Key Updates and Practice-Changing Data for Advanced NSCLC - Episode 13

Treatment Options for ALK/ROS1 Mutation


Mark A. Socinski, MD: We have all used crizotinib [Xalkori] over the past couple of years. We’ve based on the J-ALEX and ALEX trials a transition to alectinib [Alecensa] as the new first-line standard. Do you want to give us your thoughts and summarize the data?

Leora Horn, MD, MSc, FRCPC: Crizotinib was actually approved in the United States before the Profile 101-4. Many United States investigators never actually enrolled patients in that trial. We were using it up front based on the phase I and II data. That was the standard of care. The ALEX and J-ALEX data set the bar high in terms of other ALK inhibitors that are currently approved and in development. The progression-free survival [PFS] hazard ratio was 0.42. The PFS update at the American Society of Clinical Oncology [ASCO] 2018 Annual Meeting, however, was 35 months. Alectinib has become my first-line preferred ALK inhibitor at this time. We have other drugs out there as well. We saw data from the World Conference on Lung Cancer [WCLC] 2018 Annual Meeting regarding ceritinib [Zykadia] that were promising.

Mark A. Socinski, MD: You brought up the Profile 101-4 trial, in which crizotinib was compared with chemotherapy. ASCEND-4 was ceritinib versus chemotherapy. Were there similar results?

Thomas E. Stinchcombe, MD: Very similar results, yes. Ceritinib was much better in terms of PFS compared with chemotherapy. To a certain extent, in the United States at least, this trial was somewhat discounted because the ALEX trials came out that compared it with crizotinib.

Mark A. Socinski, MD: And in all fairness, ASCEND-4 used the old dose—750 mg. Now we have a new dose with food—450 mg, which was from the ASCEND-8 data.

Thomas E. Stinchcombe, MD: In the second-line experience, most people realized that 750 mg was very hard to tolerate because of gastrointestinal (GI) toxicities and increased liver tests. Many astute clinicians started at 600 mg and did some other adjustments empirically, which was not optimal. They conducted a study looking at the food effect and found that 450 mg was much better tolerated in terms of GI toxicities: nausea, vomiting, and diarrhea. At this meeting we saw some data showing it having a similar efficacy in terms of response, duration of response, and PFS. This led to the dose change. But I think Leora hit on a critical point: Now where do we insert ceritinib into our current treatment paradigm? Or is it just another option at this point?

Mark A. Socinski, MD: It becomes more complicated. You talked about the ALEX trials; I’m going to have Maximillian talk about ALTA-1L, which was a similar design: brigatinib [Alunbrig] versus crizotinib in patients who have ALK mutation. We saw some data at this meeting about the central nervous system [CNS] activity.

Maximilian Hochmair, MD: It’s complicated now. I saw the European Society of Medical Oncology [ESMO] guidelines yesterday, which stated that first-line approved drugs include brigatinib, ceritinib, and alectinib—so we have to decide. Alectinib showed a nice PFS with perhaps 3 years of PFS in the frontline setting. We saw ceritinib with sequencing, which was interesting. Now we saw another trial, the ALTA-1L, in which brigatinib was compared with crizotinib; we saw nearly the same hazard ratio that we saw with alectinib compared with crizotinib. We have a new drug coming out. Brigatinib seems to be highly effective in patients without brain metastases [mets]. The ESMO data showed convincing data regarding brain metastases; a hazard ratio comparison to crizotinib O20 was significant; it’s well tolerated, as well as alectinib. You see with brigatinib some metastasis issues, but it’s well tolerated, easy to administer, and given once daily. In comparison with alectinib, it is well tolerated. We give it twice daily; I would say my best choice first line, at the moment, is alectinib. When we have the long-term follow-up data with brigatinib, I think we will see that both drugs are quite equivalent.

Mark A. Socinski, MD: Something that is no longer a concern is this early pulmonary toxicity that may be dose related. Any comments there?

Maximilian Hochmair, MD: We treated around 60 patients with brigatinib; I saw pulmonary toxicity in 1 or 2 patients. We saw pneumonitis in the beginning when you start with 90 mg; after x-rays following a week of treatment, we saw no adverse effects, after which you could increase dose to 180 mg. I saw it once in my patient; I tell them if they are having trouble, come into the clinic—it’s not a big issue. The tolerability of alectinib and brigatinib is quite comparable.

Mark A. Socinski, MD: We saw an extension of ALK and ROS1 mutations. At the WCLC meeting we had some data with lorlatinib [Lorbrena] and entrectinib. Thomas, do you want to tell us about that data?

Thomas E. Stinchcombe, MD: There’s a lot of enthusiasm for lorlatinib in the ALK- and ROS1-mutation space. I recall the lorlatinib overall response rate in ROS1 being a mixture of crizotinib for treatment-naive patients of around 40%. We’re waiting for approval, but I could see having a role in those patients who progress on crizotinib; we’d have an option to switch them over.

Mark A. Socinski, MD: The entrectinib data were very impressive.

Thomas E. Stinchcombe, MD: That is another tyrosine kinase inhibitor [TKI]; it has slightly better blood-brain-barrier penetration. Building on the theme that Maximillian discussed regarding our new drugs, hopefully they will prevent brain metastasis so that we won’t have to just wait for them to occur.

Mark A. Socinski, MD: There’s a land of plenty in a patient population we don’t see very often.

Leora Horn, MD, MSc, FRCPC: No.

Mark A. Socinski, MD: Maybe if you’re a community oncologist you may never see it, right?

Leora Horn, MD, MSc, FRCPC: True. The entrectinib data though…were in crizotinib-naive patients.

Mark A. Socinski, MD: If I remember correctly, the entrectinib data regarding PFS were about 27 months, which is pretty impressive.

Leora Horn, MD, MSc, FRCPC: Yes. It looked great—less toxic than what we see with crizotinib.

Transcript Edited for Clarity