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PER Pulse™ Recap
The Treatment-Naïve Patient With ALK-Positive NSCLC
Several ALK inhibitors have been approved for the treatment of patients with ALK-positive non–small cell lung cancer (NSCLC), including crizotinib, ceritinib, alectinib, and brigatinib. Lorlatinib recently gained breakthrough therapy status, while entrectinib, X-396, and TPX-005 are in development. Crizotinib was the first of these agents to demonstrate efficacy in the first-line treatment of patients with ALK-positive NSCLC.1 Several second-generation ALK inhibitors have subsequently emerged, including alectinib, brigatinib, and ceritinib.1-7 These second-generation ALK inhibitors have demonstrated efficacy for many patients who have developed resistance to crizotinib. Historically, treatment paradigms have involved the sequential use of a second-generation ALK inhibitor after crizotinib for patients with advanced ALK-positive NSCLC. However, the results of the ASCEND-4 study showed that for previously untreated patients with stage IIIB/IV ALK-positive NSCLC, first-line ceritinib provided significantly greater median progression-free survival (PFS) compared with chemotherapy (16.6 vs 8.1 months; HR, 0.55; P <.00001).8
The J-ALEX study has also shaped the treatment paradigm for treatment-naïve patients with NSCLC. This study compared alectinib to crizotinib in the treatment of Japanese patients with ALK inhibitor-naïve ALK-positive NSCLC.9 At a second interim analysis, the median PFS had not yet been reached for patients treated with alectinib, while the median PFS was 10.2 months with crizotinib.9 There was also a greater incidence of grade 3 to 4 adverse events (AEs) in patients treated with crizotinib than was seen in patients treated with alectinib (52% vs 26%), as well as a greater incidence of dose interruptions (74% vs 29%) and treatment discontinuation (20% vs 9%) due to AEs.9 The phase III Global ALEX study also compared alectinib versus crizotinib for the treatment of patients with treatment-naïve, advanced ALK-positive NSCLC.10 In this randomized, open label study, patients were assigned to receive either 600 mg of alectinib twice daily (a higher dose of alectinib than used in the J-ALEX study) or 250 mg of crizotinib twice daily.10,11 Several other studies are exploring first-generation versus second- or third-generation ALK inhibitors. Although crizotinib has been the standard of care for first-line management of patients with ALK-positive NSCLC, recent investigations may change the standard of care for these treatment-naïve patients. Dr. Gandara and Dr. Gainor discuss the evolution of the treatment paradigm for untreated patients with ALK+ NSCLC.
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PER Pulse™ Recap
The Treatment-Naïve Patient With ALK-Positive NSCLC and CNS Metastases
Many patients with NSCLC develop central nervous system (CNS) metastases, including the subgroup of patients with NSCLC who are ALK-positive. Historical first-line treatment of ALK-positive+ NSCLC (crizotinib) has relatively poor CNS penetration, and development of treatment options that can control CNS metastases may help to improve outcomes. Considerations, such as side effect profiles, may influence the role of whole-brain radiotherapy versus other treatment modalities, but CNS control was found to be an important component of treatment.1
When evaluating CNS drug efficacy data for patients with NSCLC, it is important to consider several points. Comparing endpoints dominated by extracranial data, such as overall response rate, early overall nonprogressive disease, or PFS is not likely to be informative regarding CNS efficacy.2-4 CNS endpoints have to be considered based on whether the CNS is treated or not at baseline. If it is treated, the method of treatment (local or whole brain) should be considered. CNS duration of benefit is also important.2-4 Key studies, such as PROFILE 1014, ASCEND4, and J-ALEX, have shed light on the management of CNS metastases.5-7 Optimal management of CNS lesions associated with NSCLC remains a key treatment focus. Available data from second- and third-line therapies have shown improvements in extending patient survival, including patients with brain metastases.8,9 Dr. Camidge discusses the evidence pertaining to CNS metastases in patients with NSCLC, as well as treatment approaches.
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PER Pulse™ Recap
Sequencing Decisions and Evolution of Tumor Biology in Progressive ALK-Positive NSCLC
Alectinib, brigatinib, and ceritinib are all second-generation treatments that have been approved in the treatment of ALK-positive NSCLC; however, these agents have not been compared head-to-head. Ceritinib has demonstrated superior efficacy to single-agent chemotherapy for patients with ALK-positive NSCLC. There is no standard role yet for selection by specific mutation. Immunotherapy is likely relatively less active in patients with ALK-positive NSCLC based on limited data. Cross-resistance of one second-generation ALK-inhibitor versus another has not yet been studied. It is unknown if serial second-generation ALK-inhibitor agents are superior to chemotherapy. Therefore, it is imperative to define a role for molecular testing to help tailor treatment recommendations.
Genomic profiling using next-generation sequencing may help with identifying acquired ALK-resistance mutations. Gainor and colleagues recently explored mechanisms of acquired resistance to first- and second-generation ALK inhibitors and found that a greater incidence and distinct spectrums of mutations emerge with potent second-generation inhibitors.1,2 The ALK G1202R mutation increases greatly after second-generation ALK inhibitor therapy with alectinib or ceritinib. The L1196M mutation often occurs after treatment with crizotinib. These mutations influence sensitivity to available ALK inhibitors.2 ALK-resistance mutations are predictive for sensitivity to lorlatinib. Consequently, it is important to determine accurate tumor molecular characterization when disease progresses, in order to tailor therapy.2 Monitoring of patients who are treated with crizotinib or alectinib can be done with liquid biopsy.3
Many ALK mutations can be detected by next-generation sequencing with free circulating tumor DNA. Resistance mutations that emerge on the ALK gene can differ depending on the treatments used to target an ALK rearrangement.3 Liquid biopsy for ALK gene analysis may be an alternative when tissue biopsy is not feasible or of poor quality and in situations where early detection of ALK mutations associated with resistance can lead to timely change of treatment.3 Dr. West and Dr. Lovly discuss treatment sequencing for patients with progressive NSCLC, as well as tumor testing options.