Feasibility and Challenges for Sequential Treatments in ALK-Rearranged Non-Small-Cell Lung Cancer

Mei Elsayed; Farastuk Bozorgmehr; Daniel Kazdal; Anna-Lena Volckmar; Holger Sültmann; Jürgen R Fischer; Mark Kriegsmann; Albrecht Stenzinger; Michael Thomas; Petros Christopoulos

doi:10.3389/fonc.2021.670483

Feasibility and Challenges for Sequential Treatments in ALK-Rearranged Non-Small-Cell Lung Cancer

Front Oncol. 2021 Apr 20:11:670483. doi: 10.3389/fonc.2021.670483. eCollection 2021.

Authors

Mei Elsayed¹, Farastuk Bozorgmehr^{1

2}, Daniel Kazdal^{2

3}, Anna-Lena Volckmar³, Holger Sültmann^{2

4}, Jürgen R Fischer⁵, Mark Kriegsmann^{2

3}, Albrecht Stenzinger^{2

3}, Michael Thomas^{1

2}, Petros Christopoulos^{1

2}

Affiliations

¹ Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany.
² Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany.
³ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Division of Cancer Genome Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Department of Thoracic Oncology, Lungenklinik Löwenstein, Löwenstein, Germany.

Abstract

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.

Keywords: ALK-rearranged non-small-cell lung cancer; chemotherapy; overall survival; sequential therapies; tyrosine kinase inhibitors.