Alectinib Edge Over Crizotinib Supported by Patient-Reported Outcomes

Emmanuel S. Antonarakis, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Maurice Pérol, MD

In findings consistent with earlier results on efficacy and adverse events (AEs) reported for the phase III ALEX trial, investigators announced superior patient-reported outcomes for the next-generation tyrosine kinase inhibitor (TKI) alectinib (Alecensa) versus the standard of care TKI inhibitor crizotinib (Xalkori) in ALK-positive non—small cell lung cancer (NSCLC), at the 2018 European Lung Cancer Conference held April 11 to 14 in Geneva, Switzerland.

Health-related quality of life (QoL) and lung cancer-related symptoms were measured using the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires, respectively.

Fewer patients with CNS metastases at baseline in the alectinib group (n = 152) experienced a worsening in health-related QoL compared with those taking crizotinib (n = 151) starting at week 4 (10.8% vs 20.6%). This superior performance for alectinib continued for most assessments, conducted every 4 weeks during treatment, through week 84 (0% vs 16.7%).

In addition, at week 32, a smaller proportion of patients reported worsening in cognitive function with alectinib than with crizotinib (17.9% vs 34.6%, respectively.)

There was a clinically meaningful improvement in both treatment arms when it came to lung cancer symptoms, but patients on alectinib saw a longer duration of improvement versus 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).

Overall, there was a longer duration of improvement in health-related QoL for those taking alectinib versus crizotinib (88 weeks vs 68 weeks).

Investigators said the results are 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, 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, including cough, breathlessness, and chest pain.

The patient-reported data was 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.”

Based on results from the ALEX study, the FDA approved alectinib in November 2017 for the frontline treatment of patients with ALK-positive metastatic NSCLC. Compared with 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 full approval to alectinib for patients with ALK-positive NSCLC who have progressed on or are intolerant to crizotinib, converted from an accelerated approval.¹

In 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.

In the ALEX trial, 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. Median PFS, as determined by an independent review committee, was 25.7 months (95% CI, 19.9 to not reached) in the alectinib arm versus 10.4 months (95% CI, 7.7-14.6) in the crizotinib arm.

The 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% versus 6%, respectively, and the partial response rate was 66% in both arms.

Eighty-two percent of patients receiving alectinib had a response duration ≥6 months, with 64% and 37%, having response durations ≥12 months and ≥18 months, respectively. The corresponding rates in the crizotinib arm were 57%, 36%, and 14%, respectively.

Alectinib 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 and 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. CNS response duration was 12 months or longer in 59% of the alectinib group versus 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 in remarks about the findings reported at ELCC.

“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,” he said.

In the results that led to the FDA approval, Alectinib was associated with fewer serious AEs. In the ALEX trial, 41% of patients assigned to alectinib experienced grade ≥3 AEs compared with 50% in the crizotinib group. Additionally, AEs leading to discontinuation (11% vs 13%), dose reduction (16% vs 21%), and dose interruption (19% vs 25%) were all lower with alectinib.²

References

1. FDA Approves Genentech’s Alecensa (Alectinib) as First-Line Treatment for People with Specific Type of Lung Cancer. Genentech. Available at: http://bit.ly/2zmLda7. Accessed April 12, 2018.
2. Pérol M, Peters S, Pavlakis N, et al. Patient-reported outcomes (PROs) in ALEX. A phase III study of alectinib (ALEC) vs crizotinib (CRIZ in non — small lung cancer (NSCLC). Abstract 138PD. Presented at: the 2018 European Lung Cancer Conference; April 11-14; Geneva, Switzerland.

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