Brigatinib Maintains Superior PFS Benefit Over Crizotinib With High Intracranial Efficacy in ALK+ NSCLC

Sanjay Popat, BSc, MBBS, FRCP, PhD

Brigatinib (Alunbrig) resulted in a 52% reduction in the risk of disease progression or death and a 56% reduction in the risk of intracranial progression compared with crizotinib (Xalkori) in patients with ALK-positive non–small cell lung cancer (NSCLC), according to final data from the phase 3 ALTA-1L trial (NCT02737501) presented during the 2021 ESMO Congress.¹

At a median follow-up of 40.4 months (range, 0-52.4) with brigatinib (n = 137) and 15.2 months (range, 0.1-5.7) with crizotinib (n = 138), the median progression-free survival (PFS) per blinded independent review committee (BIRC) assessment was 24.0 months (95% CI, 18.5-43.2) and 11.1 months (95% CI, 9.1-13.0), respectively (HR, 0.48; 95% CI, 0.35-0.66; P < .0001).

The 3-year PFS rate achieved with brigatinib was 43% (95% CI, 34%-51%) vs 19% (95% CI, 12%-27%) with crizotinib; at 4 years, these rates were 36% (95% CI, 26%-46%) and 18% (95% CI, 11%-26%), respectively.

Moreover, the median intracranial PFS in the intent-to-treat population per BICR assessment was 44.1 months (95% CI, 32.2–not evaluable [NE]) vs 21.2 months (95% CI, 12.9-35.9) with crizotinib (HR, 0.44; 95% CI, 0.30-0.65; P < .0001). In patients with brain metastases at baseline, the median intracranial PFS per BICR assessment was 24.0 months (95% CI, 12.9-30.8) with brigatinib (n = 47) vs 5.5 months (95% CI, 3.7-7.5) with crizotinib (n = 49; HR, 0.29; 95% CI, 0.17-0.51; P < .0001).

“Final ALTA-1L results confirm the significant improvement in PFS with brigatinib compared with crizotinib in ALK-positive NSCLC with no new safety signals,” Sanjay Popat, BSc, MBBS, FRCP, PhD, a medical oncologist at the Royal Marsden Hospital, and colleagues, wrote in a poster on the data. “These results support brigatinib as a standard treatment option for treatment-naïve [patients with] ALK-positive NSCLC.”

Although the first-generation ALK inhibitor crizotinib has showcased superiority over chemotherapy in treatment-naïve patients with advanced ALK-positive NSCLC, most will experience disease progression within 1 year because of acquired resistance mutations and/or poor central nervous system (CNS) penetration.

Found to have broad preclinical activity against ALK resistance mutations, brigatinib has been under investigation in ALTA-1L, which had met statistical significance at the first preplanned interim analysis. By the second interim analysis, brigatinib was reported to have maintained durable BIRC-assessed PFS superiority over crizotinib (HR, 0.49; P < .0001).

Notably, in patients with brain metastases at baseline, the hazard ratio for BIRC-assessed PFS favored brigatinib over crizotinib at the second interim analysis, at 0.25 (95% CI, 0.14-0.46; P < .0001). The overall survival (OS) data had still been maturing at the time of the second analysis (HR, 0.92; 95% CI, 0.57-1.47).

To be eligible for enrollment on ALTA-1L, patients needed to be at least 18 years of age, have stage IIIB/IV ALK-positive NSCLC, and have received 1 or fewer prior systemic therapies for locally advanced/metastatic disease. Patients could not have previously received treatment with an ALK inhibitor. Notably, those with asymptomatic CNS metastases were permitted.

Study participants were randomized 1:1 to receive either a daily dose of brigatinib at a once-daily dose of 180 mg with a 7-day lead-in at 90 mg/day, or crizotinib at a twice-daily dose of 250 mg.

Patients were stratified based on baseline brain metastases (yes vs no) and whether they received prior chemotherapy for locally advanced/metastatic disease (yes vs no).

Investigators conducted disease assessments every 8 weeks through cycle 14 and then every 12 weeks, and patients on the crizotinib arm were able to crossover to the brigatinib arm upon disease progression per BICR assessment.

The primary end point of the trial was BIRC-assessed PFS per RECIST v1.1 criteria, and key secondary end points comprised confirmed objective response rate (ORR), confirmed intracranial ORR, intracranial PFS, OS, and safety.

A marginal structural model (MSM) was composed on OS to adjust for the possible time-dependent confounding effects of crossover following crizotinib discontinuation. Specifically, the MSM censors switches at the time of the treatment switch and then re-weights the data using information on baseline and time-dependent covariates.

In the final model, age, initial diagnosis stage, baseline ECOG performance status, histopathological class at study entry, measurable intracranial CNS disease (yes vs no), race group (Asian vs non-Asian), sex, smoking history, and strata at randomization represented the baseline covariates. Time-dependent covariates comprised intracranial disease progression, target lesion size, and ECOG performance status.

Forty-two percent of patients (n = 58) on the brigatinib arm and 12% of patients (n = 16) on the crizotinib arm were still receiving treatment prior to study conclusion. Forty-seven percent of patients (n = 65) crossed over from crizotinib to receive brigatinib following disease progression.

In these patients, the median duration of brigatinib received was 17.3 months (0.1-37.5). Forty-six percent (n = 19) of 41 patients who had brain metastases at baseline crossed over from the crizotinib arm to the brigatinib arm. Thirty-five percent (n = 23) of these crossover patients were still receiving brigatinib up until the end of the study.

Additional findings from the trial indicated that the median PFS per investigator assessment with brigatinib was 30.8 months (95% CI, 21.3-40.6) vs 9.2 months (95% CI, 7.4-12.7) with crizotinib (HR, 0.43; 95% CI, 0.31-0.58; P < .0001). The 3-year investigator-assessed PFS rates with brigatinib and crizotinib were 45% (95% CI, 36%-54%) and 18% (95% CI, 11%-26%), respectively; the 4-year rates were 36% (95% CI, 26%-46%) and 16% (95% CI, 9%-23%), respectively.

OS was still maturing at the time of the final analysis, with a 30% event rate, and indicated similar survival benefit in both arms (HR, 0.81; 95% CI, 0.53-1.22).

“An MSM OS sensitivity analysis that adjusted for possible confounding from crossover suggested that brigatinib treatment would have been associated with improved OS if treatment crossover from crizotinib to brigatinib had not been permitted,” the authors wrote. Specifically, the OS hazard ratio was 0.54 (95% CI, 0.31-0.92; P = .023).

The OS benefit was also reported with brigatinib (n = 40) vs crizotinib (n = 41) in patients with brain metastases at baseline was (HR, 0.43; 95% CI, 0.21-0.89; P = .020), despite the high rate of crossover from crizotinib. These data suggest “a survival benefit in patients with brain metastases who received brigatinib as the first ALK inhibitor,” according to the study authors.

The hazard ratio for OS in patients without brain metastases (n = 97 in each arm) at baseline was 1.16 (95% CI, 0.69-1.93; P = .603).

More patients who received treatment with crizotinib went on to receive subsequent anticancer therapy following discontinuation vs brigatinib. Among the 136 patients with brain metastases at baseline who received brigatinib, 33% received 1 subsequent systemic anticancer regimen, 5% received 2, and 21% received 3 or more. Among 137 patients with brain metastases at baseline who received crizotinib, 50% received 1 subsequent regimen, 17% received 2, and 19% received 3 or more.

Subsequent systemic therapy included ALK TKIs in the form of brigatinib, alectinib (Alecensa), lorlatinib (Lorbrena), crizotinib, or ceritinib (Zykadia); chemotherapy/or targeted therapy such as carboplatin, cisplatin, gemcitabine, paclitaxel, docetaxel, etoposide, erlotinib (Tarceva), or ifosfamide; immunotherapy such as atezolizumab (Tecentriq), nivolumab (Opdivo), or pembrolizumab (Keytruda); a VEGFR inhibitor; radiotherapy; or surgery.

Brigatinib also showcased health-related quality-of-life benefits over crizotinib, with a median time to worsening of EORTC QLQ-C30 Global Health Status of 26.7 months (95% CI, 8.3-NE) vs 8.3 months (95% CI, 5.7-13.5), respectively (HR, 0.69; 95% CI, 0.49-0.98; P = .047).

Regarding safety, all patients in both arms experienced any-grade adverse effects (AEs). Seventy percent of those who received brigatinib reported grade 3/4 AEs vs 56% of those who received crizotinib. Eleven patients on each arm experienced a grade 5 AE that resulted in death but none of these cases were determined to be related to treatment.

Moreover, 13% of those on brigatinib had an AE that resulted in treatment discontinuation vs 9% of those on crizotinib. Toxicities that resulted in dose reductions were reported in 44% of those on the brigatinib arm vs 25% of those on the crizotinib arm. AEs that required dose interruption were experienced by 72% and 47% of patients, respectively.

Reference

1. Popat S, Kim HR, Ahn M-J, et al. Brigatinib vs crizotinib in ALK TKI–naive ALK+ NSCLC: final results from ALTA-1L. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1195P. https://bit.ly/3CgcR7K

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