Brigatinib in Patients with ALK+ NSCLC – Final Results of the J-ALTA Clinical Study

Challenges of Targeted Therapy with ALK Inhibitors

Anaplastic lymphoma kinase (ALK) inhibitors have demonstrated significant clinical benefit over chemotherapy in patients with ALK-positive non-small cell lung cancer (NSCLC). However, resistance to therapy often develops during targeted therapy with tyrosine kinase inhibitors (TKIs) due to newly acquired mutations. Brigatinib is a next-generation TKI with strong activity against mutations causing resistance to ALK inhibitors.

J-ALTA Clinical Study

J-ALTA is the first prospective study with sufficient statistical significance to evaluate the effectiveness of brigatinib in patients after progression on alectinib. In addition to evaluating the effectiveness of brigatinib after alectinib, the goal of this open-label multicenter phase II study was also to confirm the efficacy of brigatinib in a cohort of TKI-naive patients.

The study involved 104 patients with ALK⁺ NSCLC in clinical stages IIIB–IV: 72 patients (56% women, median age 53 years) were refractory to TKI treatment, most frequently treated with alectinib or crizotinib followed by alectinib (alectinib-refractory; n = 47). The TKI-naive cohort consisted of 32 patients (53% women, median age 60.5 years). Study participants received brigatinib at a dose of 90 mg once daily for the first 7 days and then 180 mg once daily. The median follow-up duration was 22.1 months for the TKI-naive cohort and 24.2 months for the refractory cohort.

The primary objective of the study was to determine the objective response rate (ORR) in the refractory cohort. For the TKI-naive cohort, the primary objective was to determine the 12-month progression-free survival (PFS) rate. Another parameter assessed was the duration of response (DoR).

Results

At the time of the final analysis, the median follow-up was 24.2 months in the TKI-refractory cohort and 23.0 months in those refractory to alectinib.

Alectinib-Refractory Patients

In alectinib-refractory patients (n = 47), ORR was 34% (95% confidence interval [CI], 21–49; 16 partial remissions) with a median PFS of 7 months (95% CI, 4–13). The median duration of response was 15 months. In 8 patients from this subgroup, brain metastases were present at baseline, and the intracranial ORR in these was 25%. The median intracranial PFS in the entire subgroup was 21 months (95% CI, 9.2 to not reached).

Multi-TKI Refractory Patients

Among all patients refractory to TKI treatment (n = 72), the confirmed ORR was 32% (95% CI, 21–44%; 22 of them achieved partial remission).

TKI-Naive Patients

In TKI-naive patients (n = 32), the 12-month PFS rate was 90% (90% CI, 75–96%) and the 24-month PFS rate was 73% (90% CI, 55–85%). The median PFS was not reached, and the confirmed ORR was 97% (95% CI, 84–100%). Five participants had brain metastases at the start of the study, with an intracranial ORR of 40% in this group.

Safety Profile

The most common adverse events reported during treatment were increased creatine kinase levels (79%), hypertension (48%), and diarrhea (47%). In 63% of patients in the refractory cohort, treatment was interrupted due to adverse events, the dose was reduced in 31% of patients, and 7% discontinued treatment due to adverse events. Among TKI-naive patients, 94% paused treatment, 69% required dose reduction, but none had to discontinue treatment due to poor tolerability.

Conclusion

The final results on the efficacy and safety of brigatinib in patients with ALK-positive NSCLC were consistent with previous data analyses from the J-ALTA study and demonstrated efficacy even in alectinib-refractory patients. No new safety signals were observed in any of the cohorts. Brigatinib in this indication showed a favorable benefit-risk ratio in the monitored patients.

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Sources:
1. Kumagai T., Yoshida T., Nishio M. et al. P9075 Brigatinib in Japanese patients with ALK⁺ NSCLC: final results from the phase 2 J-ALTA trial [poster]. ASCO Annual Meeting, 2022 Jun 3.
2. Zhang P., Kumagai T., Yoshida T. et al. Brigatinib in Japanese patients (pts) with ALK⁺ NSCLC: final results from the phase 2 J-ALTA trial. J Clin Oncol 2022; 40 (suppl. 16): abstr. 9075, doi: 10.1200/JCO.2022.40.16_suppl.9075.

More information on the J-ALTA clinical study:

• Nishio M., Yoshida T., Kumagai T. et al. Brigatinib in Japanese patients with ALK-positive NSCLC previously treated with alectinib and other tyrosine kinase inhibitors: outcomes of the phase 2 J-ALTA trial. J Thorac Oncol2021 Mar; 16 (3): 452–463, doi: 10.1016/j.jtho.2020.11.004. 
• Kondo M., Sugawara S., Yokoyama T. et al. Brigatinib in Japanese patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC): first results from the J-ALTA tyrosine kinase inhibitor (TKI)-naive expansion cohort. J Clin Oncol 2021; 39 (suppl. 15): abstr. 9042, doi: 10.1200/JCO.2021.39.15_suppl.9042.