Impact of Depth of Treatment Response on Outcomes of ALK+ NSCLC Treatment with Brigatinib and Crizotinib

Previous Results with Brigatinib in the Treatment of ALK⁺ NSCLC

The phase II ALTA¹ clinical trial, which involved patients with ALK⁺ NSCLC following progression on crizotinib therapy, demonstrated a significant response to brigatinib, with a median PFS of 16.7 months. In a retrospective analysis of this study, a deeper lesion response to treatment correlated with longer PFS and OS.²

The phase III ALTA-1L clinical trial subsequently demonstrated the superiority of brigatinib over crizotinib in patients with advanced ALK⁺ NSCLC who had not yet been treated with ALK inhibitors.³ Participants were randomized 1:1 to receive brigatinib 180 mg once daily (with a 7-day lead-in of 90 mg once daily) or crizotinib 250 mg twice daily. Brigatinib significantly extended PFS compared to crizotinib^{3, 4}, by more than 1 year (median PFS 24.0 vs 11.1 months; hazard ratio [HR] 0.48; 4-year PFS 36% with brigatinib vs 18% with crizotinib).

New post hoc Analysis of the ALTA-1L Trial

At the 2022 ASCO congress, the results of a post hoc analysis of the ALTA-1L trial focusing on the relationship between the depth of treatment response and the risk of disease progression or death were presented.⁴ Patients were stratified into 3 groups based on the largest reduction in the size of target lesions from the beginning of therapy according to RECIST 1.1 criteria:

• ≤ 50% reduction
• 51–75% reduction
• 76–100% reduction

The group with the smallest reduction in lesions served as a control for the other two groups.

Correlation of Target Lesion Volume Reduction with PFS and OS

Results were analyzed for 249 patients with available lesion size data. Basic clinical and demographic characteristics were comparable to the overall population in both groups. The median follow-up was 41 months (range 1–52 months) for patients treated with brigatinib and 16 months (range 1–52 months) for those treated with crizotinib.

Treatment with brigatinib was associated with a significantly deeper response of target lesions compared to crizotinib. A 76–100% reduction in target lesions was achieved in 56% of brigatinib-treated patients, compared to 34% of crizotinib-treated patients (p = 0.0005). A moderate (51–75%) reduction in target lesion size was achieved in 27% of patients treated with brigatinib and 30% with crizotinib; a minimal (≤ 50%) reduction was observed in 16% of brigatinib-treated patients and 35% with crizotinib. The median time to the deepest regression of the target lesion in patients with a confirmed treatment response was 14.6 months with brigatinib and 7.4 months with crizotinib.

Patients with a ≥ 50% reduction in target lesion size showed a lower risk of progression or death compared to those with a < 50% reduction, in both therapeutic groups. Similarly, patients with a ≥ 75% reduction in target lesions had a lower risk of progression or death compared to those with a < 50% reduction.

Conclusion

Patients with ALK⁺ NSCLC treated with brigatinib were significantly more likely to achieve a ≥ 75% reduction in target lesion size compared to crizotinib; a ≥ 75% reduction in target lesions compared to a < 50% reduction was associated with a reduced risk of disease progression or death, irrespective of treatment.

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Sources:
1. Kim D. W., Tiseo M., Ahn M.-J. et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol 2017; 35 (22): 2490−2498, doi: 10.1200/JCO.2016.71.5904. 
2. Huber R. M., Hansen K. H., Paz-Ares Rodríguez L. et al. Brigatinib in crizotinib-refractory ALK+ NSCLC: 2-year follow-up on systemic and intracranial outcomes in the phase 2 ALTA trial. J Thorac Oncol 2020; 15 (3): 404−415, doi: 10.1016/j.jtho.2019.11.004.
3. Camidge D. R., Kim H. R., Ahn M.-J. et al. Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. J Thorac Oncol 2021; 16 (12): 2091−2108, doi: 10.1016/j.jtho.2021.07.035.
4. Camidge D. R., Kim H. R., Ahn M.-J. et al. Association of depth of target lesion response to brigatinib with outcomes in patients with ALK inhibitor-naive ALK⁺ NSCLC in ALTA-1L. J Clin Oncol 2022 Jun 2; 40 (16 suppl.): 9072−9072, doi: 10.1200/JCO.2022.40.16_suppl.9072.