Alectinib induces CNS responses in pretreated, ALK–positive NSCLC

Alectinib effectively treated central nervous system metastases and demonstrated systemic activity in crizotinib-refractory anaplastic lymphoma kinase–rearranged non–small cell lung cancer, according to a pooled analysis of two studies published in the Journal of Clinical Oncology.

Patients with anaplastic lymphoma kinase (ALK)–positive NSCLC initially respond well to standard treatment with crizotinib (Xalkori, Pfizer); however, the majority will experience progressive disease within 1 year, and 70% of patients will have CNS progression as a new or nontarget lesion during treatment.

“New treatments are needed, not only to overcome acquired resistance to crizotinib, but also to achieve better clinical efficacy in the CNS,” Shirish M. Gadgeel, MD, thoracic oncologist at Karmanos Cancer Institute of Wayne State University, and colleagues wrote.

The phase 2 NP28673 and NP28761 studies — designed to evaluate alectinib (Alecensa, Genentech) in crizotinib-refractory ALK–positive NSCLC — showed activity in the CNS.

Therefore, Gadgeel and colleagues pooled safety and efficacy data from both studies to characterize the role of alectinib in the CNS.

All patients received 600 mg of alectinib twice daily.

Of the 225 patients enrolled in both studies, the CNS pooled analysis included 136 patients (60% of study populations) with baseline CNS metastases. Fifty of these patients had measurable CNS disease at baseline and 86 patients had nonmeasurable disease.

Further, 95 patients received prior CNS radiotherapy, 55 of whom completed CNS radiotherapy more than 6 months before starting alectinib.

At data cutoff, median follow-up was 12.4 months.

The group of patients with baseline measurable CNS disease demonstrated an ORR — determined by a central independent review committee — of 64% (95% CI, 49.2-77.1), with 11 complete responses observed; a CNS disease control rate of 90% (95% CI, 78.2-96.7); and a median CNS duration of response of 10.8 months (95% CI, 7.6-14.1).

For patients with measurable or nonmeasurable CNS disease at baseline, ORR by central independent review was 42.6% (95% CI, 34.2-51.4); CNS disease control rate was 85.3% (95% CI, 78.2-90.8); and median CNS duration of response was 11.1 months (95% CI, 10.3-not evaluable).

The ORR was lower among patients who received prior radiotherapy (35.8%; 95% CI, 26.2-46.3) than among patients without prior radiotherapy (58.5%; 95% CI, 42.1-73.7). Patients who received radiation less than 6 months prior to alectinib treatment also achieved an inferior ORR (27.5%; 95% CI, 14.6-43.9) compared with those who received treatment more than 6 months prior (41.8%; 95% CI, 28.7-55.9).

Complete responses were observed in 18% of patients with prior radiotherapy and 49% of patients without.

Eighty-three patients with baseline CNS metastases had a PFS event. The median time to a PFS event was 8.3 months (95% CI, 5.9-11.2), and the 6-month event-free rate was 58% (95% CI, 49.6-66.4).

Thirty-one of the patients with measureable CNS disease at baseline experienced a PFS event after a median of 9.2 months (95% CI, 7.4-15.9), equating to a 6-month event-free rate of 67.9% (95% CI, 54.9-80.9).

The researchers found no new adverse events, and alectinib was well tolerated regardless of baseline CNS disease.

“[This study demonstrates] that alectinib can provide CNS benefit regardless of whether the disease is measurable according to RECIST,” the researchers wrote. “Importantly, the responses observed in the CNS were durable ... and were comparable to those observed for the overall systemic disease assessment.”

Two phase 3, head-to-head trials designed to compare the systemic and CNS efficacy of alectinib with crizotinib in patients with ALK–positive NSCLC who are ALK inhibitor naive are ongoing. Preliminary results of the J-ALEX trial have showed promising PFS results with alectinib. – by Kristie L. Kahl

Disclosure: Gadgeel reports research funding from ACEA Biosciences, Acerta Pharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Five Prime Therapeutics, Genentech, Halozyme Therapeutics, Incyte, Janssen Oncology, Merck, Millennium, Novartis, OncoMed and Pfizer, as well as consultant and/or speakers bureau roles with ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Novartis, Pfizer. Please see the full study for a list of all other authors’ relevant financial disclosures.