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

Abstract

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.

TP53 co-mutations as an independent prognostic factor in 2nd and further line therapy—EGFR mutated non-small cell lung cancer IV patients treated with osimertinib

“…Similarly, in ALK translocated NSCLC, it is well known that TP53 mt+ impact PFS and OS, an effect which is independent of the ALK fusion variant (21,22). In a recent analysis with the 3 rd generation ALK inhibitor Lorlatinib, it was shown that TP53 mt+ impact significantly on PFS and OS therefore underlining the overriding effect of TP53 mt+ on the effectiveness of the 3 rd generation ALK inhibitor (23).…”

Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study

“…Finally, as in other publications, several treatment discontinuations were observed following cognitive or mood disorders, highlighting the difficulty of managing this type of toxicity, which may also be exacerbated by the high frequency of brain metastases and prior radiation therapy. 14,15 In our study, we were able to analyze the subsequent therapies received after lorlatinib progression. Although significant efficacy of pemetrexed-based chemotherapy has been reported in ROS1þ NSCLC, data are lacking regarding the value of systemic treatment after lorlatinib failure.…”

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

“…), of the targeted therapy or the immuno/chemotherapy responsiveness and the follow‐up of the disease is a major challenge for the better understanding of NSCLC. Notably, it is essential to look for the different concurrent genomic alterations, notably TP53 mutations, in NSCLC showing a gene fusion 31,171–174 . This may lead to the development of new therapeutic strategies in the future.…”

“…Notably, it is essential to look for the different concurrent genomic alterations, notably TP53 mutations, in NSCLC showing a gene fusion. 31,[171][172][173][174] This may lead to the development of new therapeutic strategies in the future. So, a longterm vision of integration of NSCLC associated with a gene fusion is of strong interest.…”