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ALK+ NSCLC Paradigm Bursting With Frontline Options

Angelica Welch
Published: Friday, Nov 30, 2018

Stephen V. Liu, MD

Stephen V. Liu, MD

The first-line treatment landscape of ALK-positive non–small cell lung cancer (NSCLC) has been flooded with multiple targeted agents with more on the way, according to Stephen V. Liu, MD.

Alectinib (Alecensa) has become the current standard of care for most of these patients, but positive results with frontline brigatinib (Alunbrig) has the potential to shake up the landscape once more.

“The first-line space continues to rapidly evolve. We are talking about being on your first treatment for 3 years with metastatic NSCLC,” said Liu. “It really is a new era, and we have become accustomed to excellent outcomes with these drugs.”

In an interview during the 2018 OncLive® State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Liu, an associate professor of Medicine at Medstar Georgetown University Medical Center, recapped ongoing developments in the treatment of patients with ALK-positive NSCLC.

OncLive: How has ALK-positive NSCLC treatment evolved in the last few years?

Liu: If we think of our frontline treatment for patients with ALK-positive cancer, it is almost an embarrassment of riches. It has evolved a lot in a pretty short period of time. Going back to PROFILE 1014, we saw that crizotinib (Xalkori) was superior to chemotherapy, but now after more than 4 years of follow-up, we can see that those patients have a significant improvement in survival if they receive the right treatment. What is the most interesting is that patients who start with crizotinib instead of chemotherapy and continue with ALK-targeted therapy afterward have the best possible outcomes. This suggests that targeted therapy is the best first treatment, and also the best subsequent treatment. For most patients, we want to keep them on targeted therapy for as long as we can. 

The first-line space has gone onto evolve. We saw ceritinib (Zykadia) in the ASCEND-4 study was superior to chemotherapy, but the biggest change was with the ALEX trial when alectinib was head-to-head compared with crizotinib. Alectinib was far superior, and chemotherapy is no longer an appropriate standard of care. We saw an updated progression free survival (PFS) of almost 3 years compared with 11 months with crizotinib at the 2018 ASCO Annual Meeting.

At the 2018 ESMO Congress, we saw that the ALESIA trial, which was an Asian study, but had the same design of ALEX. We saw that again, [alectinib] was far superior. In the investigator-initiated PFS comparing alectinib with crizotinib, the hazard ratio was 0.22, which is “ridiculous.” This clearly cemented it as our preferred first-line option. Alectinib is an excellent, well-tolerated, highly effective drug.

This space will continue to evolve with brigatinib. Brigatinib had a very compelling PFS of longer than 16 months in the second-line space—much greater than even alectinib in that space—allowing for cross-trial comparison. What will the activity of brigatinib be in the frontline setting? We saw D. Ross Camidge, MD, PhD, of the University of Colorado, present some relatively immature data on the ALTA-1L trial after an 11-month follow-up. [ALTA-1L] trial compared brigatinib with crizotinib, which is another very effective, well-tolerated, and highly central nervous system (CNS)-penetrant drug. We saw a very impressive investigator-assessed PFS, but the median PFS was not reached.

In light of these advancements, what is the role of crizotinib now?

The role of crizotinib is very small. For specific mutations that it can restore sensitivity in, then crizotinib may play a role. It is going to be few and far between. Really, I view crizotinib as sub-standard care. Could you sequence therapy, starting with crizotinib and save other drugs for later? I really think that is an inferior strategy. In part because the act of progression itself is such a violent one at times, and if you spare patients that progression—especially if it is in the brain—it’s a much better outcome. 




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35th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Clinical Vignette SeriesJan 31, 20192.0
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