Brigatinib Demonstrates Modest Activity in Select Patients with Crizotinib-Resistant ROS1+ NSCLC

Patients with ROS1-positive non–small cell lung cancer (NSCLC) who have resistance to the ROS1 and ALK inhibitor crizotinib (Xalkori) had intracranial and systemic responses to brigatinib (Alunbrig), according to findings from a small cohort published in Clinical and Translational Oncology.

Brigatinib is a potent ROS1 inhibitor, but there is limited evidence of its activity in ROS1-positive NSCLC. Prior research on brigatinib in patients who were either crizotinib-naïve or resistant to crizotinib showed that the agent could induce partial responses. To add to the data around brigatinib, 6 patients with ROS1-altered disease were selected from databases and evaluated for objective response rate (ORR), progression-free survival (PFS), duration of treatment, and safety.

Four out of 6 patients were evaluable for response, which was assessed by CT/PET-CT/MRI scans. Brigatinib achieved a partial response (PR) in 1 of the patients, and the remaining 3 displayed progressive disease (PD). In the patients who achieved a PR, the tumor diameter decreased to by 30% following treatment with brigatinib. Two patients in the study achieved stable disease (SD) with brigatinib. The ORR was 25%.

Patients 1 through 4 had PFS durations of over 7.6 months, 2.9 months, 2.0 months, and 0.4 months, respectively. It was noted, however, that 1 patient died shortly after discontinuation of brigatinib. Another patient remained progression-free for more than 9.7 months from the time of initiation of brigatinib until data cutoff.

The group of patients evaluated had a median age of 66 years (range, 55-80) and were predominantly male (83%). The ROS1 rearrangement partner was CD74 for 3 patients, EZR for 1 patients, and HNRNPC for 1 patient. The cohort had a median of 1 prior line of therapy (range, 1-7), with crizotinib being the most common prior treatment (100%). Notably, though, 33% of patients had received prior immune checkpoint inhibitors and 17% of patients each received prior lorlatinib (Lorbrena) and chemotherapy. The ECOG performance status was 0 or 1 for 50% of patients and 2, 3, or 4 for the remaining half of the study population. Only 1 patient had brain metastases at the time of brigatinib initiation.

One notable component of the obtained baseline information was that 2 patients had genomic testing prior to receiving brigatinib, but the remaining 4 patients did not. This became a relevant factor at the time of initial diagnosis when multiple genetic alterations aside from ROS1 were found in 2 of the patients who had PD, including MET c.2888-10_2909del and KRAS G12A in 1 patient and TP53 K139N, FGFR2 E250G, ATM G2695D, and NF1 R2258Q in the second patient. Investigators led by Elizabeth Dudnik, MD, of Thoracic Cancer Service, Davidoff Cancer Center, Rabin Medical Center, stated that the presence of multiple genetic alteration explains the lack of response to brigatinib in those select patients.

In terms of safety and tolerability, there was 1 case each of grade 1 maculopapular rash, grade 2 hyperamylasemia, and grade 1 creatine phosphokinase elevation. No patients experienced pneumonitis of any grade 3 to 5 toxicity that required reduction of brigatinib dosage or treatment discontinuation. There were no new safety signals observed with brigatinib in this assessment.

As part of the assessment of brigatinib in ROS1-positive NSCLC, Dudnik et al also evaluated the literature on 4 additional patients. Of the patients assessed 3 had failed crizotinib prior

to receiving brigatinib and was naïve to ROS1 inhibitor therapy. The best response was observed in the treatment-naïve patient, which was PR that led to a 60% decrease in tumor diameter. The response in this patient continued for more than 21.6 months. One of the patients with crizotinib-resistant disease also had a PR to brigatinib which resulted in a 59% reduction in tumor size. Of the remaining 2 patients, 1 had SD and the other had PD.

Together, these analyses show a modest activity with brigatinib in patients with crizotinib-resistant, ROS1-positive NSCLC. Dudnik et al anticipated a larger analysis to further evaluate sed activity.

_Reference:

_{Dudnik E, Agbary A, Grinberg R. et al. Clinical activity of brigatinib in ROS1‑rearranged non‑small cell lung cancer. Clin Transl Oncol. 2020; 22, 2303–2311. doi: 10.1007/s12094-020-02376-w}