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DOI: 10.1055/s-0037-1619262
Impact on OS and PFS of 2nd and 3 rd Generation TKI in EGFR mt+ and ALK+ patients: Results of the NOWEL network
Publication History
Publication Date:
21 February 2018 (online)
Introduction:
EGFR TKI treatment is standard of care in pts with metastasized NSCLC carrying an activating EGFR mutation. Targeted therapies achieve a higher ORR, OS, PFS and a better quality of life than chemotherapy in mt+ pts. 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 pts in a real life setting in 3 lung cancer centers.
Methods:
1477 pts from 3 cancer centers diagnosed with non-squamous cell NSCLC stage IV (UICC 7) were examined. Methods for the mutation testing were performed according to the German Oncopedia guidelines using either Sanger Sequencing, COBAS® or Next Generation Sequencing.
Results:
945/1477 (64%) pts with non-squamous cell NSCLC from 3 cancer centers were studied for the presence of tumor mutations, especially for EGFR and ALK mutations. The EGFR mutation rate was 16% (149/912), and the ALK-translocation rate 4% (26/700). Median OS in EGFR mt+ pts was 27 months (n = 149) compared to 11 months (n = 763) in pts with EGFR WT (p < 0.000). Median OS in EGFR mt+ pts depending on the center was 25 (n = 97) vs. 28 (n = 38) vs. 16 (n = 14) months respectively (center 1 vs. center 2 vs. center 3). Median OS in ALK+ pts was 24 months (n = 19) in center 1, 11 months (n = 5) in center 2 and in center 3 median OS was not reached (p < 0.025). The ORR in the CR/PR group was 54.2% for pts treated with chemotherapy and 77% for pts treated with TKI on 1st line therapy. The chance to reach a CR/PR on 1st line therapy is 2.83 higher for pts on TKI than for pts on chemotherapy (p < 0.02). The use of 3rd gen TKI Osimertinib lead to a significantly higher OS (n = 20, median OS 67 months) than the use of only 1st and 2nd gen TKI (n = 122, median OS 23 months, p < 0.000). The hazard ratio HR for pts treated without Osimertinib was 4.66 [95% CI 2.006 – 10.81] (p < 0.000). Similarly, use of 2nd and 3rd gen ALKi impacted significantly on median OS: Crizotinib alone (n = 8), 15 months, Crizotinib followed by Ceritinib and/or Brigatinib/Alectinib (n = 14) median OS 25 months and 3 months for other therapies (n = 3) (p < 0.001).
POPLAR study |
||||
ITT (n = 287) |
BEP (n = 211) |
|||
OS HR (95% CI) |
0.73 (0.53, 0.99) |
0.68 (0.50, 0.93) |
||
PFS HR (95% CI) |
0.94 (0.72, 1.23) |
0.90 (0.68, 1.20) |
||
bTMB subgroup |
> 10 |
> 16 |
> 20 |
|
No. of patients |
96 |
63 |
42 |
|
OSHR |
0.59 |
0.56 |
0.51 |
|
PFS HR |
0.68 |
0.57 |
0.58 |
|
OAK study |
||||
ITT (n = 850) |
BEP (n = 583) |
|||
OS HR (95% CI) |
0.73 (0.62, 0.87) |
0.64 (0.53, 0.77) |
||
PFS HR (95% CI) |
0.95 (0.82, 1.10) |
0.87 (0.73, 1.04) |
||
bTMB subgroup |
≥10 |
≥16 |
≥20 |
|
No. of patients |
251 |
158 |
105 |
|
OS HR |
0.69 |
0.64 |
0.65 |
|
PFS HR |
0.73 |
0.65 |
0.61 |
|
BEP, biomarker-evaluable population; bTMB, tumor mutational burden in blood; ITT, intention to treat. |
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 pts with EGFR mt and ALK-alterations in a real life setting.