ALK Alterations in Advanced NSCLC

Mark A. Socinski, MD: ALK was initially discovered around 1994 in a patient with large-cell lymphoma. It subsequently was discovered in patients with lung cancer by Japanese investigators in 2007. In terms of normal development, what does ALK normally do? It is believed to play a pivotal role in cellular communication and in the normal development and function of the nervous system, and that's derived from information on animal models in this setting. It's been an interesting journey from that initial description in large cell lymphoma to being part of our standard thinking and our standard evaluation in non–small cell lung cancer (NSCLC).

Stephen Liu, MD: If we think about the role that ALK plays in lung cancer development, we know that it is an oncogene. In lung cancer, we have chromosomal rearrangements or gene fusions that can transform a normal cell into a cancer. These fusions typically retain the kinase domain of ALK, and they link to the amino-terminal portion of various partners, most commonly EML4. We're not sure [about] the significance of these partners. It may be important, but it doesn't impact treatment today. If we look at something like splice variants just within EML4-ALK, there are at least 15 different variants that are named in the order that they were described. The most common is variant 1, and the next most common is variant 3. An examination of those two variants, which [represent] 40% to 45% of the EML4 fusions, shows their differences. Variant 3 is associated with a much worse prognosis and very different resistance patterns. About one third of patients with variant 3 have the G1202R point mutation that confers resistance to a lot of TKIs [tyrosine kinase inhibitors]. You don't see such resistance in patients with variant 1, so there are differences in these ALK fusions. Today, they don't guide our therapy; in the future, I'm willing to bet that they will.

Mark A. Socinski, MD: ALK fusion should be a standard part of the initial evaluation of any patient with advanced-stage NSCLC. The presence of an ALK fusion allows you to proceed without directed therapy, which is highly effective. I'll talk about that in a moment. We test for ALK, both with IHC [immunohistochemistry] and next-generation sequencing. This is one of the examples in which IHC is an accepted testing method for this biomarker. Like many of these targeted fusions and oncogenic drivers, if you find one, you tend not to find any other driver mutations, except for rare situations where you may have 2. I've had a couple of cases where you see both EGFR mutations and ALK fusions. For the most part, they're mutually exclusive. And if you find one, you can act on that and go down that pathway of treatment. We know we have a number of different ALK agents, the first one being crizotinib. And then the second-generation drugs include agents like alectinib, ceritinib, brigatinib, and lorlatinib in this setting. In my practice, it's standard to test plasma for these genetic alterations, and that leads me to discuss the BFAST trial. This ongoing, multicenter clinical trial is examining the use of next-generation sequencing in the blood, the identification of molecular alterations, and the outcomes after the patient is relegated to a specific therapy. There are multiple cohorts in the BFAST trial, and we’ve recently seen some data for the ALK-positive cohort. In the BFAST trial at the time of this reporting, there are about 2200 patients who were screened; 119 were found to be ALK-positive. That's a rate of about 5.4%, which is what we would expect in this setting. These patients were treated with alectinib at the standard dose of 600 mg given twice daily. EML4 was the most common fusion partner at 84% of the time. About 44% of the ALK population had a co-mutation with P53. Interestingly, the tumor mutation burden was, at a median, only 2. This is a low TMB [tumor mutational burden] population. Now, again, these were identified by plasma-based testing. With use of alectinib, the overall confirmed response rate was 87% by investigators and 92% by independent radiologic review. At 1 year, 75% of those patients were still in response. About 40% of patients at baseline had asymptomatic brain metastases, which is an issue with the ALK-positive population. The response rate in the measurable brain metastasis population at baseline was 91%. This underscores the clinical usefulness of plasma-based testing. Again, in my practice, I do both tissue and plasma testing. But this data from BFAST shows that you can detect ALK at a similar frequency in blood as you do in tissue, and the outcomes with alectinib therapy in this experience were quite good. This reinforces the clinical usefulness of plasma-based next-generation sequencing.

Benjamin Levy, MD: The prognosis for patients with ALK-rearranged lung cancer is favorable. It is quite different than for patients with other mutations that we see in lung cancer. That underscores how important it is to test for these fusions/rearrangements. We have a lot of data now. The updated overall survival analysis from the ALEX trial, which compared use of front-line alectinib versus crizotinib in patients with advanced ALK-rearranged lung cancer, shows that more than 60% of patients are still alive at 5 years. This is remarkable in the context of what we generally saw maybe 10 years ago, which was a median survival of only 12 months for patients with stage IV lung cancer. We have now moved to 5-year survival rates of more than 50%. Again, this underscores the importance of testing for the rearrangement. You can’t give the drug unless you test. Patients with ALK-rearranged lung cancer generally present with advanced-stage disease, like many of our patients who are driver mutation-positive. A malignancy with this mutation or fusion has a proclivity to go to the CNS [central nervous system] or brain. Many patients present with brain metastases. Importantly, the drugs that we leverage in this setting can cross the blood-brain barrier and elicit intracranial responses in the brain. For all these reasons—good drugs, better outcomes, unprecedented survival times—we need to identify these fusions up front and give the right targeted therapy. And in this case, we have many targeted therapies for our patients with ALK-rearranged lung cancer.

Transcript edited for clarity.