Mace Rothenberg, MD

The FDA has granted a breakthrough therapy designation to lorlatinib for use in patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have previously received 1 or more ALK inhibitors, according to Pfizer, the company developing the next-generation ALK/ROS1 tyrosine kinase inhibitor (TKI).

“This regulatory designation recognizes the potential for lorlatinib to provide an important treatment option for patients with ALK-positive NSCLC whose cancers have progressed despite treatment,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a release. “Pfizer’s rapid development of lorlatinib reflects a commitment to developing biomarker-driven therapies to meet the evolving needs of patients.”

The FDA grants Breakthrough Therapy status to expedite the development and review of a potential new medicine that treats a serious or life-threatening disease, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies.

Many patients with ALK- or ROS1-positive NSCLC develop resistance to TKI therapy, with the central nervous system (CNS) as a common site of relapse. Lorlatinib is a selective brain-penetrant ALK/ROS1 TKI active against most known resistance mutations.

The company submitted results to the FDA from the ongoing phase I/II study NCT01970865 (N = 54) presented at the 17th World Conference on Lung Cancer in 2016. As of January 2016, the study had accrued 41 patients who were ALK-positive, 12 who were ROS1-positive, and the mutation status of 1 patient was not recorded at cutoff.

Twenty-seven patients had received at least 2 prior TKIs before joining the study, 20 had received 1 prior TKI, and 7 were TKI-naïve. At baseline, 39 patients had CNS metastases. Twenty-six patients remain on-trial.

Patients received lorlatinib on day —7, then daily at 10 dose levels from 10 mg to 200 mg.

Overall response rate (ORR) was 47%, with 3 compete responses (CR) and 22 partial responses (PR).

ORR was 57% for ALK-positive patients with 1 prior TKI treatment (n = 14) with 1 CR (7%) and 7 PRs (50%). For ALK-positive patients with ≥2 prior TKI treatments (n = 26), ORR was 42% with 2 CRs (8%) and 9 PRs (34%).

For patients with target and nontarget lesions (n = 39) intracranial ORR was 36%. Ten patients had CR (26%) and 1 had unconfirmed CR, while 4 patients (10%) had PR and 2 others had unconfirmed PR.

Among patients with target lesions (n = 23), intracranial ORR was 47%. Seven patients (30%) had CR while 4 (17%) had PR and 2 others had unconfirmed PR.

Median duration of response was 10.5 months (95% CI 2.9— not reached [NR]) among ALK-positive patients and 12.4 months (95% CI 6.5—NR) among ALK+/ROS1+ patients.

The most common treatment-related adverse events (AEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was also the most common grade 3/4 treatment-related AE (11%) and most frequent reason for dose delay or reduction. No patient discontinued because of a treatment-related AE. Researchers determined that the highest acceptable dose was 100 mg once daily.

Researchers plan to present updated data at the upcoming 2017 ASCO Annual Meeting.

Felip E, Bauer TM, Solomon B, et al. Safety and efficacy of lorlatinib (PF-06463922) in patients with advanced ALK+ or ROS1+ non-small-cell lung cancer (NSCLC). Presented at: 17th World Conference on Lung Cancer; Dec. 4-7, 2016; Vienna, Austria. Abstract MA07.11.