Re-Evaluating Progression in an Era of Progress: A Review of First- and Second-Line Treatment Options in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer

Abstract

The advent of crizotinib, the first small molecule inhibitor against anaplastic lymphoma kinase (ALK), has led to impressive advances in the care of patients with advanced ALK‐rearranged non‐small cell lung cancer. The development of second‐generation ALK inhibitors, starting with the recent U.S. Food and Drug Administration approval of ceritinib, promises to expand the therapeutic landscape for this cohort of patients. With increasing use of molecularly targeted therapy options, it has been observed that disease progression in patients receiving targeted agents has a heterogeneous biology, manifesting as either oligoprogressive or widely progressive disease, which may require development of innovative treatment strategies. This review discusses the first‐ and second‐generation ALK inhibitors approved or in clinical development, as well as the novel challenges and approaches to disease progression in patients on targeted agents. Implications for Practice: The identification of driver mutations in non‐small cell lung cancer (NSCLC), most prominently epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has expanded treatment options for a significant cohort of patients. However, the success of targeted agents has brought new challenges, particularly regarding management of progression. Progression manifests heterogeneously, and management of oligoprogression may differ from diffusely progressive disease. Multiple options for treatment at progression exist, and it is becoming evident that selecting the best avenue of care requires understanding the biology and potential drivers of disease progression. This review discusses the array of treatment options available for patients with ALK‐positive NSCLC, as well as evaluation and treatment of progressive disease.

Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial

“…[3][4][5] Most crizotinibtreated patients with ALK-positive NSCLC eventually experience progression, because of acquired changes in the dominant biology of the cancer, poor CNS drug penetration resulting in CNS progression, or both. [6][7][8] Mechanisms of acquired resistance to crizotinib typically involve changes in the ALK gene or activation of signaling pathways that bypass ALK. [9][10][11] Second-generation ALK inhibitors currently approved in the postcrizotinib setting, ceritinib and alectinib, have been associated with a median PFS of 5.7 to 6.9 months 12-14 and 8.1 to 8.9 months, 15,16 respectively.…”

Targeting ALK: Precision Medicine Takes on Drug Resistance

“…While most patients develop systemic, multisite progression requiring a change in systemic therapy, a subset of patients develop progression limited to only one or a few anatomic sites, with the remaining disease sites continuing to be controlled by the TKI. This phenomenon has been termed “oligoprogression” (155, 156). In the case of oligoprogressive disease, local ablative therapy (LAT) using surgery or radiation may serve as a strategy that offers several advantages (Figure 4).…”

Role of Local Ablative Therapy in Patients with Oligometastatic and Oligoprogressive Non–Small Cell Lung Cancer

“…This phenomenon may be due in part to poor blood-brain barrier penetration of targeted agents and a predilection of EGFR-mutated or ALK-positive NSCLC for the CNS. 66,67 In a study of 100 patients with advanced EGFR-mutant NSCLC treated with gefitinib or erlotinib (including 19 patients with brain metastases at the time of diagnosis), the 2-year cumulative risk of CNS progression was 19%. 68 Another study of 232 patients treated with gefitinib or erlotinib showed that the site of first disease progression was the CNS in 37 patients (16%).…”