Sequencing Therapy in ALK/ROS1-Rearranged NSCLC

Alexander Drilon, MD:The phase II ALTA trial looked at the utility of brigatinib inALK-rearranged lung cancers who had prior ALK-directed TKI therapy. Brigatinib is a later-generation TKI that targets many mechanisms of acquired resistance to earlier generation therapy with crizotinib, meaning on-target mutations that might emerge with treatment. And so, it’s no surprise that this drug was active in this trial, with a response rate that exceeded 40% and really good progression-free survival compared with some of the other TKIs. And so, because of this, brigatinib is currently approved by the FDA as a second-line therapy for patients withALK-rearranged lung cancers who previously received crizotinib.

Justin Gainor, MD:In July 2018, we had 4 approved ALK inhibitors in the United States: the first-generation inhibitor crizotinib and 3 second-generation ALK inhibitors—ceritinib, alectinib, and brigatinib. The historical paradigm was to start with crizotinib, which induced high response rates, followed by use of a second-generation ALK inhibitor such as ceritinib, alectinib, or brigatinib. The second-generation inhibitors are generally characterized by increased potency compared with crizotinib, increased selectivity, and better CNS [central nervous system] penetration. All 3 of those second-generation inhibitors are currently approved in the United States for use after crizotinib.

As I mentioned earlier, alectinib is also approved for first-line use based upon the ALEX study, and ceritinib is also approved for first-line use. Together, though, I would consider that alectinib is really the first-line standard of care, putting together the data from the ALEX study with impressive activity combined with CNS penetrability and a favorable safety profile. Nonetheless, there are a number of patients who are currently still on crizotinib in the United States or receiving crizotinib in other areas of the world. And so, it is very much a question of, if patients have started with crizotinib, what should be the preferred next second-generation ALK inhibitor? There are currently no head-to-head comparisons across the second-generation ALK inhibitors, so we’re generally left with cross-trial comparisons.

The most recent drug that was approved in this space is brigatinib, another second-generation inhibitor that has shown very high response rates and, in the crizotinib-resistant-setting, has shown impressive progression-free survival—around 15 to 16 months in the latest update. And so, based upon that impressive data, brigatinib is now being explored in the first-line space with a head-to-head comparison against crizotinib, and I think we’ll eagerly await that data.

Finally, the question is, what do we do for patients who are progressing on first-line alectinib, which I argued was the new standard of care? The agent that has the most data in that setting is still an experimental agent. This is a so-called third-generation ALK inhibitor, lorlatinib, which was a granted breakthrough therapy designation by the FDA. And that was based upon encouraging response rates among patients who were treated with 1, 2, and even 3 prior ALK inhibitors. And so, that’s an agent that has shown activity in the postalectinib setting and, if approved, would be an option in that setting.

Alexander Drilon, MD:Alectinib is currently the standard of care forALK-rearranged lung cancers, and because we’ve moved 1 of our better drugs into the first-line setting, the question becomes what to use after that. I think there are 2 potential options in terms of TKI therapy: brigatinib and lorlatinib, which do have very broad coverage against possible on-target resistance mechanisms. But it’s still not very clear what the response rate is going to be like when we treat more patients. I think that until we have definite FDA approval for another TKI after alectinib beyond exploring 1 of these TKIs on either clinical trial, or if we’re able to prescribe it for patients, a very viable option is that after alectinib, consider giving patients chemotherapy plus/minus immunotherapy.

Transcript edited for clarity.