Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study

Abstract

Overall survival (OS) with the anaplastic lymphoma kinase (ALK) inhibitor (ALKi) crizotinib in a large population of unselected patients with ALK-positive non-smallcell lung cancer (NSCLC) is not documented. We sought to assess OS with crizotinib in unselected ALK-positive NSCLC patients and whether post-progression systemic treatments affect survival outcomes.ALK-positive NSCLC patients receiving crizotinib in French expanded access programs or as approved drug were enrolled. We collected clinical and survival data, RECIST-defined progressive disease (PD) and post-PD systemic treatment efficacy. We performed multivariable analysis of OS from crizotinib initiation and PD under crizotinib. Unselected ALK-positive NSCLC patients achieve good survival outcomes with crizotinib therapy. Next-generation ALKi may provide survival improvement after PD under crizotinib.

EML4‐ALK fusion variant V3 is a high‐risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non‐small cell lung cancer

“…8 This represents a major therapeutic success, but at the same time underscores the need to identify ALK 1 NSCLC patients with worse outcome, for which alternative management strategies should be pursued. Through sequential TKI administration combined with local ablative treatments median OS currently exceeds 5 years after two ALK inhibitors.…”

“…Most patients were irradiated as part of initial treatment for metastatic disease, while three patients (one V1, two V3) received radiotherapy as part of a CBDP strategy. 8 Nodules and/or effusion. 6 All patients were irradiated as part of initial treatment for metastatic disease and received as systemic first-line therapy crizotinib; two patients received 30 Gy in 5 fractions (one V3 and one V1), one patient a single fraction of 18 Gy at the 70% isodose (V3) and one patient a single fraction of 20 Gy at the 50% isodose for one 1 cm large supratentorial metastasis as well as for nine other 2-4 mm large lesions discovered during the radiotherapy planning brain MRI (V3).…”

“…For most patients with disease progression under these targeted treatments, after 1 to 2 years on average depending on the compound used, a second and even a third disease remission of several months' duration is still possible by treatment with a different TKI, ideally based on the results of conventional or liquid tumor biopsy. 8 This represents a new situation for thoracic oncology, in which median overall survival (OS) intervals with chemotherapy-based treatment of metastatic disease have always lain below one-and-ahalf years, 9 and poses a special challenge: the identification within the now generally favorable ALK 1 NSCLC patient group of cases with higher risk, which should preferentially be offered access to experimental treatments and more aggressive surveillance strategies, similar to the practice regarding other relatively favorable tumor entities, like various B-cell malignancies. [5][6][7] Thus, owing to TKI sequencing combined with local treatments, patients with metastatic ALK 1 NSCLC nowadays have the most complex management and experience the longest survival among all stage IV NSCLC patients, currently exceeding 5 years in median after two ALK inhibitors.…”

Identification of a highly lethal V3+TP53+ subset in ALK+ lung adenocarcinoma

“…2 However, the disease remains incurable, and patient outcomes vary widely. 3 The systematic identification of molecular factors critical for adverse outcome could refine risk assessment and guide preclinical studies that will advance therapeutic options.…”

Lorlatinib in ALK- and ROS1-positive NSCLC: the future has a start

“…With particular regard to ALK-and ROS1-positive tumors, the sequential development of oral tyrosine kinase inhibitors (TKIs) has allowed survival outcomes unconceivable before their availability (1)(2)(3). ALK and ROS1 are usually approached together as lung cancer oncogenes due to their similitudes arising from the phylogenic origin, structural similarities and way of activation (i.e., by gene rearrangement) (4).…”