Changing the Treatment Paradigm for ALK-Rearranged NSCLC

Transcript:Benjamin P. Levy, MD: Let’s move on for the sake of time to another genotype that has witnessed significant advances in therapy, ALK rearrangements. Maybe we can briefly talk about ROS, if there’s time. This is another mutation rearrangement in 3% to 5% of all non—small cell lung cancer adenocarcinoma. It’s become a crowded therapeutic space for ALK. We had crizotinib, of course, from the PROFILE trials. We now have other drugs, with ceritinib and alectinib and brigatinib and erlotinib. Maybe we can sort out some of this in a short amount of time. Sanjay, I’m going to task you with the ALEX, ASCEND, and then brigatinib data that have thrown a curveball regarding how we sequence these ALK-directed therapies.

Sanjay Popat, PhD, FRCP: This area has been moving very quickly over a very short amount of time. Each of these agents have slightly different efficacy, slightly different CNS [central nervous system] penetration, and slightly different toxicity profiles. I think we now have a wide variety of agents that we can use. The data that we initially had in the frontline setting from the PROFILE 1014 dataset demonstrated that crizotinib is superior to chemotherapy, and that’s really become our standard of care for some time.

Shortly thereafter, we had efficacy data from the ASCEND studies showing ceritinib was superior to chemotherapy. At that time, ceritinib had very impressive CNS-penetrance activity, although with a difficult toxicity profile at the standard dose of 750 mg on a fasting diet. Since then, both the FDA [US Food and Drug Administration] and EMA [European Medicines Agency] have changed the label to allow 450 mg with food, which reduces the side effects but maintains the efficacy.

In parallel, last year at the ASCO [American Society of Clinical Oncology] meeting, we had the dramatic dataset from the ALEX study. This builds on the previous Japanese dataset, the J-ALEX study, randomizing patients between crizotinib, which was a standard of a care at the time when the trial was open, and alectinib, demonstrating a market superiority with a PFS [progression-free survival] in excess of 24 months with alectinib. Rapidly, in parts of the world where this has become established and approved, alectinib has become the standard of care for this group of patients.

Meanwhile, we have other data sets brewing. At this World Conference on Lung Cancer, we now have a presentation of the ALTA-1L data regarding the next-generation inhibitor, brigatinib. Brigatinib is another highly potent and penetrant next-generation ALK inhibitor that has, in the postcrizotinib setting, perhaps one of the strongest efficacies, with a PFS of around 16 months, compared to where we are with alectinib in the postcrizotinib setting, 8 months or so.

These data randomizing to brigatinib versus crizotinib, which was the standard at the time, were very eagerly anticipated. These data are really quite markedly interesting, demonstrating a marked superiority of brigatinib compared to crizotinib, with a hazard ratio of 0.49, with the crizotinib arm performing as you would expect it to perform as the control arm and a very nice efficacy for brigatinib, which has a median that hasn’t been reached yet. As you would expect, we have marked intracranial activity compared to crizotinib, with a hazard ratio of less than 0.3 for intracranial PFS in patients with CNS metastases, really reinforcing the efficacy of brigatinib.

Now, the key question that people are asking is, which agent should I choose? That’s a difficult question to answer at this point because the ALTA-1L data potentially represent a new standard of care. But we have alectinib, which is already established in many parts of the world. Making crosstrial comparisons is very difficult because the data that we have for ALTA-1L are really very immature at this point, and we just need some more mature PFS data so that we can really cement what the magnitude of the benefit is here.

Transcript Edited for Clarity