INTRODUCTION: We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. PATIENTS AND METHODS: 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. RESULTS: 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 versus 10.8 month, HR 3.3, p = 0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p = 0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS. CONCLUSIONS: 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.
- Frost, N.
- Christopoulos, P.
- Kauffmann-Guerrero, D.
- Stratmann, J.
- Riedel, R.
- Schaefer, M.
- Alt, J.
- Gütz, S.
- Christoph, D. C.
- Laack, E.
- Faehling, M.
- Fischer, R.
- Fenchel, K.
- Haen, S.
- Heukamp, L.
- Schulz, C.
- Griesinger, F.
Keywords
- Alk
- Nsclc
- Ros1
- Tp53
- brain metastases
- early access program
- lorlatinib
- 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.
