The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of lorlatinib for the treatment of adult patients with ALK-positive advanced non–small cell lung cancer whose disease has progressed after alectinib or ceritinib as the first ALK TKI, or crizotinib and at least one other ALK TKI.
Chris Boshoff, MD, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of lorlatinib (Lorviqua, EU; US, Lorbrena) for the treatment of adult patients with ALK-positive advanced non—small cell lung cancer (NSCLC) whose disease has progressed after alectinib (Alecensa) or ceritinib (Zykadia) as the first ALK TKI, or crizotinib and at least one other ALK TKI.
The CHMP recommendation is based on a nonrandomized, dose-ranging, multicohort, multicenter phase II study (B7461001) that included a subgroup of 215 patients with ALK-positive metastatic NSCLC previously treated with ≥1 ALK kinase inhibitors. The overall response rate with lorlatinib in these 215 patients was 48% (95% CI, 42-55), including a complete response rate of 4% and a partial response rate of 44%. The median duration of response was 12.5 months (95% CI, 8.4-23.7).
The European Commission will now review the CHMP recommendation and make a final decision on the lorlatinib application. The FDA approved lorlatinib in November 2018 for this indication.
“Addressing drug resistance and relapse remains a challenge in the treatment of ALK-positive non—small cell lung cancer,” Chris Boshoff, MD, PhD, chief development officer, Oncology, Pfizer Global Product Development, the developer of lorlatinib, said in a press release. “This CHMP opinion represents a step forward in bringing Lorviqua to patients in Europe living with advanced ALK-positive non—small cell lung cancer who have limited treatment options.”
In the 215-patient efficacy population, 29 patients had prior crizotinib and no prior chemotherapy, 35 patients had prior crizotinib and 1 to 2 lines of prior chemotherapy, 28 patients had a prior ALK inhibitor (not crizotinib) with or without prior chemotherapy, 75 patients had 2 prior ALK inhibitors with or without prior chemotherapy, and 48 patients had 3 prior ALK inhibitors with or without prior chemotherapy.
The median age was 53 years (range, 29-85), 59% were female% 51% were white, and 34% were Asian. Ninety-six percent of patients had a baseline ECOG performance status of 0 or 1 and 95% had adenocarcinoma.
Sixty-nine percent of the 215 patients had a history of brain metastases, and 60% (n = 89) of these patients had measurable disease. Among this subgroup with measurable disease the intracranial response rate was 60% (95% CI, 49%-70%), comprising a 21% CR rate and a 38% PR rate. The median duration of response was 19.5 months (95% CI, 12.4 — not reached).
The safety population from Study B7461001 included 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who were treated with 100 mg of lorlatinib orally once daily. The median duration of treatment exposure was 12.5 months (range 1 day to 35 months), with 52% receiving the drug for at least 12 months.
The most common (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea; the most common (≥20%) laboratory abnormalities were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase.
Thirty-two percent of patient had serious AEs. The most common serious AEs were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). AEs resulting in death occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%).
AE-related discontinuations occurred in 8% of patients, 48% of patients needed dose interruptions, and 24% needed at least 1 dose reduction.
Lorlatinib prescribing information. FDA. Accessed November 2, 2018. https://bit.ly/2P6uini.