Lorlatinib Granted Breakthrough Therapy Designation by FDA for NSCLC

Lorlatinib has been granted a breakthrough therapy designation by the FDA for use in patients with <em>ALK</em>-positive metastatic non-small cell lung cancer who have previously received 1 or more ALK inhibitors.

Mace Rothenberg, MD

Lorlatinib has been granted a breakthrough therapy designation by the FDA for use in patients withALK-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 withALK- orROS1-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 wereALK-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% forALK-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]) amongALK-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.

Reference:

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.