Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program.

We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed. In total, 52 patients were included [median age 57 years (range 32-81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1-4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4 months, 8.0 months, 54% and 13.0 months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6 months. TP53 mutations were associated with a substantially reduced PFS (3.7 Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.

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© The Author(s), 2021.

Déclaration de conflit d'intérêts

Conflict of interest statement: Dr. Frost reports personal fees and other from AstraZeneca, personal fees and other from BMS, personal fees and other from AbbVie, personal fees and other from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Roche, personal fees from MSD, personal fees from Takeda, outside the submitted work; Dr. Christopoulos reports grants and personal fees from Novartis, grants and personal fees from Roche, grants and personal fees from AstraZeneca, personal fees from Pfizer, grants and personal fees from Takeda, personal fees from Chugai, personal fees from Boehringer, outside the submitted work; Dr. Kauffmann-Guerrero reports personal fees from Pfizer, personal fees from Takeda, outside the submitted work; Dr. Stratmann reports personal fees from Bristol-Myers Squibb, personal fees from Novartis, personal fees from Roche Pharma, outside the submitted work; Dr. Riedel has nothing to disclose. Dr. Schäfer has nothing to disclose. Dr. Alt has nothing to disclose. Dr. Guetz has nothing to disclose. Dr. Christoph reports personal fees and non-financial support from Pfizer, during the conduct of the study; personal fees and non-financial support from Amgen, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Bayer, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Bristol-Myers Squibb, personal fees and non-financial support from Chugai, personal fees and non-financial support from Merck, Sharp & Dohme, personal fees and non-financial support from Novartis, personal fees and non-financial support from Roche, personal fees and non-financial support from Takeda, outside the submitted work; Dr. Laack has nothing to disclose. Dr. Faehling has nothing to disclose. Dr. Fischer has nothing to disclose. Dr. Fenchel has nothing to disclose. Dr. Haen has nothing to disclose. Dr. Heukamp reports personal fees from Roche, personal fees from NEO NewOncology, personal fees from Pfizer, personal fees from Bayer, personal fees from BMS, personal fees from Astra Zeneca, outside the submitted work; Dr. Schulz reports personal fees from Pfizer, personal fees and non-financial support from Roche, outside the submitted work; Dr. Griesinger reports grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, grants, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from Eli Lilly, grants, personal fees and non-financial support from MSD, grants, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from Pfizer, grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Takeda, personal fees from AbbVie, personal fees from Tesaro/GSK, grants and personal fees from Amgen, personal fees from Blueprint Medicines, outside the submitted work.