ALK Gene Rearrangements As A Therapeutic Target in Non-small Cell Lung Cancer - Episode 4
Karen Reckamp, MD, and Jyoti Patel, MD, review currently available frontline treatment options for ALK+ advanced NSCLC and discuss updated efficacy and safety data from key clinical trials of these agents in advanced NSCLC.
Karen Reckamp, MD: Speaking about the clinical activity, let’s go into some of the studies that have been recently published or presented at some of the recent meetings, to talk about some of these subtle differences and the data we now know. The first 2 trials that have the longest follow-up are the global ALEX and the J-ALEX trial. The J-ALEX was done in Japan and was the first study done with alectinib. Both of these trials have significant follow-up time, and presented and published last year was the updated overall survival and progression-free survival for the global ALEX study. This was with follow-up of 48 months, so nearly 5 years follow-up, and the updated progression-free survival was 34.8 months versus 10.9 months, which is something similar to what we’re seeing, as we’ll talk about, in the J-ALEX trial. The overall survival is still not reached for alectinib, and it was 57.4 months in the crizotinib control arm. That’s remarkable, to see nearly 60 months even in the control arm for patients who received crizotinib. To see nearly a 5-year overall survival is impressive.
This overall survival benefit with alectinib is seen in both patients with and without brain metastases, and it’s important to know that this study is done with the global dosing of 600 mg BID [twice a day]. In this trial, there was very limited crossover, only about 20%, because as we start talking about survival in some of the other studies, we don’t see as dramatic differences in survival.
Moving on to the J-ALEX trial, in this trial again they used 300 mg [twice a day], which is the Japanese dosing for alectinib, and in this study they now have 68 months of follow-up. Based on that, they did not find a significant difference in the overall survival. It was about 60.8 months versus 64 months with crizotinib. In this study, again a differing factor, 78% crossed over and went on to receive alectinib and quit the crizotinib arm. That does tell us about sequencing, that as long as you’re getting access to these drugs, you may be able to extend your survival regardless of what you ended up starting with, which is a helpful piece of information to know. Again, the progression-free survival is very similar, 10 months for the control arm and 34 months in the alectinib arm, and again with good brain penetration.
Dr Patel, would you like to tell us about updates for the ALTA-1 trial and brigatinib?
Jyoti Patel, MD: Yes. The ALTA-1 trial was a frontline trial, brigatinib versus crizotinib, and updates were presented at ESMO [European Society for Medical Oncology annual meeting] this year. Similarly, we’re looking at high progression-free survival at 12 months, a response rate of 79%, an intracranial response rate of 78%. Early toxicity, I mentioned before, was low, grade 3/4 events with ILD [interstitial lung disease] or pneumonitis was 0.7% in this trial. This is something to keep in mind, very unusual, but real.
The overall survival at 4 years was incredible. Patients with CNS [central nervous system] metastasis had a 4-year overall survival of 64%, and those who did not have CNS metastasis at diagnosis, 71%. It was about 66% in all-comers; there was a high rate of brain metastases in these patients. It’s certainly exciting.
It’s important in both of these trials to think about discontinuation. The number of patients who had to drop doses in both the ALEX studies as well as in brigatinib remained low. There was a little bit of dose reduction in ALEX compared to brigatinib, but overall these drugs were very well tolerated.
Karen Reckamp, MD: That’s very helpful. As you mentioned, the lorlatinib data were recently presented and published from the CROWN study, and unlike the brigatinib and alectinib data, this is based on an interim analysis and relatively short follow-up. Knowing that, we see these overall survivals nearing 5 years, it’s going to be a while before we have full data. But as you had mentioned before, what’s really profound is the CNS data. The median progression-free survival was not reached as we would expect, and it was 9.3 months for crizotinib. Again, similar to what we’ve seen for the control arm, maybe a little bit lower.
Those patients without CNS progression of all-comers within the first 12 months was 96% without CNS metastasis versus 60% in the crizotinib arm, and the hazard ratio, an impressive 0.07. Seeing that hazard ratio tells you that the extent of activity, even as the duration of the follow-up goes on, that level of activity is profound. The CNS penetration is one of the things to watch with lorlatinib as we start to see some of the data mature for this drug.
Transcript edited for clarity.