Impact on OS and PFS of 2nd and 3rd generation TKI in EGFR mt+ and ALK+ pts: Results of the NOWEL network

Abstract

Introduction: Available clinical research data shows that early mutation testing for patients with NSCLC stage IV could lead to an effective choice of therapy for patients with proven mutations. Targeted therapies achieve a higher ORR, OS, PFS and a better quality of life than chemotherapy in mt+ patients. With the advent of 2nd and 3rd generation TKI's effective in 1st generation TKI resistant tumors, we wanted to study the impact of these drugs on the outcome of patients in a real life setting in 3 lung cancer centers. Methods: 1381 patients from three cancer centers diagnosed with non-squamous cell NSCLC stage IV (UICC 7) were examined. Methods for the mutation testing was performed according to the German Oncopedia guidelines using either Sanger Sequencing or COBAS × or Next Generation Sequencing (hybrid capture NGS, New Oncology Cologne). Results: 879/1381 (64%) consecutive patients with non-squamous cell NSCLC from three cancer centers were studied for the presence of tumor mutations, especially for EGFR and ALK mutations. The EGFR mutation rate was 16.6% (141/847), and the ALK-translocation rate 3.8% (24/635). Median OS in EGFR mt+ patients was 28 (n = 79) vs. 28 (n = 38) vs. 16 (n = 14) months respectively (center 1 vs. center 2 vs. center 3). Median OS in ALK mt+ patients was 24 months (n = 17) in center 1 and 11 months (n = 5) in center 2 (p < 0.033). The ORR in the CR/PR group was 54.2% for patients treated with chemotherapy and 77% for patients treated with TKI on 1st line therapy. The chance to reach a CR/PR on 1st line therapy is 2.83 higher for patients on TKI than for patients on chemotherapy (p < 0.02). The use of 3rd generation TKI Osimertinib (n = 19) lead to a significantly higher OS (n = 19, median OS 67 months) than the use of only 1st and 2nd generation TKI (n = 111, median OS 23 months, p < 0.000). Patients treated with 3rd gen TKI had significantly longer PFS (11 months, n = 7) than patients treated without 3rd generation TKI (5 months, n = 45) (p < 0.037). Similarly, use of 2nd and 3rd generation ALKi impacted significantly on median OS: Crizotinib alone (n = 8), 17 months, Crizotinib followed by Ceritinib and/or Brigatinib (n = 10) median OS not reached and 3 months for other therapies (n = 6) (p < 0.001). Conclusion: Small differences in OS were observed, depending on the treatment centers, but the use of multiple EGFR and ALK-I impacted highly significantly on the outcome of patients with EGFR and ALK-alterations in a real life setting.