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<i>ALK</i>+ NSCLC: Brigatinib
My Thoughts on First-line Treatment for ALK-Positive NSCLC Today

Released: October 24, 2018

Matthew Gubens
Matthew Gubens, MD, MS
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Since the FDA approved the ALK/ROS1 inhibitor brigatinib for ALK-positive non-small-cell lung cancer (NSCLC) patients who progressed on or are intolerant to crizotinib, we have been waiting to see how this drug performs in the first-line setting. At WCLC 2018, Camidge and colleagues reported positive interim results from the phase III ALTA-1L trial on first-line brigatinib vs crizotinib in ALK inhibitor–naive patients with ALK-positive NSCLC. After less than a year of follow-up, the HR for progression or death was 0.49 for brigatinib vs crizotinib (P = .0007). This is comparable to the updated HR of 0.43 with first-line alectinib vs crizotinib in ALK-positive NSCLC recently reported from the ALEX trial at ASCO 2018. In the ALTA-1L trial, the median PFS was not reached with brigatinib vs 9.8 months with crizotinib, which is what we expect with crizotinib. ALTA-1L also reported an intracranial ORR of 78% with brigatinib, which compares well with the 81% rate with alectinib on ALEX.

Regarding safety, there was a higher dose-reduction rate of 29% with brigatinib vs 21% with crizotinib compared with the updated rate of 16% with alectinib. That said, most dose reductions with brigatinib were due to laboratory abnormalities rather than symptomatic events. Of special interest to clinicians was whether we would see the early-onset of pneumonitis that was seen within the first week of dosing in some of the earlier brigatinib trials which is why brigatinib dosing in ALTA-1L started at 90 mg and increased to 180 mg after a week of good tolerance. In ALTA-1L, 3% of patients had to come off study due to early-onset pneumonitis.

Clinical Implications
The positive results of ALTA-1L show that brigatinib, like alectinib, is clearly superior to crizotinib in the first-line setting. The magnitude of benefit indicates that brigatinib or alectinib should be used in the first line to forestall the development of resistance, rather than after first-line crizotinib as the overall PFS is clearly longer with this strategy. Now, if brigatinib is approved in the first-line setting, how might we decide between brigatinib and alectinib for our patients? I believe that the jury is still out on this question. Alectinib is currently our standard of care in the first-line setting due to its excellent safety profile and intracranial efficacy; the latter is especially important in ALK-positive NSCLC, which commonly metastasizes to the brain. Although the ALTA-1L and ALEX data look very comparable, it is difficult to compare across trials. Furthermore, alectinib has more than 2 years of follow-up data whereas the brigatinib data are fairly immature at this time.

In my own clinic, I will still prefer alectinib in the first-line setting for now. That said, I do plan to choose brigatinib over crizotinib when a patient cannot tolerate alectinib as first-line therapy. I will be awaiting to see how the ALTA-1L data mature before making further decisions regarding the use of brigatinib instead of alectinib as initial therapy for my patients.

ALK Inhibitor Resistance and Future Directions
Although alectinib and brigatinib appear to have comparable efficacy, will they have different ALK resistance mutation profiles that emerge over time? Ceritinib, alectinib, and brigatinib each appear to have varying levels of potency against the various ALK resistance mutations that can develop. Currently, most of our data on the effectiveness of the individual ALK inhibitors for specific ALK resistance mutations are preclinical. Aside from biopsy or liquid biopsy at the point of clinical resistance to determine a resistance mutation profile, efforts are under way to use liquid biopsies to serially profile a tumor as it develops early resistance to ALK TKI therapy and to use those results to potentially guide the selection of another ALK inhibitor, rather than moving on to other options like chemotherapy or immunotherapy (which performs quite poorly in ALK patients, unfortunately). Our hope is that we can determine the optimal sequencing of ALK inhibitors and lengthen the overall benefit of ALK-targeted therapy by identifying emerging resistance mutations and switching promptly to a new ALK inhibitor or even combination therapy. In that vein, we look forward to further trial results not only of brigatinib and alectinib but also emerging agents like lorlatinib and other next generation ALK inhibitors.

To see how 5 other lung cancer specialists currently approach the first-line and second-line management of patients with ALK-positive NSCLC in different clinical scenarios, please visit the NSCLC Treatment Decision Support Tool.

Your Thoughts
Will you consider using brigatinib as first-line therapy in your patients with metastatic ALK-positive NSCLC if it is approved? Why or why not? Please join the conversation by leaving a comment.