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Lorlatinib significantly improved progression-free survival in treatment-naive patients with advanced ALK-positive non–small cell lung cancer versus crizotinib, meeting the primary end point of the phase 3 CROWN trial.
Lorlatinib (Lorbrena) significantly improved progression-free survival (PFS) in treatment-naive patients with advanced ALK-positive non–small cell lung cancer (NSCLC) versus crizotinib (Xalkori), meeting the primary end point of the phase 3 CROWN trial (NCT03052608).1
“Almost a decade ago, we pioneered the first biomarker-driven medicine for ALK-positive NSCLC, which transformed treatment of this disease,” Chris Boshoff, MD, PhD, chief development officer of Oncology at Pfizer Global Product Development, stated in a press release. “These topline results of the CROWN study reinforce the significant benefit of [lorlatinib] demonstrated in later-line settings, and we are excited to share these data soon with physicians and other healthcare providers, as well as engage with global regulatory authorities to potentially provide people with previously untreated metastatic NSCLC this third-generation ALK inhibitor.”
Results from the trial were reviewed by an independent data monitoring committee (DMC) as part of a prespecified interim analysis. Regarding safety, the profiles for both agents proved to be consistently with prior reports. Data from CROWN will likely be presented at an upcoming medical meeting.
In the open-label, parallel 2-arm, phase 3 trial, a total of 296 treatment-naïve patients with advanced ALK-positive NSCLC were randomized 1:1 to receive either continuous single-agent oral lorlatinib at 100 mg once daily or continuous oral crizotinib monotherapy at 250 mg twice daily.2
The primary end point of the trial is PFS per blinded independent central review (BICR) assessment. Key secondary end points include overall survival, PFS based on investigator’s assessment, objective response based on BICR and investigator assessment, intracranial objective response based on BICR, intracranial time to progression per BICR, and duration of response (DOR) per BIRC, time to second objective disease progression per investigator assessment, and safety, among others.
In November 2018, the FDA granted an accelerated approval to lorlatinib as a treatment for patients with ALK-positive metastatic NSCLC following disease progression on 1 or more prior ALK-targeted TKIs. The regulatory decision was based on data from a phase 2 study (B7461001); CROWN is the confirmatory trial to convert that decision to a full approval, according to Pfizer.
The pharmaceutical company plans to share the results from the phase 3 trial with the FDA and other health authorities to support the conversion to a full approval, as well as to expand the indication to include patients with previously untreated ALK-positive metastatic disease.
Data from the phase 2 study showed an overall response rate (ORR) of 48% (95% CI, 42%-55%) in a subgroup of 215 patients with ALK-positive metastatic NSCLC who were previously treated with 1 or more ALK TKIs; this included a complete response (CR) rate of 4% and a partial response (PR) rate of 44%. The median DOR was 12.5 months (95% CI, 8.4-23.7).
Within the 215-patient efficacy population, 29 patients had received previous treatment with crizotinib and no prior chemotherapy, 35 patients had previously received crizotinib and 1 to 2 lines of prior chemotherapy, 28 patients received a prior ALK TKI that was not crizotinib with or without prior chemotherapy, 75 patients received 2 prior ALK TKIs with or without prior chemotherapy, and 48 patients had received previous treatment with 3 ALK TKIs with or without prior chemotherapy.
The median age of participants was 53 years and 59% were female; moreover, approximately half of the patients (51%) were white and 34% were Asian. With regard to ECOG performance status, 96% had a status of 0 or 1. Ninety-five percent of patients had adenocarcinoma.
Notably, 69% of all participants in this subgroup had a history of brain metastases and 60% had measurable disease (n = 80). Of patients with measurable disease, the intracranial response rate with lorlatinib was 60% (95% CI, 49%-70%); this was composed of a CR rate of 21% and a PR rate of 38%. Moreover, the median DOR with lorlatinib was 19.5 months (95% CI, 12.4–not reached).
The safety population in the trial was comprised of 295 patients with either ALK-positive or ROS1-positive metastatic disease who had received treatment with oral lorlatinib at 100 mg once daily. The median duration of treatment exposure was 12.5 months and approximately half of patients (52%) received the drug for at least 12 months.
With regard to safety, the most common adverse effects (AEs) reported in 20% or more of patients included edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. The most commonly reported laboratory abnormalities included hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased aspartate aminotransferase, hypoalbuminemia, increased alanine transaminase, increased lipase, and increased alkaline phosphatase.
Additionally, 32% of patients experienced serious AEs (SAEs). The most commonly reported SAEs included pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). AEs that led to death were reported in 2.7% of patients who received the treatment; these effects 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%).
Toxicities that led to treatment discontinuation were reported in 8% of patients and 48% of patients required dose interruptions. Twenty-four percent of patients needed at least 1 dose reduction.