ANAPLASTIC LYMPHOMA KINASE (ALK) was first identified in anaplastic large cell lymphoma. The ALK gene itself is not oncogenic, but it can become oncogenic by at least three mechanisms: by forming a fusion gene with a number of other partner genes, by copy number gain, or by mutations in the gene. The most common aberration in non–small cell lung cancer (NSCLC) is an inversion in chromosome 2, resulting in a fusion of the ALK gene with the echinoderm microtubule associated protein-like 4 (EML4) gene. The EML4-ALK–rearranged gene was first described in a patient with adenocarcinoma and shown to be oncogenic.
Approval of ALK Inhibitors
BY SERENDIPITY, the multikinase inhibitor crizotinib (Xalkori), which was being evaluated as a MET inhibitor, was found to be an inhibitor of ALK kinase, with striking activity in ALK-rearranged NSCLC, and was subsequently quickly approved for use in patients with ALK-rearranged NSCLC whose tumors had progressed on a platinum-containing doublet. Approval in these same patients in the first-line setting soon followed.
After the discovery of crizotinib as an ALK kinase inhibitor, a number of other pharmaceutical companies developed more-specific ALK kinase inhibitors, with the subsequent approval of the second-generation inhibitors ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig), in that order.
Currently, regulatory approval of ALK inhibitors in the United States is as follows:
• Crizotinib is approved for previously untreated NSCLC patients with ALK-rearranged tumors (median progression-free survival = 10.9 months) and in patients whose tumors have progressed on platinum-based chemotherapy (median progression-free survival = 7.7 months).
• Ceritinib is approved in patients with ALK-rearranged NSCLC whose tumors have progressed on crizotinib (median progression-free survival = 5.4 months). In the first-line setting, ceritinib has been approved with a median progression-free survival of 16.6 months in patients with ALK-rearranged NSCLC.
• Brigatinib is approved for patients whose tumors have progressed on or who are intolerant of crizotinib (median progression-free survival = 12.9 months).
• Alectinib is approved in patients whose tumors have progressed on crizotinib (median progression-free survival = 8.9 months).
There are a number of other ALK inhibitors with promising activity also in development. Notable among them are the third-generation agents lorlatinib and ensartinib. Why so many agents for a subset of patients that comprises only roughly 5% of the NSCLC population?
One reason seems to be that these patients’ tumors inevitably develop resistance, and subsequent therapies are needed. For instance, approximately 20% of patients treated initially with crizotinib acquire crizotinib-resistant secondary mutations, and about 50% of patients treated with second-generation ALK inhibitors become resistant due to secondary ALK mutations. In addition, one must note that in the United States, 5% of NSCLC represents more patients than testicular cancer, Hodgkin lymphoma, cholangiocarcinoma, or chronic myelogenous leukemia. Thus, the availability of multiple agents may allow oncologists to tailor treatment in the refractory setting based on the resistance mutation(s) in a particular tumor.
Key Findings From ALEX Trial
THE RECENT RESULTS of the phase III ALEX trial comparing alectinib with crizotinib in the first-line setting in ALK-rearranged NSCLC—reported by Peters and colleagues1—represent an advance in the therapy of this disease. In this study, which accrued patients from August 2014 to January 2016, progression-free survival on independent assessment was 25.7 months with alectinib vs 10.4 months with crizotinib, after a median follow-up of 18.6 vs 17.6 months; on investigator assessment, median progression-free survival was not reached vs 11.1 months.
This was a global study, thus ensuring that patients accrued represent a cross-section of patients with ALK-rearranged NSCLC. In addition, the patient population is highly representative of ALK-rearranged NSCLC patients being seen in oncology practices over the past several years. This internal consistency is supported by the fact that the median progression-free survival of 10.4 months in the crizotinib control arm is similar to the median of 10.7 months observed in the first-line crizotinib study performed between January 2011 and July 2013. Based on the efficacy and toxicity data, alectinib is clearly the most effective front-line ALK inhibitor at this time.
Debate Over First-Line Strategy
AN ONGOING PHILOSOPHICAL DEBATE in the oncology field is whether one should use the most effective agent in the front-line setting, thus unloading our strongest agent in our arsenal against the cancer first, or use the “weaker” agent first and then “rescue” tumors that progress with the most effective agent in the second-line setting. The rationale for the “weaker agent first” approach is the goal is prolonging patients’ lives, and using our most effective agent first leaves us with nothing effective to use in the second-line after disease progression.
In this instance, though, alectinib should clearly be used in the front-line setting for several reasons. First, this agent has significant activity in the central nervous system, a notorious sanctuary site and a common site of relapse for ALK-rearranged NSCLC. Second, the median progression-free survival of 25.7 months is much longer than one can obtain with any sequence of approved agents for which data are available at the present. Third, alectinib is much better tolerated, thus giving patients the best quality of life at the time of initial diagnosis. This has patient-level as well as societal benefits. Patients can be functional, taking care of themselves and their families and continuing to be productive in the work place.
Finally, there is always attrition with lives lost when we go from front-line to the second-line setting. Not all patients who receive a less-effective agent upfront are able to receive second-line therapy. The issue of resistance will need to be addressed. It is expected that more data will become available on the efficacy of various ALK inhibitors against specific alectinib-resistant mutations. For example, the ALK V1180L mutation has been reported to confer resistance to alectinib but not to ceritinib.
THE RESULTS of this well-performed study of alectinib represent an important advance for patients with ALK-rearranged NSCLC. Alectinib can now be considered the drug of choice for the front-line therapy of NSCLC patients with ALK-rearranged tumors. ■
DISCLOSURE: Dr. Adjei reported no conflicts of interest.
1. Peters S, Camidge DR, Shaw AT, et al: Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med. June 6, 2017 (early release online).