Advances in Treatment for ALK-Positive NSCLC - Episode 3

ALK-Positive NSCLC: ASCEND-4 Trial


Robert C. Doebele, MD, PhD: The ASCEND-4 trial was a randomized clinical trial—ceritinib versus standard chemotherapy. In this case that standard chemotherapy was carboplatin or cisplatin, with pemetrexed followed by maintenance pemetrexed. A very commonly administered chemotherapy regimen for our lung adenocarcinoma patients. It was randomized 1-to-1, approximately 350 or so patients. The patient population I think was very representative of what we would expect from our ALK-positive patients. You had to be ALK-positive to be enrolled in the study. About a third of the patients, roughly 30%, had brain metastasis at baseline. Unfortunately, that’s a common feature for ALK-positive non—small cell lung cancer and other types of non–small cell lung cancer as well.

The reason that’s important, of course, is because we know it’s important to control brain metastases as well as metastases that may occur in the lung, liver, bones, and other places. Understanding how these drugs work in patients with brain metastases at baseline is a really important factor. Of the patients who were treated in this trial, about half of the patients with brain metastases were previously treated with radiation to the brain; that’s another standard therapy that we use to control brain metastases.

The outcome of the trial, I think, was somewhat expected based on prior clinical trials. Ceritinib was clearly superior to chemotherapy. The response rate, for example, was approximately 72% for patients who received ceritinib, and only approximately 30% for patients who received the standard-of-care chemotherapy.

Importantly, that disease control was long-lived. In the patients who received ceritinib, the progression-free survival was just over 16 months. Whereas with chemotherapy it was only about 8 months. Patients not only had a better chance of tumor shrinkage and control but also had much longer duration of therapy before their tumors progressed and they needed to move on to a different therapy.

Another critical result, or another critical sub finding of this clinical trial, was that the patients who had brain metastases typically did worse. And that’s common. Even though ceritinib was shown to be effective in the brain, the progression-free survival was a lot shorter in patients who had brain metastases at baseline; only about 10 months, versus 26 months for those who didn’t have brain metastases. We saw a much less impactful trend for brain metastases on chemotherapy.

Patients who had brain metastases at baseline had a progression-free survival in the range of about 6 months. Those without brain metastases had 8 months. It didn’t impact chemotherapy as much. But for both groups it was significantly shorter.

Other critical aspects that were evaluated in the study were the response rate in the brain. And there again we saw good activity in the brain, meaning that ceritinib demonstrated a response rate of about 72%, very similar to what we saw for the extra CNS [central nervous system] response rate, or the systemic response rate, suggesting that the drug does have very good CNS penetration, or brain penetration. Patients who received chemotherapy also had a similar response rate in the sense that the response rate was only about 27% in the brain and similar to what it was for the systemic response rate.

It’s notable that the dosing regimen used in ASCEND-4 trial was 750 mg daily. That dose has now been associated with far more significant GI [gastrointestinal adverse] effects: nausea, vomiting, diarrhea. And then I think most people who are administering this drug now use the 450 mg per day with food, which significantly improves the toxicity profile and adverse effects that are experienced with this ALK tyrosine kinase inhibitor.

David Spigel, MD: Ceritinib is a fantastic drug. It proved its worth in a second-line setting and has proven its worth over crizotinib in a first-line setting. The dilemma with ceritinib, I think, has come down to some of the tolerability issues. It got approved initially at a dose that probably was a little too high in terms of causing adverse effects for patients. And it turns out at a lower dose with food, it’s a much more manageable drug. And when all we had was ceritinib, that was something that you figured out with experience.

But now that you have multiple drugs available to you and specifically alectinib in the first-line setting or ceritinib, a drug that you probably have to modify from the get-go and probably thereafter, I think for those reasons, doctors tend to choose alectinib, but it’s important to be clear. We do not know that alectinib is better than ceritinib head-to-head. We do not have data to prove that. Now there are some studies ongoing with other agents like brigatinib, perhaps, compared [with] alectinib.

One day we might see lorlatinib versus alectinib. But we don’t have data to say that alectinib is superior to ceritinib. Ceritinib is a great drug, and for a long time I have had patients on ceritinib do quite well even with managing their dose. I just think because of alectinib’s availability, because of its excellent safety profile and ease of disease management and fantastic CNS control, it’s become the easier choice for doctors to make. But ceritinib has a place in the care of patients with ALK lung cancer. It’s just that it’s harder to know how that fits in when you’re using alectinib first line.

Transcript Edited for Clarity