Findings from the phase III ALEX trial were consistent with earlier results on efficacy and adverse events. Investigators said there were superior patient-reported outcomes for the next-generation tyrosine kinase inhibitor (TKI) alectinib (Alecensa) compared to the standard of care TKI inhibitor crizotinib (Xalkori) for patients with ALK-positive non–small cell lung cancer.
Maurice Pérol, MD
Findings from the phase III ALEX trial were consistent with earlier results on efficacy and adverse events (AEs). According to an announcement at the 2018 European Lung Cancer Conference held on April 11 to 14, 2018 in Geneva, Switzerland, investigators said there were superior patient-reported outcomes for the next-generation tyrosine kinase inhibitor (TKI) alectinib (Alecensa) compared to the standard of care TKI inhibitor crizotinib (Xalkori) for patients with ALK-positive nonsmall cell lung cancer (NSCLC).
The health-related quality of life (QoL) was measured using the EORTC QLQ-C30, while lung cancer-related symptoms were measured with EORTC QLQ-LC13 questionnaires.
Less patients with CNS metastases at baseline in the alectinib group (n = 152) experienced a worsening in health-related QoL versus those taking crizotinib (n = 151) beginning at week 4 (10.8% vs 20.6%). The superior performance of alectinib continued in most of the following assessments which were conducted every 4 weeks during treatment until week 84 (0% vs 16.7%).
A smaller proportion of patients were reported at week 32 with worsening in cognitive function with alectinib (17.9%) than with crizotinib (34.6%).
A clinically meaningful improvement was found in both treatment arms when it came to lung cancer symptoms. However, patients on alectinib had a longer duration of improvement compared to those on crizotinib (cough, 96 weeks vs 84 weeks; chest pain, 96 weeks vs 80 weeks; fatigue, 96 weeks vs 68 weeks; pain in other parts of the body, 96 weeks vs 68 weeks).
There was a longer duration of improvement overall in health-related QoL for those taking alectinib versus crizotinib (88 weeks vs 68 weeks).
Investigators explained that the results were significant because improving QoL for patients during treatment should be a goal in itself, as opposed to targeting the tumor without being able to mitigate harsh symptoms for patients.
“In this context of palliating advanced lung cancer, living better is as important, if arguably not more important, than living longer,” said Fiona Blackhall, MD, honorary consultant in medical oncology at The Christie NHS Foundation Trust, Manchester, United Kingdom. “And for this reason, patient-reported outcomes and health-related QoL are crucial to assess and analyze.”
In advanced lung cancer, the symptom burden is high which can induce cough, breathlessness, and chest pain.
Patient-reported data was found to be consistent with the earlier-reported, main findings of the study. “The primary analysis showed a similar response rate for crizotinib and alectinib, but a longer duration of response with alectinib,” said lead author Maurice Pérol, medical oncologist, Centre Léon Bérard, Lyon, France. “This is consistent with the improvements in health-related QoL and lung cancer symptoms, which were of similar magnitude in both groups but lasted longer with alectinib.”
The FDA approved alectinib in November 2017 for the frontline treatment of patients with ALK-positive metastatic NSCLC, bsed on results from the ALEX study. Compared to crizotinib, alectinib improved progression-free survival (PFS) by 47% (hazard ratio [HR], 0.53; 95% CI, 0.38-0.73;P< .0001) in the trial, as assessed by an independent review panel. The FDA also gave its full approval to alectinib for patients with ALK-positive NSCLC who progressed on or are intolerant to crizotinib, converted from an accelerated approval.1
According to results from the ALEX trial, alectinib not only extended the time that people lived without worsening of disease compared to crizotinib but also markedly reduced the risk of cancer spreading to the brain or CNS.
Researchers at 161 locations in 31 countries randomly assigned treatment-naïve patients to twice daily dosages of 600 mg of alectinib or 250 mg of crizotinib for the ALEX trial. Determined by an independent review committee, median PFS was 25.7 months (95% CI, 19.9 to not reached) in the alectinib arm compared to 10.4 months (95% CI, 7.7-14.6) in the crizotinib arm.
Overall response rate (ORR) with alectinib was 79% (95% CI, 72-85) versus 72% (95% CI, 64-79) with crizotinib (P= .1652). The complete response rates were 13% with alectinib versus 6% with crizotinib. Partial response rate was found to be 66% in both arms.
Overall, 82% of patients receiving alectinib had a response duration ≥6 months, with 64% and 37%, having response durations ≥12 months and ≥18 months, respectively. Corresponding rates found in the crizotinib arm were 57%, 36%, and 14%, respectively.
Alectinib was found to have reduced the risk for progression in the CNS by 84% compared with crizotinib (HR, 0.16; 95% CI, 0.10-0.28;P< .0001). The 12-month cumulative incidence rate of CNS progression for people with or without existing CNS metastases at baseline was 9.4% (95% CI, 5.4-14.7) in the alectinib arm compared to 41.4% (95% CI, 33.2-49.4) for crizotinib.
The CNS objective response rate was 81% (95% CI, 58-95) in the alectinib arm versus 50% (95% CI, 28-72) in the crizotinib arm. The complete response rates were 38% versus 5%, respectively. There was a CNS response duration of 12 months or longer in 59% of the alectinib group compared to 36% of the crizotinib group.
“The high level of CNS activity shown with alectinib in the primary analysis is consistent with the fact that fewer patients treated with alectinib reported clinically meaningful worsening in health-related QoL or cognitive function compared to crizotinib,” Pérol said. “Finally, the superior tolerability profile of alectinib compared to crizotinib shown in this analysis is consistent with the adverse events profile recorded during the study."
Results leading to an FDA approval found that alectinib was associated with fewer serious AEs. From the findings of the ALEX trial, 41% of patients assigned to alectinib experienced grade ≥3 AEs compared with 50% in the crizotinib group. It is also noted that AEs leading to discontinuation (11% vs 13%), dose reduction (16% vs 21%), and dose interruption (19% vs 25%) were all lower with alectinib.2