Dr Santos on Frontline Therapies in ALK+ NSCLC

Edgardo Santos, MD, FACP, FCCP, clinical affiliate associate professor, Florida Atlantic University; treasurer, Florida Society of Clinical Oncology, discusses first-line treatment options for patients with ALK-positive non–small cell lung cancer (NSCLC).

Patients with NSCLC whose tumors harbor alterations in the ALK fusion protein have 3 effective first-line treatment options: the second-generation ALK inhibitors brigatinib (Alunbrig) and alectinib (Alecensa), as well as the third-generation ALK inhibitor lorlatinib (Lorbrena), Santos says. All 3 of these agents have generated high overall response rates (ORRs) when compared with crizotinib (Xalkori) in the phase 3 ALTA-1L (NCT02737501), ALEX (NCT02075840), and CROWN (NCT03052608) trials, Santos adds.

In ALTA-1L, brigatinib elicited an ORR of 71% (95% CI, 62%-78%) vs 60% (95% CI, 51%-68%) with crizotinib, as well as estimated 12-month progression-free survival (PFS) rates of 67% (95% CI, 56%-75%) and 43% (95% CI, 32%-53%), respectively. In ALEX, patients who received alectinib achieved an ORR of 82.9% (95% CI, 76.0%-88.5%) vs 75.5% (95% CI, 67.8%-82.1%) with crizotinib. Furthermore, the investigator-assessed 12-month event-free survival rates were 68.4% (95% CI, 61.0%-75.9%) and 48.7% (95% CI, 40.4%-56.9%) with alectinib and crizotinib, respectively. In CROWN, the ORRs were 76% (95% CI, 68%-83%) with lorlatinib and 58% (95% CI, 49%-66%) with crizotinib, and the 12-month PFS rates were 78% (95% CI, 70%-84%) and 39% (95% CI, 30%-48%), respectively.

In these pivotal trials, each of these ALK inhibitors also exhibited brain penetration, Santos notes. These agents induce responses in the brain if patients present with brain metastases, or lessen the cumulative incidence of metastatic events in the brain in patients who develop brain metastases during treatment, according to Santos.

Of all 3 agents, lorlatinib demonstrated the most efficacy in the brain, Santos says. This agent elicited an intracranial response rate of 82% (95% CI, 57%-96%) in patients with measurable brain metastases vs an intracranial response rate of 23% (95% CI, 5%-54%) in those who received crizotinib. Of the patients in the lorlatinib arm who had brain metastases, 71% achieved an intracranial complete response.