Lorlatinib Prolongs PFS Over Crizotinib in ALK+ NSCLC, Adds to Existing Data for FDA Submission

Lorlatinib (Lorbrena) demonstrated an improvement in progression-free survival (PFS) compared with crizotinib (Xalkori) as treatment of patients with treatment-naïve advanced ALK-positive non–small cell lung cancer (NSCLC), meeting the primary end point of the phase 3 CROWN trial. Pfizer, Inc, announced the findings in a press release.¹

The safety profiles in CROWN were consistent with those observed in prior clinical trials, for both study drugs. Results from the study will be submitted to be presented during an upcoming medical congress.

“Almost a decade ago, we pioneered the first biomarker-driven medicine for ALK-positive NSCLC, which transformed treatment of this disease,” said Chris Boshoff, MD, PhD, chief executive officer, Oncology, Pfizer Global Product Development, in a statement. “These top-line results of the CROWN study reinforce the significant benefit of Lorbrena 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.”

Lorlatinib was granted a partial approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib along with a minimum of 1 other ALK inhibitor therapy for metastatic disease. It was an accelerated approval based on the tumor response rate and duration of response (DOR) observed with the drug in a 334-patient non-randomized, dose-ranging, multicohort, multicenter study (NCT01970865) of lorlatinib 100 mg once daily.^1,2

The objective response rate (ORR) observed was 48% (95% CI, 42%-55%), which included a complete response (CR) rate of 4% and a partial response (PR) rate of 44%. The median DOR was estimated to be 12.5 months (95% CI, 8.4-23.7).

Intracranial responses were also evaluated in 89 patients and showed an ORR of 60% (95% CI, 49%-70%) per RECIST v1.1. The intracranial CR rate was 21% and the PR rate was 38%. The estimated median DOR for intracranial response was 19.5 months (95% CI, 12.4-not reached).

Adverse events (AEs) were seen in over 20% of patients who receive lorlatinib in the study. The AEs were mainly edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. Laboratory abnormalities observed in patients were commonly hypercholesterolemia and hypertriglyceridemia.

CROWN was designed as a confirmatory study for the conversion to full FDA approval. Pfizer plans to share updated results from CROWN with the FDA and other health authorities to support the full approval of lorlatinib as treatment of treatment-naïve advanced ALK-positive metastatic NSCLC.

The CROWN study (NCT03052608) is a randomized, open-label, parallel 2-arm trial that includes 296 patients. The primary end point is assessed per blinded independent central review (BICR). The secondary end points of the study include overall survival, PFS by investigator assessment, ORR per BICR and investigator assessment, intracranial objective response, intracranial time to disease progression, DOR, intracranial DOR, time to tumor response, (TTR) intracranial TTR, PFS2 per investigator assessment, and safety.

Patients in CROWN receive lorlatinib 100 mg once daily on a continuous basis versus crizotinib 250 mg twice daily, continuously.

To be eligible, patients must be at least 18 years of age with a histological or cytologically confirmed diagnosis of local advanced or metastatic ALK-positive NSCLC with at least 1 extracranial measurable target lesion. Patients are also required to have an archival FFPE tissue specimen, an ECOG performance status of 0 to 2, adequate bone marrow, liver, renal, and pancreatic function.

Lorlatinib is a tyrosine kinase inhibitor with promising activity in preclinical models in lung cancer. The drug is known to inhibit tumor mutation that drive ALK inhibition resistance and surpass the blood brain barrier.

_References:

_{Lorbrena® (lorlatinib) significantly improves progression-free survival in first-line ALK-positive lung cancer. News release. Pfizer, Inc. August 05, 2020. Accessed August 05, 2020. https://bwnews.pr/3gxz1b0}

_{FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. News release. FDA website. November 2, 2018. Accessed August 05, 2020. https://bit.ly/2XvkpkW}