Lorlatinib Approved in Europe for ALK+ Advanced NSCLC

The European Commission has granted a marketing authorization for lorlatinib for use as a single agent in the treatment of adult patients with ALK-positive advanced non–small cell lung cancer who did not receive a prior ALK inhibitor.

The European Commission has granted a marketing authorization for lorlatinib (Lorviqua) for use as a single agent in the treatment of adult patients with ALK-positive advanced non–small cell lung cancer (NSCLC) who did not receive a prior ALK inhibitor.1

The regulatory decision was supported by data from the phase 3 CROWN trial (NCT03052608), in which the agent resulted in a 72% reduction in the risk of disease progression or death vs crizotinib (Xalkori); 78% (95% CI, 70%-84%) of those in the lorlatinib arm were alive without disease progression at 12 months vs 39% (95% CI, 30%-48%) of those in the crizotinib arm (hazard ratio [HR], 0.28; 95% CI, 0.19-0.41; P < .001). Moreover, lorlatinib elicited an objective response rate (ORR) of 76% (95% CI, 68%-83%) vs 58% (95% CI, 49%-66%) with crizotinib.2

Notably, 82% (95% CI, 57%-96%) of 30 patients with measurable central nervous system (CNS) brain metastases at baseline who received lorlatinib achieved an intracranial response vs 23% (95% CI, 5%-54%) of those who were given crizotinib; 71% of patients in the investigative arm experienced an intracranial complete response vs 8% of those in the control arm.

“For more than a decade, Pfizer has worked tirelessly in its pursuit to help transform the trajectory for people living with advanced, biomarker-driven lung cancers,” Andy Schmeltz, global president and general manager of Pfizer Oncology, stated in a press release. “The European Commission’s approval of [lorlatinib] as a first-line therapy is a significant milestone that we hope will help bring a needed and meaningful difference to those impacted by this deadly disease in Europe.”

The global, randomized, phase 3 CROWN trial enrolled patients with histologically or cytologically confirmed, locally advanced or metastatic NSCLC with ALK positivity, and at least 1 extracranial measurable target lesion that had not been previously irradiated, an ECOG performance status of 0 to 2, as well as acceptable bone marrow, pancreatic, renal, and liver function.

Notably, those with asymptomatic treated or untreated CNS metastases were permitted. Patients were not allowed to have received prior systemic treatment for metastatic disease.

A total of 296 participants were randomized 1:1 to receive either oral lorlatinib at a daily dose of 100 mg (n = 149) or oral crizotinib at a twice-daily dose of 250 mg (n = 147). Treatment was continued until disease progression, death, withdrawn consent, or intolerable toxicity.

Stratification factors included the presence of brain metastases (yes vs no) and ethnic group (Asian vs non-Asian). Crossover between the arms was not allowed.

The primary end point of the trial was progression-free survival (PFS) per blinded independent central review (BICR), and key secondary end points were investigator-assessed PFS, overall survival (OS), ORR, objective intracranial response, and safety.

The median age among those who received lorlatinib was 61 years (range, 51-69) vs 56 years (range, 45-66); 56% and 62% of patients, respectively, were female, and 48% and 49% of patients, respectively, were White. Moreover, 53% of patients had an ECOG performance status of 1 vs 55% of those on the control arm. The majority of patients across the arms were never smokers, had stage IV disease, and had adenocarcinoma.

Eight percent of those in the lorlatinib arm previously received anticancer treatment vs 6% of those on the crizotinib arm; 6% and 7%, respectively, previously received brain radiotherapy, and 26% vs 27%, respectively, had brain metastases at baseline.

Additional data published in the New England Journal of Medicine showed that the investigator-assessed PFS was also significantly longer with lorlatinib vs crizotinib, with 80% (95% CI, 73%-86%) and 35% (95% CI, 27%-43%) of patients, respectively, free of disease progression at 12 months (HR, 0.21; 95% CI, 0.14-0.31).

Seventy percent of patients who received lorlatinib had a response to treatment that persisted for at least 12 months vs 27% of those who were given crizotinib. Similar responses were observed in the investigator assessment.

Among the 78 patients with measurable or nonmeasurable CNS metastases at baseline, the percentage of those who received lorlatinib and had a confirmed objective intracranial response per BICR was significantly higher than with crizotinib, at 66% (95% CI, 49%-80%) and 20% (95% CI, 9%-36%), respectively; 61% and 15% of patients, respectively, achieved a complete intracranial response.

In the intent-to-treat population, lorlatinib significantly prolonged the time to CNS progression vs crizotinib. Ninety-six percent (95% CI, 91%-98%) of patients who received lorlatinib were alive without CNS progression at 12 months vs 60% (95% CI, 49%-69%) with crizotinib (HR, 0.07; 95% CI, 0.03-0.17). At 1 year, the cumulative incidence of CNS progression as the first event was 3% in the investigative arm and 33% in the control arm (HR, 0.06; 95% CI, 0.02-0.18).

The OS data were still evolving at the time of data cutoff, which was March 20, 2020. The HR for death was 0.72 (95% CI, 0.41-1.25) and the between-group difference in OS was not found to be significant.

The toxicity profile observed with lorlatinib was compared to what has been observed in prior studies. The most common toxicities that occurred in 20% or more of the 149 patients who received the agent included edema, weight gain, peripheral neuropathy, cognitive effects, diarrhea, dyspnea, and hypertriglyceridemia.

Serious adverse effects were reported in 34% of those who received lorlatinib, the most common of which were pneumonia, dyspnea, respiratory failure, cognitive effects, and pyrexia. Moreover, 3.4% of patients who received lorlatinib experienced fatal toxicities, and 6.7% of patients permanently discontinued treatment with the agent.

“The expanded approval for [lorlatinib] in Europe is a considerable advancement – especially for the close to 40% of patients with ALK-positive metastatic NSCLC who are faced with brain metastases at diagnosis,” professor Benjamin Solomon, MBBS, PhD, of the Department of Medical Oncology, at Peter MacCallum Cancer Centre, added in the press release. “It is exciting to see the significant data generated from the CROWN trial continuing to support expanded use around the world and providing physicians in Europe with a highly effective option from the onset of their patients’ treatment journey.”

In November 2018, the FDA granted an accelerated approval to lorlatinib (Lorbrena) for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on 1 or more ALK TKIs.3 The decision was supported by findings from the phase 2 B7461001 trial (NCT01970865), which showed that the agent induced an ORR of 48% (95% CI, 42%-55%) among 215 patients.

In March 2021, the FDA approved a supplemental new drug application for lorlatinib to expand the indication to include the frontline treatment of patients with ALK-positive NSCLC based on findings from CROWN.4


  1. European Commission approves LORVIQUA (lorlatinib) as a first-line treatment for ALK-positive advanced lung cancer. News release. Pfizer Inc.; January 28, 2022. Accessed January 28, 2022. https://bit.ly/3ACOtxD
  2. Shaw AT, Bauer TM, dr Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187
  3. FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. News release. FDA; November 2, 2018. Accessed January 28, 2022. https://bit.ly/3sY5jBO
  4. US FDA expands approval of Pfizer's Lorbrena as first-line treatment for ALK-positive metastatic lung cancer. News release. March 3, 2021. Accessed January 28, 2022. http://bit.ly/30e9cWU