nausea and vomiting, insomnia, appetite loss, constipation, diarrhea, and cough, were found to significantly improve over time in patients who received lorlatinib versus those given crizotinib. With lorlatinib, investigators noted a trend toward delayed TTD in their global quality-of-life (QoL) score relative to crizotinib.

“PROs were consistent with the observed safety/tolerability profile of lorlatinib relative to crizotinib,” lead study author Julien Mazières, MD, PhD, professor of respiratory medicine and thoracic oncology specialist at the Toulouse University Hospital, in Toulouse, France, said during an oral presentation on the data. “Based on efficacy and QoL data, lorlatinib may be considered as a new standard of care in untreated ALK-positive NSCLC.”

The open-label, phase 3 CROWN trial enrolled a total of 296 patients with stage IIIB/IV ALK-positive NSCLC who had not received any previous systemic treatment for metastatic disease. To be eligible for enrollment, patients had to have an ECOG performance status of 0-2, and at least 1 extracranial measurable target lesion per RECIST v1.1 criteria. Notably, patients with either asymptomatic treated or untreated central nervous system metastases were allowed to participate.

In the trial, patients were randomized 1:1 to receive either lorlatinib at a once-daily dose of 100 mg (n = 149) or crizotinib at a twice-daily dose of 250 mg. Patients were stratified based on whether they had brain metastases (yes vs no) and their ethnicity (Asian vs non-Asian).

The primary end point of the trial was progression-free survival (PFS) per blinded independent central review (BICR), while secondary end points comprised PFS per investigator assessment; overall response rate (ORR) per BICR and investigator; intracranial (IC) ORR, duration of response (DOR), and IC-DOR; IC-time to progression per BICR, overall survival, safety, and QoL.

Results from the interim analysis of the trial showed that the third-generation ALK TKI elicited a higher overall and intracranial response compared with crizotinib in this patient population.2 The agent was also found to result in a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.19-0.41; 1-sided P <.001). The median PFS per BICR had not been estimable (NE) in the lorlatinib arm versus 9.3 months in the crizotinib arm.

In patients with brain metastases, the IC-ORR achieved with lorlatinib was 82%, which included a complete response rate of 71%. Notably, lorlatinib also significantly prolonged time to IC progression versus crizotinib. These data supported the supplemental new drug application for the agent’s use in patients with ALK-positive metastatic NSCLC; the FDA granted a priority review designation to lorlatinibin December 2020.

Patients who received lorlatinib also experienced an improvement in global QoL over those who were given crizotinib. At the 2020 WCLC, additional PRO data from the trial were shared. Investigators evaluated PROs by using the EORTC QLQ-C30 and the QLQ-LC13. Patients were evaluated at baseline and on the first day of each 28-day treatment cycle through the end of treatment.

To evaluate score changes from baseline, investigators used a longitudinal random-intercept, random-slope, mixed-effect model; they compared mean score changes between the arms from baseline through the other time points. Moreover, investigators compared TTD in pain of chest, dyspnea, cough, and global QoL between the arms through the use of a 1-sided log-rank test that was stratified using randomization stratification factors. By using the Cox Proportional Hazard model, investigators estimated the effect of treatment.

Completion rates were 100% at baseline and continued to be high, at above 96%, through treatment cycle 18 in both arms. No significant differences were observed between the treatment arms in any of the functioning domains. Regarding symptoms, a clinically meaningful and statistically significant difference in diarrhea was found to favor lorlatinib over crizotinib.

Additionally, no significant difference in time to deterioration in composite end point was observed between the 2 treatment arms. The TTD in the investigative arm was 3.3 months (95% CI, 2.1-4.7) versus 3.7 months (95% CI, 2.0-5.5) in the control arm (HR, 1.09; 95% CI, 0.822-1.444; 1-sided P = .7293).

No significant difference in TTD in global QoL was observed between lorlatinib and crizotinib, either. The median TTD in global QoL with lorlatinib was a median of 24 months (95% CI, 6.5-NE) versus a median of 12 months (95% CI, 6.5-NE) with crizotinib (HR, 0.92; 95% CI, 0.650-1.294; 1-sided P = .3127).

“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 [patients given] lorlatinib,” Mazieres said. “PROs in the phase 3 CROWN trial support the improved PFS and are consistent with safety/tolerability of lorlatinib relative to crizotinib.”


  1. Mazieres J, Iadeluca L, Shaw AT, et al. Patient-reported outcomes from the randomized phase 3 CROWN study of first-line lorlatinib versus crizotinib in ALK+ NSCLC. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract MA11.08.
  2. Solomon B, Bauer T, de Marinis F, et al. Lorlatinib vs crizotinib in the first-line treatment of patients with advanced ALK-positive non–small cell lung cancer: results of the phase 3 CROWN study. Ann Oncol. 2020;31(suppl 4):S1180-S1181. doi:10.1016/j.annonc.2020.08.2282
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