Pfizer Inc. (NYSE: PFE) announced today that the European Commission (EC) granted marketing authorization for LORVIQUA® (lorlatinib, available in the U.S. under the brand name LORBRENA®) as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)- positive advanced non-small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor.

Pfizer Korea said that its ALK (anaplastic lymphoma kinase)-positive non-small cell lung cancer (NSCLC) treatment Lorviqua 25mg and 100mg had received approval from the Ministry of Food and Drug Safety....hospitals can use the drug as a monotherapy only when a patient received alectinib or ceritinib as a first-line ALK inhibitor or when treated with crizotinib or at least another ALK inhibitor.

LORBRENA is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Lorviqua as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive advanced non small cell lung cancer (NSCLC)…

NON-SUPPORTIVE EVIDENCE: Lorlatinib is not recommended, within its marketing authorisation, for treating anaplastic lymphoma kinase (ALK)-positive advanced non-smallcell lung cancer (NSCLC) in adults who have not had an ALK inhibitor.

The NCCN NSCLC Panel recommends lorlatinib (category 2A) as a subsequent therapy option for select patients with ALK-positive NSCLC who have progressed after treatment with ALK inhibitors…

A clinically meaningful improvement in investigator-assessed PFS was also observed in the lorlatinib group compared with the crizotinib group (HR = 0.24, 95% CI: 0.14–0.41) (Fig. 2B)....Overall, 80% of patients with an objective response in the lorlatinib group and 29% in the crizotinib group had a duration of response (DOR) of at least 12 months....The findings of this subgroup analysis support the third-generation ALK TKI, lorlatinib, as a highly effective and safe first-line treatment option for Asian patients with ALK-positive NSCLC.

These updated, long-term data from CROWN show the durable benefit of lorlatinib over crizotinib in patients with treatment-naive, ALK-positive non-small-cell lung cancer and support the use of first-line lorlatinib in patients with and without baseline brain metastases.

Both ORR and IC ORR were clinically improved with lorlatinib vs crizotinib….Efficacy and safety results in the Asian subgroup were consistent with those in the overall population in the CROWN study. Our data support the use of lorlatinib as a first-line treatment option in Asian patients with ALK+ NSCLC.

In patients with brain metastases at baseline (n = 78), PFS by BICR was improved with lorlatinib (n = 38) compared with crizotinib (n = 40...patients without brain metastases at baseline (n = 218) showed a significant improvement in PFS with lorlatinib (n = 111) versus crizotinib (n = 107; median PFS NR v 11.0 months; 12-month PFS rate 78% [95% CI, 69 to 85] v 45% [95% CI, 34 to 55]; HR, 0.32; 95% CI, 0.20 to 0.49; P < .0001; Fig 1B)...lorlatinib improved PFS outcomes and reduced CNS progression in patients with previously untreated advanced ALK-positive NSCLC with or without brain metastases at baseline.

Pfizer Inc. (NYSE: PFE) announced updated results from the Phase 3 CROWN trial, which evaluated LORBRENA® (lorlatinib, available in Europe under the brand name LORVIQUA) versus XALKORI® (crizotinib) in people with previously untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). This analysis reported after a median follow-up of three years, LORBRENA continued to demonstrate meaningful improvement in progression-free survival (PFS) assessed by blinded independent central review (BICR), the primary endpoint, compared to XALKORI (HR, 0.27; 95% CI, 0.18–0.39), corresponding to a 73% reduction in the rate of progression or death.

Pfizer Inc...announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending LORVIQUA® (lorlatinib, available in the U.S. under the brand name LORBRENA®) for marketing authorization as a first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).

In this ongoing phase III trial (NCT03052608), untreated patients (n = 296) with ALK-positive advanced NSCLC were randomised to lorlatinib or crizotinib...Lorlatinib prolonged PFS and increased overall and intracranial response vs crizotinib….In the Asian subgroup, a consistent and clinically meaningful improvement in PFS was observed for lorlatinib vs crizotinib. The efficacy and safety of lorlatinib vs crizotinib in the Asian subgroup of CROWN was consistent with the overall population.

Pts with untreated ALK+ advanced NSCLC had higher ORRs and potentially longer DOR and PFS across predefined biomarker subgroups when treated with lorlatinib compared with crizotinib in a phase 3 CROWN study.

...Pfizer Inc. (NYSE:PFE) today announced that the U.S. Food and Drug Administration (FDA) has accepted for Priority Review the supplemental New Drug Application (sNDA) for LORBRENA ® (lorlatinib) as a first-line treatment for people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC).

In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. 

...Phase 3 CROWN study of LORBRENA® (lorlatinib) in people with previously untreated advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) met its primary endpoint by demonstrating significantly improved progression-free survival (PFS), as compared to XALKORI® (crizotinib).

Pfizer Inc. today announced that its investigational next-generation ALK/ROS1 tyrosine kinase inhibitor, lorlatinib, was granted Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), previously treated with one or more ALK inhibitors.

...Histologically or cytologically confirmed diagnosis of locally advanced or metastatic ALK-positive NSCLC; at least 1 extracranial measurable target lesion not previously irradiated. CNS metastases allowed if asymptomatic and not currently requiring corticosteroid treatment...

With approximately 2 years of additional follow-up since the prior analysis, the updated long-term data confirm robust overall and intracranial clinical activity of lorlatinib, with emergence of no new safety signals, and support the use of lorlatinib in Chinese patients with previously treated ALK-positive NSCLC with and without brain metastases.

With a median follow-up of 15.3 months (IQR: 6.2-19.2), median time-to-treatment discontinuation of lorlatinib was 15.3 months (95% CI: 7.9-not reached), with 54.2% (95% CI: 40.8-65.9%) of patients without treatment discontinuation at 12 months….Thus, patients with ALK-positive NSCLC post second-generation ALK TKI remained on lorlatinib for a meaningful duration of time while their quality-of-life was preserved.

The aim of the present study was to investigate the efficacy and safety of ALKis in ALK-positive NSCLC….Lorlatinib seemed to prolong PFS compared with alectinib (0.64, 0.37 to 1.07), brigatinib (0.56, 0.3 to 1.05), and ensartinib (0.53, 0.28 to 1.02).

We retrospectively analyzed patients with advanced ALK+ NSCLC previously treated with 1L alectinib….Among the 51 patients included in the study, 29 (56.9%) received 2L and 22 (43.1%) received ≥3L lorlatinib treatment….Median TTF with lorlatinib was 11.1 months (95% confidence interval [CI]: 4.6-13.8) in any line, 10.8 months (95% CI: 3.9-13.8) in 2L, and 11.5 months (95% CI: 2.9-not reached) in ≥3L....ORR was 35.7% with any-line lorlatinib treatment....Patient characteristics and efficacy were comparable with previous reports when lorlatinib was given after 1L alectinib in patients with ALK+ NSCLC.

...a systematic review with network meta-analysis (NMA) was developed to compare the efficacy (PFS and OS) and safety of lorlatinib with alectinib...NMA showed that lorlatinib was superior to alectinib for PFS (HR: 0.61; CI95%: 0.38 to 0.99)...Considering the NMA and the lower cost of treatment compared to alectinib, lorlatinib was incorporated into the Brazilian private healthcare system in May 2022, becoming another treatment option for patients with ALK+ NSCLC.

Objective response (lorlatinib versus crizotinib) was 68.0% (95% CI: 46.5-85.1) versus 52.2% (95% CI: 30.6-73.2) in all patients, and intracranial response was 100.0% (three of three, 95% CI: 29.2-100.0) versus 28.6% (two of seven; 95% CI: 3.7-71.0) in patients with brain metastases at baseline....The efficacy and safety of lorlatinib in the Japanese subgroup were similar to those in the CROWN global population, revealing improved outcomes versus crizotinib in Japanese patients with previously untreated, advanced ALK-positive NSCLC.

This was a multicenter, retrospective, observational study (NCT04979988) conducted at 16 sites in Japan that included patients who had been treated with lorlatinib in any line after 1L alectinib treatment as a systemic therapy....The TTF was 10.8 months (95% CI, 3.9-13.8 months) with 2L lorlatinib and 11.5 months (95% CI, 2.9 months-not evaluable [NE]) with ≥3L lorlatinib after 1L alectinib. The median TTF was 11.5 months (95% CI, 3.9-NE months) in patients with brain metastases and 9.9 months (95% CI, 4.3-13.8 months) in patients without brain metastases. The ORR was 44.0% (95% CI, 24.4%-65.1%) with 2L lorlatinib and 23.5% (95% CI, 6.8%-49.9%) with ≥3L lorlatinib after 1L alectinib.

A real-world analysis was performed on ALK-positive NSCLC patients enrolled in lorlatinib...For lorlatinib, the objective response rate was 36.7%, and disease control rate was 83.0%. Their median progression-free survival (PFS) and overall survival (OS) were 7.5 months and 87.9 months respectively.

We reviewed TRAEs and therapeutic efficacy for advanced non-small-cell lung cancer (NSCLC) patients receiving lorlatinib at our centre….Overall, the ORR was 53.8% and 71.4% for ALK- and ROS1- positive NSCLC, respectively….Lorlatinib is an effective treatment for ALK- and ROS1-driven NSCLC.

Lorlatinib showed substantial overall and intracranial activity in pretreated patients with ALK-positive NSCLC among both Asian and non-Asian patients.

There were 171 patients with ALK-positive advanced NSCLC admitted to our department from 2011 to 2019…The application of next-generation ALK-TKI after crizotinib failure significantly prolonged survival and direct sequencing lorlatinib seemed advantageous. Similarly, lorlatinib also prolonged survival in patients with first- and second-generation ALK-TKIs failure.

Open-label, dual-cohort study (NCT03909971); patients had progressive disease after ALK tyrosine kinase inhibitor (TKI) treatment (Cohort 1: previous crizotinib; Cohort 2: one ALK TKI other than crizotinib [±prior crizotinib]), ≥1 unirradiated extracranial target lesion, ECOG PS of 0–2. Patients received oral lorlatinib 100 mg once-daily in continuous 21-day cycles....Lorlatinib demonstrated a robust and durable response and high intracranial objective response in previously treated Chinese patients with ALK-positive NSCLC.

The median PFS, median overall survival (OS) from lorlatinib initiation and median OS from advanced NSCLC diagnosis were 9.9 months (95% confidence interval [CI] 6-12.3 months), 32.9 months (95% CI 18.7 months to not reached) and 97.3 months (95% CI 75.7-152.8 months), respectively. The median duration of treatment with lorlatinib was 11.8 months (95% CI 8.5-18.8 months). Overall response and disease control rate were 49% and 86%, respectively....Real-world evidence indicates that lorlatinib offers a significant clinical benefit and high intracerebral antitumour activity in heavily pretreated patients with ALK+ NSCLC.

Median OS post-progression for Groups A and B was NR (95% CI 21.4-NR) and 14.6 months (95% CI 11.2-19.2) in LBPD patients, and 8.0 months (95% CI 1.5-NR) versus 5.3 months (95% CI 2.8-14.3) in non-LBPD patients....In these retrospective analyses of a single-arm, multi-cohort, pivotal phase II study of lorlatinib in patients with previously treated ALK-positive NSCLC, the majority of patients who experienced investigator-assessed progression continued lorlatinib treatment post-RECIST progression.

We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC...Lorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity.

All those who took part had changes in a gene called ALK, which is involved in cell growth. In total, 296 participants from 23 countries took part. Half the participants took lorlatinib and half took crizotinib. After participants started taking lorlatinib or crizotinib...More participants who took lorlatinib had cancer that shrank (76%) compared with the participants who took crizotinib (58%)....Overall, the CROWN study showed that fewer participants with advanced ALK+ non-small cell lung cancer died or had tumor growth with lorlatinib compared with crizotinib treatment.

Lorlatinib showed robust clinical activity in Chinese patients with previously treated ALK-positive NSCLC...

At data cutoff (August 10, 2020), ORR (95% CI) by ICR in Cohort 1 was 70.1% (57.7–80.7) and in Cohort 2 was 47.6% (32.0–63.6). IC-ORR was 80.6% in Cohort 1 and 47.6% in Cohort 2….Lorlatinib showed robust clinical activity in Chinese patients with previously treated ALK-positive NSCLC, including those with CNS metastases.

Here we report primary data from a multicenter Phase 2 study conducted in China that investigated lorlatinib in ALK inhibitor-treated patients with ALK-positive NSCLC (NCT03909971)....Lorlatinib showed robust clinical activity in Chinese patients with previously treated ALK-positive NSCLC, including those with CNS metastases.

A total of 22 ALK-positive patients were analyzed....For lorlatinib, the objective response rate was 35.7%, and disease control rate was 64.3%. Their progression-free survival (PFS) was 6.2 months....efficacy of lorlatinib and adverse events were similar to those reported in clinical trials.

...patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy...Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post−second-generation ALK TKI setting…

...eligible patients with ALK- or ROS1-positive advanced NSCLC...received lorlatinib 100 mg once daily...Efficacy results of the total Asian population (summarized in Table 1) were similar to the overall population; with ORR of 56% versus 47%, IC-ORR of 59% versus 63% and median PFS of 8.2 versus 7.3 months, respectively.

...efficacy and safety of lorlatinib in previously treated ALK/ROS1(+) NSCLC...The ALK(+) cohort...Extracranial (EC) and intracranial (IC) response rates (RR) were 60% and 62%, with disease control rates (DCR) of 91% and 88% respectively. Mean duration of therapy (DoT) was 23.9±1.6 months and median overall survival (mOS) was 89.1±19.6 months.

Lorlatinib has demonstrated clinical antitumour activity against both intracranial and extracranial lesions in patients with anaplastic lymphoma kinase- or c-ros oncogene 1 (ROS1)-positive non-small cell lung carcinoma.

Median PFS and median overall survival from lorlatinib initiation were 9.72 months (95%CI, 5.95-11.96) and 32.92 months (95%CI, 18.73-NR), respectively. Overall response rate (ORR) and disease control rate were 50.6% (95%CI, 43.3% - 57.9%) and 86.7% (95%CI, 81.7% - 91.6%) respectively. CNS ORR was 42.9% (95%CI, 35.8% - 50.1%). 100 (50.8%) patients experienced tumor progression on lorlatinib. lorlatinib NSCLC provides significant clinical benefit as well as a central nervous system anti tumoral activity in heavily pre-treated advanced ALK+ patients.

The ALK(+) cohort included 50 % males, 73 % never-smokers and 68 % with brain metastases. Extracranial (EC) and intracranial (IC) response rates (RR) were 60 % and 62 %, with disease control rates (DCR) of 91 % and 88 % respectively. Mean duration of therapy (DoT) was 23.9 ± 1.6 months and median overall survival (mOS) was 89.1 ± 19.6 months.

...143 (71.5%) ALK+, 57 (28.5%) ROS1+, 87 (44%) men...At the time of initiation of lorlatinib, 146 (74%) patients had Central Nervous System (CNS) disease (78 % for ALK+, 63% for ROS1+), 131 (76%) were PS 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 3%/17%/27%/53%of ALK+ patients and in 30%/30%/16%/24%of ROS1+ patients, respectively....Median PFS and OS from the initiation of lorlatinib were 11.8 (95% CI 7.3-14.6) months and NR (95% CI 18.6-NR) months, respectively for ALK+ patients and 7.6 (95% CI 6.2-10.2) months and 20.9 (95% CI 10.0-NR) months, respectively for ROS1+ patients....These real-life results confirmed lorlatinib as a major treatment option for patients with advanced refractory ALK or ROS1+ NSCLC.

Among ALK+ patients treated with 2 prior TKIs, ≥2 prior TKIs, and ≥3 prior TKIs, objective response rate (ORR) and median progression-free survival (mPFS) were 42% (95% CI: 26-59; n = 38)...For ROS1+ patients, ORR and mPFS were 41% (95% CI: 18-67; n = 17) and 11.9 months (95% CI: 6.4-NR; n = 19)....Lorlatinib demonstrated meaningful activity in TKI-refractory ALK+ or ROS1+ NSCLC patients enrolled in early or expanded access programs.

All consecutive patients with advanced ALK+ NSCLC treated between October 2015 and June 2019 with lorlatinib as part of EAP were included….The median PFS, median overall survival (OS) from lorlatinib initiation and median OS from advanced NSCLC diagnosis were 9.9 months (95% confidence interval [CI] 6–12.3 months), 32.9 months (95% CI 18.7 months to not reached) and 97.3 months (95% CI 75.7–152.8 months), respectively.

For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31–63)….In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC...

A 57-year-old Japanese man was diagnosed with stage IVB non-small cell lung cancer...Bronchoscopy was performed again to guide further treatment, and the non-small cell lung cancer was found to be anaplastic lymphoma kinase positive….the patient’s request for oral medication, lorlatinib (100 mg/day) was administered as fourth-line therapy....Thirty-three months after the start of treatment, stable disease has been maintained, and lorlatinib has been continued...

Here, we report the remarkable response of a 73-year-old patient with ALK-positive NSCLC...Lorlatinib administration through a nasogastric tube alleviated complications related to consciousness within three days, and the patient survived for 16 months after CNS relapse.

Here, we show that lorlatinib induced apoptosis and protective autophagy in ALK-positive NSCLC cells....In order to verify the inhibitory ability of lorlatinib in ALK-positive NSCLC cells, we first observed the proliferation of H3122 and H2228 cells under lorlatinib treatment....Growth in the two NSCLC cell lines was clearly inhibited by lorlatinib (Fig. 1A).