Brigatinib Boosts Intracranial PFS and Health-Related QoL in ALK+ NSCLC

Brigatinib (Alunbrig) demonstrated sustained improvements in overall and intracranial progression-free survival (PFS) and health-related quality of life (HRQoL) compared with crizotinib (Xalkori) in patients with ALK-positive advanced non–small cell lung cancer (NSCLC), according to subgroup analyses from the phase 3 ALTA-1L trial that were presented at the 2020 ESMO Virtual Congress.^1,2

At the second interim analysis, the overall blinded independent central review (BICR)-assessed

median PFS in the intent-to-treat (ITT) population was 24.0 months in the brigatinib arm versus 11.0 months in the crizotinib arm (HR, 0.49; 95% CI, 0.35-0.68; P < .0001). The 2-year PFS rates were 48% and 26%, respectively.

Additionally, the intracranial BICR-assessed median PFS was 32.3 months with brigatinib versus 24.0 months with crizotinib (HR, 0.45; 95% CI, 0.29-0.69; P = .0001). The 2-year intracranial PFS rates were 65% and 50%, respectively.

On May 22, 2020, the FDA approved brigatinib for the first-line treatment of patients with ALK-positive metastatic NSCLC, as detected by an FDA-approved test.³

The approval is based on interim findings from the phase 3 ALTA-1L trial, in which brigatinib led to a 51% reduction in the risk of disease progression or death compared with crizotinib in patients with advanced ALK-positive NSCLC who had not received a prior ALK inhibitor.

In the international, open-label, multicenter, ALTA-1L trial, patients with stage IIIB/IV ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor, but could have received 1 prior regimen of chemotherapy in the advanced setting, were randomized to 180 mg of brigatinib once daily (n = 137), with a 7-day lead-in period at 90 mg, or 250 mg of crizotinib twice daily (n = 138). Crossover from the crizotinib arm to receive brigatinib was permitted at BICR-assessed PFS.

The primary end point of the study was BICR-assessed PFS, and secondary end points included objective response rate (ORR) per RECIST v1.1 criteria, intracranial ORR, intracranial PFS, overall survival (OS), safety, and tolerability.

Twenty-nine percent of patients had brain metastases at baseline with comparable pre-enrollment central nervous system (CNS) radiotherapy rates among both cohorts. Overall, 27% of patients had prior chemotherapy in the locally advanced or metastatic setting.

As of the second interim analysis, 55% of patients in the brigatinib arm (n = 75) and 17% of patients in the crizotinib arm (n = 23) remained on study treatment. Just less than half of patients discontinued crizotinib and crossed over to brigatinib (n = 61; 44%).

In patients with brain metastases at baseline, the median PFS was 24 months with brigatinib versus 5.6 months with crizotinib (HR, 0.25; 95% CI, 0.14-0.46; P < .0001). The 2-year PFS rates were 43% and 10%, respectively.

In patients without brain metastases at baseline, the median PFS was 24 months with brigatinib versus 13 months with crizotinib (HR, 0.65; 95% CI, 0.44-0.97; P = .030). The 2-year PFS rates were 50% and 32%, respectively.

Additionally, the BIRC-assessed event-free survival rates favored brigatinib in all landmark analyses in patients with baseline brain metastases.

In patients with any brain metastases at baseline, the median intracranial PFS was 24 months with brigatinib versus 5.6 months with crizotinib (HR, 0.31; 95% CI, 0.17-0.56; P < .0001). The 2-year intracranial PFS rates were 48% and 15%, respectively.

In patients with measurable brain metastases at baseline, the confirmed intracranial ORR was 78% in the brigatinib arm versus 26% in the crizotinib arm (P = .0014). In patients with any brain metastases at baseline, the ORRs were 66% and 16%, respectively (P < .0001).

Moreover, brigatinib led to fewer events and longer median overall and intracranial PFS versus crizotinib in patients with baseline brain metastases, irrespective of prior brain radiotherapy. Although overall and intracranial PFS was improved most with brigatinib versus crizotinib in patients with prior brain radiotherapy, benefit was also observed in patients without prior brain radiotherapy.

The most common sites of BICR-assessed intracranial progression included the frontal lobe, parietal lobe, and cerebellum in both arms.

Patients in the brigatinib arm also experienced sustained improvements in HRQoL, displaying significant delays in time to deterioration in multiple functional and symptom subscales versus crizotinib.

In the ITT population, patients’ EORTC QLQ-C30 global health status (GHS)/QoL score deteriorated in 43.5% of patients in the brigatinib arm versus 53.4% of patients in the crizotinib arm. The median time to deterioration was 26.7 months and 8.3 months, respectively (HR, 0.70; 95% CI, 0.49-1.00; P = .0485).

The time to deterioration across all EORTC QLQ-C30 subscale scores was significantly delayed with brigatinib versus crizotinib; these included physical functioning (HR, 0.67), role functioning (HR, 0.84), emotional functioning (HR, 0.56), cognitive functioning (HR, 0.75), social functioning (HR, 0.59), fatigue (HR, 0.67), nausea and vomiting (HR, 0.55), appetite loss (HR, 0.62), and constipation (HR, 0.52).

Brigatinib also led to a significant delay in time to deterioration in GHS/QoL score in patients with baseline brain metastases, with a median time of 16.6 months versus 4.7 months with crizotinib (HR, 0.54; 95% CI, 0.29-1.00; P = .0415). A numerical delay in time to deterioration in GHS/QoL score was also reported with brigatinib versus crizotinib in patients without brain metastases at baseline, with a median time to deterioration that was not reached with brigatinib versus 10.8 months with crizotinib (HR, 0.81; 95% CI, 0.52-1.26; P = .3284).

The time to deterioration in GHS/QoL score was also delayed in patients who received brigatinib versus crizotinib, regardless of whether they had received prior chemotherapy (HR, 0.76; 95% CI, 0.40-1.43; P = .4016) or not (HR, 0.68; 95% CI, 0.44-1.04; P = .0695); however, the difference in delay between arms was not statistically significant.

A trend toward delayed time to deterioration of GHS/QoL score in brigatinib responders versus brigatinib nonresponders was also reported. The median time to deterioration in GHS/QoL score was not reached in responders versus 7.7 months with nonresponders (HR, 0.53; 95% CI, 0.28-1.02; P = .0588).

References

1. Rosario Garcia Campelo M, Zhu Y, Lin HM, et al. Health-related quality of life in a phase 3 study of first-line brigatinib vs crizotinib in NSCLC: updated results from ALTA-1L. Presented at 2020 ESMO Congress; September 19-September 21, 2020; Virtual.Abstract 1305P.
2. Popat S, Kim HR, Ahn MJ, et al. Intracranial activity of brigatinib vs crizotinib: updated results from the ALTA-1L trial. Presented at 2020 ESMO Congress; September 19-September 21, 2020; Virtual. Abstract 1300P.
3. U.S. FDA approves Takeda’s ALUNBRIG® (brigatinib) as a first-line treatment option for patients diagnosed with rare and serious form of lung cancer. Takeda. May 22, 2020. Accessed September 30, 2020. https://bit.ly/3gc8qk5.