With a response rate of approximately 75% and median progression-free survival (PFS) of nearly 1 year, crizotinib (Xalkori)—an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI)—has established itself as the standard of care for the first-line treatment of patients with ALK-mutation–positive non–small-cell lung cancer (NSCLC). Although crizotinib, the first ALK TKI to gain approval from the FDA and European Medicines Agency for the treatment of patients with ALK-positive NSCLC, significantly improves PFS compared with chemotherapy, acquired resistance makes disease progression virtually inevitable for patients treated with the drug, according to Giulio Metro, MD, and colleagues, who authored a review of treatment options for ALK-positive NSCLC in crizotinib-refractory patients.
“...Second-generation ALK-TKIs have repeatedly shown high anti-tumor activity in clinical trials of ALK-positive NSCLCs pretreated with crizotinib, reporting impressive ORRs and median PFSs ranging from 38.6% to 56.4% and from 5.4 months to 12.9 months, respectively,” Dr Metro and colleagues wrote. “On this basis, treatment with a second-generation ALK-TKI should be preferred to platinum-based chemotherapy in patients who progress on (or, less commonly, are intolerant to) first-line crizotinib.”
Crizotinib Beyond Disease Progression
Continuing crizotinib after disease progression remains an option only for patients with oligoprogressive disease, either with isolated central nervous system (CNS) relapse or progression at extracranial sites, both of which cases could be treated with continuing crizotinib with or without local ablation, generally with radiotherapy, at the sites in question. In both patient subsets, however, second-generation ALK TKIs are a viable—and perhaps preferable—option, particularly in those with oligoprogressive disease at extracranial sites.
Second-Generation ALK TKIs
The second-generation, highly selective ALK TKIs, ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig), all prove more effective than crizotinib in blocking the ALK tyrosine kinase. They also could overcome the secondary mutations that are mechanisms of resistance to crizotinib, including the L1196M gatekeeper mutation. The authors noted that sensitivity to the second-generation ALK TKIs may vary based on a patient’s ALK mutation, which could aid in treatment selection.
Showing a 20-fold greater potency versus crizotinib in enzymatic assays, ceritinib also overcomes some of the most prevalent ALK mutations associated with crizotinib resistance, including L1196M. In addition, in the phase 3 ASCEND-5 study, ceritinib showed greater efficacy than chemotherapy with pemetrexed or docetaxel in crizotinib-refractory patients who had received <2 lines of chemotherapy, 1 of which was platinum-based. In ASCEND-1 and ASCEND-2, ceritinib demonstrated particular clinical activity against brain metastases. The authors noted, however, that the available safety data from studies of the second-generation ALK TKIs point to ceritinib as the least tolerable, with nearly double the incidence of grade 1/2 gastrointestinal (GI) adverse events (AEs), and greater incidence of grade 3/4 GI AEs, increased alanine transaminase, and increased aspartate aminotransferase.
Demonstrating 5-fold greater potency than crizotinib, alectinib also shows activity against most secondary genetic mutations—including L1196M—associated with crizotinib resistance. Of note, alectinib is also highly active against CNS metastases. Alectinib’s efficacy in crizotinib-refractory patients was evaluated in the phase 2 global NP28763 and North American NP28761 studies, the results of which were the impetus for its FDA approval in December 2015 for the treatment of patients with ALK-positive NSCLC who progressed with crizotinib.
Brigatinib’s potency against ALK is 12 times greater than that of crizotinib, and it inhibits ROS1 kinase with similar potency. It has also shown preclinical activity against some secondary ALK mutations that can lead to crizotinib resistance. In a phase 1/2 trial by Gettinger and colleagues, brigatinib showed a 72% overall response rate (ORR) among 71 patients who had received previous treatment with crizotinib for ALK-positive NSCLC, with no maximum tolerated dose established. In the phase 2 ALTA trial of 222 patients with ALK-positive NSCLC pretreated with crizotinib, a 180-mg dose showed an ORR of 54%, versus 45% with a 90-mg dose; median PFS was 12.9 months versus 9.2 months, respectively. Brigatinib’s FDA breakthrough therapy designation was based on these data, which support a 180-mg dose with a 7-day lead-in period at 90 mg for crizotinib-refractory patients with ALK-positive NSCLC. In addition, brigatinib showed CNS activity in the ALTA trial, with an intracranial ORR of 67% in patients (n = 18) with measurable CNS metastases by an independent review committee. A notable characteristic of brigatinib is its potential to overcome the ALK G1202R resistance mutation, a prospect that is lacking in the other second-generation ALK TKIs.
Options After Progression with Second-Generation ALK TKIs
For patients with ALK-positive advanced NSCLC whose disease progresses with second-generation ALK TKIs, treatment options include chemotherapy with a pemetrexed-containing regimen (if such a regimen has not been previously administered), a third-generation ALK TKI such as lorlatinib (which has shown the ability to overcome ALK G1202R), or immunotherapy.
“At the present time, no prospective data have specifically addressed the use of immunotherapy in ALK-positive advanced NSCLCs, therefore this option appears to be the least recommended in patients pretreated with crizotinib,” Dr Metro and colleagues wrote.
Metro G, Tazza M, Matocci R, et al. Optimal management of ALK-positive NSCLC progressing on crizotinib. Lung Cancer. 2017;106:58-66.