BACKGROUND: Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK(+) NSCLC) is a model disease for use of targeted therapies (TKI), which are administered sequentially to maximize patient survival. METHODS: We retrospectively analyzed the flow of 145 consecutive TKI-treated ALK(+) NSCLC patients across therapy lines. Suitable patients that could not receive an available next-line therapy ("attrition") were determined separately for various treatments, based on the approval status of the respective targeted drugs when each treatment failure occurred in each patient. RESULTS: At the time of analysis, 70/144 (49%) evaluable patients were still alive. Attrition rates related to targeted treatments were approximately 25-30% and similar for administration of a second-generation (2G) ALK inhibitor (22%, 17/79) or any subsequent systemic therapy (27%, 27/96) after crizotinib, and for the administration of lorlatinib (27%, 6/22) or any subsequent systemic therapy (25%, 15/61) after any 2G TKI. The rate of chemotherapy implementation was 67% (62/93). Both administration of additional TKI (median overall survival [mOS] 59 vs. 41 months for multiple vs. one TKI lines, logrank p=0.002), and chemotherapy (mOS 41 vs. 16 months, logrank p<0.001) were significantly associated with longer survival. Main reason for patients foregoing any subsequent systemic treatment was rapid clinical deterioration (n=40/43 or 93%) caused by tumor progression. In 2/3 of cases (29/43), death occurred under the first failing therapy, while in 11/43 the treatment was switched, but the patient did not respond, deteriorated further, and died within 8 weeks. CONCLUSIONS: Despite absence of regulatory obstacles and no requirement for specific acquired mutations, 25-30% of ALK(+) NSCLC patients forego subsequent systemic therapy due to rapid clinical deterioration, in several cases (approximately 1/3) associated with an ineffective first next-line choice. These results underline the need for closer patient monitoring and broader profiling in order to support earlier and better directed use of available therapies.
- Elsayed, M.
- Bozorgmehr, F.
- Kazdal, D.
- Volckmar, A. L.
- Sültmann, H.
- Fischer, J. R.
- Kriegsmann, M.
- Stenzinger, A.
- Thomas, M.
- Christopoulos, P.
Keywords
- ALK-rearranged non-small-cell lung cancer
- chemotherapy
- overall survival
- sequential therapies
- tyrosine kinase inhibitors
- and speaker’s honoraria from AstraZeneca, BMS, Pfizer. HS: advisory board and
- speaker’s honoraria from Roche. JF: advisory board honoraria from Boehringer, Roche,
- Celgene and AstraZeneca. AS: advisory board honoraria from BMS, AstraZeneca,
- ThermoFisher, Novartis, speaker’s honoraria from BMS, Illumina, AstraZeneca,
- Novartis, ThermoFisher, MSD, Roche, and research funding from Chugai. MT: advisory
- board honoraria from Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie,
- Boehringer, speaker’s honoraria from Lilly, MSD, Takeda, research funding from
- AstraZeneca, BMS, Celgene, Novartis, Roche and travel grants from BMS, MSD,
- Novartis, Boehringer. PC: research funding from AstraZeneca, Novartis, Roche,
- Takeda, and advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim,
- Chugai, Novartis, Pfizer, Roche, Takeda. The remaining authors declare that the
- research was conducted in the absence of any commercial or financial relationships
- that could be construed as a potential conflict of interest.
