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

Abstract

BackgroundAnaplastic 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.MethodsWe 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.ResultsAt 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.ConclusionsDespite 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.

Lorlatinib and compound mutations in ALK+ large-cell neuroendocrine lung carcinoma: a case report

“…Nonetheless, our index patient had an OS of 37 mo, which is longer than that of most published TKI-treated ALK+ LCNEC ( Table 3 ). One main reason might be the administration of multiple ALK inhibitor and chemotherapy lines, because more different types and lines of treatment have been linked to longer survival in both ALK+NSCLC and LCNEC ( Elsayed et al 2021 ; Fisch et al 2021 ). Of note, pemetrexed (fifth line) and paclitaxel (seventh line) were prioritized here as platinum partners over etoposide, based on the TP53 wt and RB1 wt status of the tumor, which suggest that the tumor may have an “NSCLC-like” biology ( Rekhtman et al 2016 ) with a possibly higher sensitivity to these cytotoxic drugs ( Derks et al 2018 ).…”

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

“…ALK rearrangements (typical genomic architecture is provided in Figure 1, upper panel) are present in 2%–6% of NS‐NSCLC 10 . These genomic alterations are sensitive to different molecules, notably to next‐generation TKIs (such as alectinib, brigatinib, and lorlatinib), which if given upfront result in significantly longer survival compared to initial treatment with the first‐generation inhibitor crizotinib or chemotherapy 9,11–13 . Excluding presence of an ALK fusion is also crucial before starting immunotherapy, due to the lack of efficacy and increased toxicity of the immune checkpoints inhibitors (ICIs) in ALK‐ positive NSCLC patients 14–16 .…”

“…Fusions were visualized using Arriba 9 chemotherapy. 9,[11][12][13] Excluding presence of an ALK fusion is also crucial before starting immunotherapy, due to the lack of efficacy and increased toxicity of the immune checkpoints inhibitors (ICIs) in ALKpositive NSCLC patients. [14][15][16] Besides a very low tumor mutational burden of ALK-positive tumors, uniquely below 3 mut/MB on average, 17 an immunosuppressive tumor microenvironment also appears to contribute to the inherent ICI resistance of these tumors.…”

Novel HIVEP1-ALK fusion in a patient with lung adenocarcinoma demonstrating sensitivity to alectinib: a case report

“…In case of oligoprogression, continuation of alectinib and radiotherapy of the enlarging lesion is also reasonable, especially if the blood liquid biopsy at that time is negative, as there are some retrospective data that ALK patients with oligoprogression and negative liquid biopsies have indolent disease and a very good prognosis (14). On the other hand, the treatment switch should not be delayed too much in those who need it, because up to 1/3 of these patients might show rapid clinical deterioration and miss any subsequent therapy (15). One very sensitive way to closely monitor ALK patients under treatment are serial liquid biopsies, which have been shown to detect emergence of resistance mutations and therapy failure several months earlier than radiologic imaging (16).…”