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Brigatinib confers intracranial responses in ALK-positive non-small cell lung cancer

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July 25, 2018

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D. Ross Camidge

Brigatinib conferred substantial intracranial responses and durable PFS among patients with brain metastases and ALK-positive, non-small cell lung cancer previously treated with crizotinib, according to ongoing study results.

“Crizotinib [Xalkori; Pfizer, EMD Serono], the first licensed ALK inhibitor, is very active but has clear central nervous system liability from poor CNS penetration. All of the next-generation ALK inhibitor drugs have started to show CNS efficacy consistent with their superior activity in the brain compared with crizotinib,” D. Ross Camidge, MD, PhD, director of thoracic oncology at University of Colorado, told HemOnc Today. “The whole clinical trials field has had to evolve around these events in terms of how we should capture and present CNS data. Brigatinib [Alunbrig; Takeda Oncology, Ariad] was one of the drugs that helped with this.

“Here, across two trials of brigatinib, we can see in measurable CNS disease a high CNS response rate, prolonged CNS control and importantly, an impact of dose on these endpoints,” Camidge added.

Results from two ongoing clinical trials, a phase 1/phase 2 study and the randomized phase 2 ALTA trial have demonstrated brigatinib activity among patients with advanced ALK-positive NSCLC, including those with baseline brain metastases.

In the phase 1/phase 2 trial, brigatinib yielded activity among patients treated with crizotinib, as well as crizotinib-naive patients.

In the ALTA trial, researchers randomly assigned patients to 90 mg oral brigatinib once daily (n = 112) or 180 mg oral brigatinib once daily (n = 110) following a 7-day lead-in at 90 mg once daily. Results showed overall response rates of 48% (95% CI, 39-58) in the 90-mg group and 53% (95% CI, 43-62) in the 180-mg group. After median follow-up of 8 months, median duration of response was 13.8 months in both arms.

The FDA granted accelerated approval to brigatinib based on tumor response rate and duration of response data from the ALTA trial. The FDA recommended a dose of 90 mg brigatinib orally once daily for the first 7 days, followed by an increased dose of 180 mg orally once daily, if well tolerated.

For this study, Camidge and colleagues reported results from an exploratory analysis of the efficacy and safety of brigatinib among patients with ALK-positive NSCLC and baseline brain metastases.

In phase 1 of the phase 1/phase 2 study, researchers enrolled patients with advanced malignancies other than leukemia. In phase 2, researchers enrolled five cohorts of patients with: ALK-positive NSCLC naive to ALK inhibitors; ALK-positive NSCLC previously treated with crizotinib; epidermal growth factor receptor (EGFR) T790M-positive NSCLC resistant to one previous EGFR TKI; other cancers with abnormalities that brigatinib targets; and ALK-positive NSCLC with active, measurable brain metastases.

Camidge and colleagues included the three cohorts of patients with ALK-positive NSCLC in this analysis.

Researchers administered 90 mg to 240 mg per day oral brigatinib in the phase 1/phase 2 trial.

Patients with brain metastases in ALTA received 90 mg once daily brigatinib (n = 80) or 180 mg brigatinib once daily with a 7-day lead-in at 90 mg (n = 73).

In both trials, treatment continued until disease progression that required alternative systemic therapy, intolerable toxicity or consent withdrawal. In ALTA, patients who received 90 mg brigatinib and experienced disease progression could receive 180 mg once daily.

The final analysis included 50 patients with baseline brain metastases treated with brigatinib in the phase 1/phase 2 study — which represented 63% of 79 total patients with ALK-positive NSCLC — and 153 patients with baseline brain metastases from ALTA, which represented 69% of 222 total patients with ALK-positive NSCLC.

Among patients in the phase 1/phase 2 trial, the confirmed intracranial ORR was 53% (95% CI, 27-79) for patients with brain metastases at least 10 mm in size.

Among patients in ALTA, the confirmed intracranial ORR was 46% (95% CI, 27-67) among patients dosed with 90 mg brigatinib, and 67% (95% CI, 41-87) among patients dosed with 180 mg brigatinib.

Researchers observed similar intracranial ORRs between subsets without prior radiation or progression postradiation.

The median duration of intracranial response among responders with any brain metastases at baseline was 11.4 months in the phase 1/phase 2 trial and was not reached in the ALTA trial in either dosing groups.

In the phase 1/phase 2 trial, median intracranial PFS was 14.6 months (95% CI, 12.7-36.8) among patients with any baseline brain metastases. In the ALTA trial, intracranial PFS was 15.6 months (95% CI, 9-18.3) with 90 mg brigatinib and 18.4 months (95% CI, 12.8-not reached) with 180 mg brigatinib.

For whole-body efficacy of brigatinib among patients with ALK-positive NSCLC with baseline brain metastases, investigator-assessed confirmed ORRs were 74% (95% CI, 59-86) among patients in the phase 1/phase 2 trial, and 40% (95% CI, 29-52) among patients who received 90 mg brigatinib and 59% (95% CI, 47-70) among those who received 180 mg brigatinib in the ALTA trial.

Limitations of the study included a lack of systematically collected brain images, as well as the retrospective collection of data, which has been common among other ALK studies.

“Inevitably we are moving from capturing data retrospectively to prospectively, to more cleanly defining what is and isn’t measurable in the CNS, including logging the impact of prior radiation as a confounder, and recognizing that for some drugs, the potential to escalate the dose to determine a CNS dose or schedule may be on the table to be explored even after a general dose is determined,” Camidge said.

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“I think we will see a lot more emphasis given to CNS endpoints in trials of cancers with CNS tropism — like lung cancers — in the future,” he added.

Brigatinib appeared to have comparable intracranial efficacy determined by ORR in measurable CNS lesions; however, comparative conclusions cannot be made from retrospectively selected subsets of these different trials due to heterogeneous inclusion criteria, Jeffrey R. Zweig, MD, from Stanford University School of Medicine, and Joel W. Neal, MD, assistant professor in the division of oncology at Stanford Cancer Institute of Stanford University School of Medicine, wrote in a related editorial.

“To date, there are no prospective data comparing the various second-generation ALK inhibitors in a head-to-head fashion,” they wrote.

Following disease progression, subsequent therapy with brigatinib or another ALK TKI may be reasonable based on the identification of specific resistance mutations.

“Resistance mechanisms are heterogeneous and include both on-target kinase mutations, such as ALK amplification and ALK secondary mutations, as well as target independent mechanisms through activation of bypass signaling pathways,” Zweig and Neal wrote. “Although repeat tissue or blood biopsies is an evolving standard of care, and resistance may be predicted based on the initial ALK fusion variant, CNS disease presents a unique barrier to repeat biopsy.”

Still, as more therapeutic options have emerged for patients with ALK-positive NSCLC over the last several years, there is “renewed optimism for achieving long-term control of this disease,” they added. – by Melinda Stevens

For more information:

D. Ross Camidge , MD, PhD, can be reached at University of Colorado Cancer

Center, 1665 Aurora Ct, Aurora, CO 80045; e-mail: ross.camidge@ucdenver.edu.

Disclosures: Camidge reports honoraria from G1 Therapeutics, Mersana Therapeutics, Roche and Takeda; and research funding from Takeda. Please see the study for all other authors’ relevant financial disclosures. Zweig reports no relevant financial disclosures. Neal reports consultant/advisory roles with AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genentech/Roche and Takeda; and research funding from ArQule, Boehringer Ingelheim, Exelixis, Genentech/Roche, Merck, Novartis and Takeda.

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