The ALTA-1L trial was a randomised phase III trial evaluating the efficacy of brigatinib, a next generation ALK inhibitor, in the front line setting for ALK positive patients. It’s a randomised phase III trial, multicentre global trial, in which patients with advanced non-small cell lung cancer who could have been exposed previously to chemotherapy were randomised either to receive brigatinib or crizotinib. Patients with baseline CNS metastases that were active could have been enrolled and the primary endpoint of the trial was progression free survival by blinded independent central radiology review

How are ALK TKIs effective against ALK positive NSCLC that shows CNS metastasis?

ALK inhibitors are generally very effective against patients with CNS metastases if they have ALK positive lung cancer. In fact, we know that CNS metastases are an important problem for patients with ALK positive lung cancer. Across many of the trials that have looked at ALK positive lung cancer around 30% or so of patients had CNS metastases at baseline. Indeed, when we look at ALTA-1L this is exactly what we see – 30% of patients had CNS metastases.
Previously we’ve been using crizotinib which is a highly effective ALK inhibitor but it does have some limited efficacy within the CNS and often the CNS is one of the first sites of progression in patients on crizotinib. Therefore, as the trials have matured we’ve identified that the next generation ALK inhibitors are superior to crizotinib and also have superior intracranial control.

What endpoints were analysed in the ALTA-1L trial?

In the ALTA-1L trial we looked at progression free survival by blinded independent central review as the primary endpoint. Secondary endpoints included progression free survival by investigator review, safety, response, intracranial efficacy as well as quality of life.
What differences in outcome were observed in the brigatinib arm in comparison to the crizotinib arm?
In the ALTA-1L trial we’ve recently had an update of efficacy from this trial. This was presented at the ESMO Asia meeting last year which is the second interim analysis. This is a much more mature dataset and this demonstrates the marked superiority of brigatinib over crizotinib with a hazard ratio for progression free survival by blinded independent central review of 0.49.

Importantly, we continued to show that there were improved response rates for brigatinib over crizotinib and, of course, because of the crossover design of the trial there was no overall survival advantage. Indeed, overall survival is immature, really, to make any meaningful conclusions at this stage.

How will the results from the ALTA-1L trial affect the future treatment of ALK positive NSCLC?

The second interim analysis of ALTA-1L does demonstrate a superiority for brigatinib over crizotinib. To my mind, it does translate to it becoming a first line treatment option for patients with untreated ALK positive metastatic non-small cell lung cancer. We know that patients with CNS metastases have inferior outcomes in general with ALK positive disease and so therefore having intracranial control is really quite important.
When we look at the CNS outcomes of the ALTA-1L trial we see a highly effective outcome with brigatinib insofar as patients with CNS involved at the time of enrolment, with CNS positive disease, the progression free survival by blinded independent review committee hazard ratio was 0.25 in favour of brigatinib over crizotinib. Indeed, it remained very effective also in patients without CNS metastases with a Burke PFS hazard ratio of 0.65.

Can you explain a bit regarding the CNS activity of this drug?

At the ESMO 2020 meeting we presented further details of the CNS activity of brigatinib. We know that around 30% of patients had CNS metastases at baseline and around 15% of these had prior radiotherapy. Overall, brigatinib was highly effective in patients with CNS metastases with a progression free survival hazard ratio of 0.25. In those patients that had had prior radiotherapy it was extremely effective with an intracranial progression free survival hazard ratio of 0.15. In patients with CNS metastases brigatinib was highly effective with a response rate of 80% which compared very favourably to crizotinib with a response rate of 30%. When we look at patterns of progression in the brain we see that patients on crizotinib tended to relapse first within the brain which was less frequently seen with brigatinib. Indeed, when we look at patterns of relapse within the brain we see new lesions really as the major issue in both groups rather than loss of control of established lesions.