NGS Key to Guiding Treatment Decisions in ALK+ NSCLC

Miguel A. Villalona-Calero, MDD

For patients with metastatic ALK-positive non—small cell lung cancer (NSCLC), next-generation sequencing (NGS) is now not only recommended in the frontline setting, but at the time of relapse, as well, said Miguel A. Villalona-Calero, MD.

“You need to order extensive panels with NGS to look for things that you would might not necessarily expect. Between 4% and 8% of patients with lung cancer have translocations or inversions in the ALK gene,” said Villalona-Calero. “You have to consider that. There are powerful diagnostic tools that can [lead you to the right targeted therapy].”

If an ALK alteration is found, there are several agents that can be prescribed, starting with alectinib (Alecensa). Results from the phase III ALEX trial showed that the agent led to a 53% reduction in the risk of progression or death when compared with crizotinib (Xalkori) as frontline therapy in treatment-naïve patients with advanced ALK-positive NSCLC.

If a patient develops an acquired resistance mutation to alectinib, both lorlatinib (Lorbrena) and brigatinib (Alunbrig) are available as second-line options. However, Villalona-Calero cautioned that patients who progress on alectinib may have ALK independence, in which case chemotherapy or localized therapy may be warranted.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Villalona-Calero, deputy director, and chief scientific officer, Miami Cancer Institute, Baptist Health, discussed the availability of ALK inhibitors for patients with ALK-positive NSCLC and the importance of implementing sequencing panels to guide treatment decisions.

OncLive: Could you discuss the development of ALK inhibitors in NSCLC?

Villalona-Calero: We are in an era of molecular diagnosis and targeted therapy. ALK has become one of the major breakthroughs for patients. ALK was originally [detected] in lymphoma, but about 13 years later, it was identified in lung cancer, too. We have many active agents that have emerged. We started with crizotinib, then we added alectinib, ceritinib (Zykadia), and brigatinib. [Brigatinib] provided us with the capability of treating patients who had crizotinib-resistant disease. Moreover, the agent is able to penetrate the blood-brain barrier, allowing us to treat patients who have brain metastases.

We're blessed with the fact that we have these targets in lung cancer, and that we can offer patients different options. It is unclear what the effect of immunotherapy is in patients who have an ALK translocation, but we do know that in patients who have EGFR-positive disease, [that approach is] unlikely to work. In patients who develop ALK independence, the question is whether the combination of immunotherapy and chemotherapy can offer an advantage. We don't know the answer to that question yet. That may be something to explore in the future.

How has alectinib affected your frontline treatment approach for patients with ALK-positive disease?

We consider the toxicity profile [of the agent], the potential survival prolongation with treatment, and the time to progression. We also consider the ability of the agent to treat patients with brain metastases, which are frequently observed in patients with this disease. Alectinib was the first agent with a very good [safety profile] to show activity against crizotinib-resistant disease and brain metastases. Now, it is the first-line option for most patients. Patients [are on alectinib] for a long period of time. At some point, however, resistance develops, and that resistance tends to be acquired. Now, we have a next-generation agent with lorlatinib that can treat patients with some of these resistance mutations from alectinib. Biopsies are very important in those patients.

Should repeat testing ever be done?

Yes. However, it’s important that we talk about what “repeat testing” means. If you can access a tumor specimen without causing many complications, you should do a tumor biopsy. Unlike in the first-line setting, where we would use florescence in situ hybridization to look for translocations, we would look for specific mutations. As such, you really need NGS to understand what is happening. In many cases, you have to do RNA [sequencing]. Identifying the type of mutation is critical because the spectrum of mutations that these agents can hit varies.

Are there specific trials being planned in this space that you're looking forward to?

In the ALK space, we already have a lot of data available. The data that we were waiting for were the data on lorlatinib. It was a good trial, and it showed that [the agent has] a spectrum of activity. The question is how to best sequence these agents. In the first-line setting, everyone is likely going to receive alectinib; however, brigatinib could be an alternative.

What situations would warrant the use of brigatinib as frontline therapy?

In my clinical practice, [a situation like that] has not appeared yet. However, [if it did, it would be a result of] the toxicity profile. Patients can develop musculoskeletal pains or have fluid retention with alectinib. You may have to modify treatment based on that. Nonetheless, it's my preference to choose alectinib as frontline therapy at this point.

Are resistance mechanisms mutually exclusive, or are they associated with a specific ALK inhibitor?

Not everyone who progresses on a particular agent does so as a result of additional mutations. Patients could have ALK independence, in which case you would need to consider chemotherapy. We tend to forget the effectiveness of chemotherapy. We know that pemetrexed works very well in patients with ALK-positive disease. The question is whether you can also combine chemotherapy with these agents. In the setting of EGFR-positive disease, I have combined EGFR TKIs with chemotherapy. I had one patient in particular for whom I combined chemotherapy with brigatinib when the patient was progressing on brigatinib. I didn't have lorlatinib available, but the patient had a response. There is a group of patients in whom progression may not be mutation-dependent.

Additionally, there are patients who develop oligoprogression, which occurs in one particular site. In that case, you need to consider locally ablative therapy. A tumor has heterogeneity, and one particular area may become resistant [to a drug]. You might be able to eliminate it using targeted radiation or surgery. Those are [all options that] you need to consider.

What is your advice for navigating the ALK space?

First, you need to know what you're treating. In a patient with metastatic lung cancer, you need to know exactly what the molecular profile of the patient is. There are many tests that are available. Relying on one or two molecular tests is not enough. You have to do the leg work, otherwise you’re going to harm the patient.

Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Eng J Med. 2017;377(9):829-838. doi: 10.1056/NEJMoa1704795.