Emerging Options After Progression During Crizotinib Therapy
Authors: Solange Peters
Journal: Journal of Clinical Oncology (2015)

ALK-rearranged non–small-cell lung cancer (NSCLC) constitutes a tiny subset of oncogene-addicted NSCLCs, representing 2% to 3% of early and 4% to 7% of advanced NSCLCs, respectively. A higher proportion of never-smokers and female patients are affected as compared with the typical lung cancer population. Crizotinib, the first available anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superiority over first-line chemotherapy, prolonging progression-free survival (PFS) from 7 to 10.9months and improving the response rate (RR) from 45% to 74% in the PROFILE 1014 trial. This mirrors the second-line trial, where crizotinib prolonged PFS by 4.5 months in comparison with docetaxel or pemetrexed. Crizotinib treatment invariably results in the emergence of resistance. Some resistance mechanisms have been elucidated. In 30% to 50% of cases, secondary ALKmutations, an ALK gene copy number gain, or both are documented. Alternatively, bypassing of ALK inhibition through alternative signaling pathways such as epidermal growth factor receptor, human epidermal growth factor receptor 2, KIT, or KRAS has been reported. A unique finding is the occurrence of CNS progression in patients treated with crizotinib. The CNS was the first site of progression in 46%, and the only site in 40% in a retrospective series of patients. The response of untreated brain lesions to crizotinib therapy was significantly lower than the response of systemic disease (18% v 53%) in a pooled analysis of crizotinib trials. In addition, the response duration and time to progression were significantly shorter in the CNS compared with other sites in patients with untreated brain lesions. The CNSwas the first site of progression in 72% of patients. In PROFILE 1014, where patients with treated brain metastases were enrolled, the progression rate of CNS disease was 15% in both the crizotinib and the chemotherapy groups. In PROFILE 1007, where patients with asymptomatic lesions were allowed, crizotinib impact on PFSwas stronger in the subgroupwithout a history of brain disease. Crizotinib penetration into the cerebrospinal fluid (CSF) is negligible (, 0.3% of plasmatic concentration). This pharmacologic limitation is of paramount importance in treatment decisions taking into account the high propensity of ALK-rearranged NSCLC to metastasize to the brain. Such metastases occur in 26% of naive, 35% of chemotherapy-pretreated, and 50% to 70% of crizotinib-pretreated ALK-positive NSCLCs. Additionally, the clinical impact of brain metastasis justifies a specific caution in preventing brain progression in cancer care in general. The use of crizotinib beyond progression occurs in routine clinical practice and in randomized clinical trials. In PROFILE 1014, 73% of patients with progressive disease continued to receive crizotinib beyond disease progression for a median duration of 3.1 months. This strategy has been adopted as a result of the lack of alternatives to relatively toxic chemotherapy regimens, as well as of the frequent progression restricted to the brain, allowing for irradiation and continuation of crizotinib. Some retrospective case series have suggested a potential clinical benefit of such therapy, despite data set limitations. In the retrospective series by Ou et al, overall survival from the time of progression was 16.4 months in patients who continued crizotinib (62%) versus 3.9 months in those who did not. However, the absence of randomization confounded these results. Today, this strategy has to be questioned. First, the assumption of indolent disease at progression, as described for T790M EGFR resistance, has not been demonstrated in ALK-rearranged NSCLC. Patients may therefore be denied effective subsequent chemotherapy options. Second, several ALK inhibitors are currently in clinical development. They are all more potent than crizotinib, with broader activity against a number of mutated ALK genes. They are also characterized by higher brain activity. Unfortunately, there are no CSF penetration data for most of these compounds. For five patients with CNS metastases at baseline treated with alectinib, a linear relationship between concentrations of alectinib in the CSF and paired systemic concentrations of alectinib was reported, with CSF concentrations approximating unbound systemic concentrations. Another complexity in evaluating brain activity of new ALK inhibitors is the frequent lack of serial prospective brain imaging. Finally, we lack rigorous criteria for measuring response in the brain. Two second-generation ALK inhibitors have been approved to date: ceritinib, approved worldwide for ALK-positive NSCLC after crizotinib failure, and alectinib, approved in Japan for all patients with advanced ALK-positive NSCLC. Alectinib doses up to 300 mg twice per day were evaluated in the crizotinib-naive AF-001 Japanese study. Because of Japanese regulatory constraints on themaximum amount of the vehicle sodium lauryl sulfate, dose escalation in the AF-001 study was stopped at 300 mg twice per day, and the maximum-tolerated dose was not reached. Alectinib doses ranging from 300 to 900 mg twice per day were assessed in the NP28761 study conducted in North America. Alectinib exposure after 300 mg twice per day was lower than that reported in Japanese patients, potentially related to variations in body weight. A dose of 600 mg twice per day resulted in equivalent to slightly higher exposure than that shown to be active in AF-001. The article by Ou et al that accompanies this editorial confirms sustained