In two phase II trials, reported in the Journal of Clinical Oncology and The Lancet Oncology, the ALK inhibitor alectinib (Alecensa), which is active against acquired crizotinib resistance mutations and exhibits high central nervous system (CNS) penetration, was associated with considerable activity in crizotinib (Xalkori)-resistant/refractory ALK-positive non–small cell lung cancer (NSCLC), including CNS metastases.^1,2 Sai-Hong Ignatius Ou, MD, PhD, of the University of California School of Medicine, is the corresponding author of the Journal of Clinical Oncology article, and Alice T. Shaw, MD, PhD, of Massachusetts General Hospital, is the corresponding author of The Lancet Oncology article.

Global Phase II Study Details

In the study reported by Ou et al,¹ 138 patients from 56 sites in 16 countries were treated with oral alectinib at 600 mg twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment could continue beyond disease progression if considered to be of benefit by the treating physician. The primary endpoint was objective response rate by central independent review committee assessment. A total of 16 patients did not have Response Evaluation Criteria I Solid Tumors (RECIST)-measurable target lesions when assessed by the independent review committee, with 122 thus being considered evaluable for response.

These patients had a median age of 52 years, 56% were female, and 66% were white. Among all patients, 61% had CNS metastases, 42% had measurable CNS metastases, and 73% had received prior brain radiation (64% of these at > 6 months before starting alectinib). Best response to prior crizotinib was a partial response in 54%.

Responses

At the time of primary analysis, at a median follow-up of 30 weeks, the objective response rate was 49% (95% confidence interval [CI] = 40%–58%). At updated analysis at a median follow-up of 47 weeks, the response rate was 50% (95% CI = 41%–59%). The disease control rate was 79% (95% CI = 70%–86%), and median duration of response was 11.2 months (95% CI = 9.6 months to not reached). Among 96 patients (79%) who had received prior chemotherapy, the objective response rate was 45% (95% CI = 35%–55%), and the disease control rate was 77% (95% CI = 67%–85%). Median progression-free survival was 8.9 months (95% CI = 5.6–11.3 months) among all patients and 13.0 months (95% CI = 5.5 months to not reached) among 28 chemotherapy-naive patients.

CNS Response

Among 84 patients with baseline CNS metastases, 23 (27%) had a CNS complete response, and the overall CNS disease control rate was 83% (95% CI = 74%–91%); CNS duration of response was 10.3 months (95% CI = 7.6–11.2 months). The CNS response rate in 35 patients with measurable CNS lesions was 57% (95% CI = 39%–74%; 7 with a complete response). Of 23 patients with measurable or nonmeasurable CNS metastases and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate was 24.8%, and the cumulative non-CNS progression rate was 33.2% for all patients.

Adverse Events

Median duration of treatment was 27.1 weeks (range = 2.4–53.0 weeks) at data cutoff. The most common adverse events of any grade were constipation (33%, all grade 1 or 2), fatigue (26%, 1% grade 3), and peripheral edema (25%, 1% grade 3). The most common grade 3 or 4 adverse event was dyspnea (3%, grade 3). The most common adverse events considered related to study treatment were myalgia (17%), constipation (15%), fatigue (14%), and asthenia (11%).

Adverse events led to dose reduction/interruption in 21% of patients and to treatment discontinuation in 8%. Four patients (3%) died due to adverse events (intestinal perforation, dyspnea, pulmonary embolism, and hemorrhage), with a death due to intestinal perforation considered possibly related to study treatment.

The investigators concluded: “Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.”

North American Phase II Study Details

In the study reported by Shaw et al,² 87 patients with stage IIIB to IV ALK-positive NSCLC who had progressed after crizotinib from 27 sites in the United States and Canada were enrolled between September 2013 and August 2014 and treated with oral alectinib at 600 mg twice daily until disease progression, death, or withdrawal. Treatment could continue beyond disease progression if it was considered to be of benefit by the treating physician.

The primary endpoint was the proportion of patients achieving objective response on independent review committee assessment using RECIST criteria; response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were performed in the intent-to-treat population. The study is ongoing, and patients are still receiving treatment.

Patients had a median age of 54 years, 55% were women, 84% were white, 90% had an Eastern Cooperative Oncology Group performance status of 0 or 1, 62% were never-smokers, 99% had stage IV disease, 94% had adenocarcinoma, 60% had CNS metastases, and 74% had received prior chemotherapy. Of 34 patients (39%) who had received prior brain radiotherapy, treatment had occurred > 6 months before starting alectinib in 16 (47%).

Response Rates

At the time of primary analysis, at median follow-up of 4.8 months, 33 of 69 patients with measurable disease had a confirmed partial response, yielding a response rate of 48% (95% CI = 36%–60%); an additional 22 patients (32%) had stable disease. At updated analysis at a median follow-up of 9.9 months, 35 (52%, 95% CI = 40%–65%) of 67 patients with measurable disease had independent review committee–assessed objective response. Among the 35 patients with an objective response, median duration of response was 13.5 months (95% CI = 6.7 months to not estimable), with data from 21 of these patients censored at the time of data cutoff.

Estimated median progression-free survival among all 87 patients was 8.1 months (95% CI = 6.2–12.6 months), with data from 38 patients censored at the time of data cutoff. Estimated overall survival at 12 months was 71% (95% CI = 61%–81%).

CNS Response

Among 16 patients with measurable CNS disease at baseline, 4 (25%) achieved complete CNS response and 8 (50%) had a partial response, for an overall response rate of 75% (95% CI = 48%–93%); median duration of CNS response was 11.1 months (95% CI = 5.8–11.1 months). All 16 patients had disease control in the CNS. Among 52 patients with measurable or nonmeasurable CNS disease, 21 (40%, 95% CI 27%–55%) had an objective response, including 13 (25%) with a complete response; 33 (63%) with a noncomplete response or stable disease. Median duration of response was 11.1 months (95% CI = 10.8 months to not estimable). Disease control was achieved in 46 patients (89%, 95% CI = 77%–96%). Among 18 of the 52 patients who had not received previous brain radiation therapy, an objective response occurred in 12 (67%), including a complete response in 10; 5 patients had stable disease.

Adverse Events

The most common adverse events of any grade were constipation (36%), fatigue (33%), myalgia (24%), and peripheral edema (23%). The most common grade 3 or 4 adverse events were changes in laboratory values, including increased levels of blood creatine phosphokinase (8%), alanine transaminase (6%), and aspartate transaminase (5%) as well as dyspnea (3%).

Serious adverse events occurred in 15% of patients. Dose interruption occurred in 36%, and dose reduction occurred in 16%. Death due to adverse events occurred in two patients and was considered possibly related to study treatment in one patient (due to hemorrhage in a patient on anticoagulant therapy).

The investigators concluded: “Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.” ■

Disclosure: Both studies were funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit www.jco.ascopubs.org and www.thelancet.com.

References

1. Ou SI, Ahn JS, De Petris L, et al: Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: A phase II global study. J Clin Oncol. November 23, 2015 (early online release).

2. Shaw AT, Gandhi L, Gadgeel S, et al: Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial. Lancet Oncol. December 18, 2015 (early release online).

See commentary by Alice T. Shaw, MD, PhD, here.