Assessing Treatment Strategies ALK+ Lung Cancer

Luis E. Raez, MD

It should be standard of care to use next-generation sequencing (NGS) upfront as well as at the time of disease progression, so that treatment can be tailored to patients with ALK-mutant non—small cell lung cancer (NSCLC) throughout their care, explained Luis E. Raez, MD.

The detection of an ALK mutation should signal the use of an ALK TKI such as alectinib (Alecensa) rather than chemoimmunotherapy, according to Raez. When a patient develops resistance to the drug, repeat testing should be done to identify the optimal second-line therapy.

“Everybody believes lorlatinib (Lorbrena) is the best drug to use [upon progression]. However, [a patient may have] a resistance mutation to lorlatinib that is sensitive to crizotinib (Xalkori); this is why we cannot say that a certain drug is the best choice upon progression,” said Raez.

In an interview with OncLive during the 2020 Winter Lung Cancer Conference, Raez, medical director and chief scientific officer of Memorial Cancer Institute, and chief of Hematology/Oncology at Memorial Healthcare System, provided insight into therapies available to patients with ALK-mutant NSCLC and underscored the role of genetic testing in informing treatment decisions.

OncLive: Could you provide an overview of research on ALK mutations lung cancer?

Raez: Approximately 4% to 5% of Americans have ALK [mutations]; however, many patients have lung cancer—more than 225,000. A significant number of patients carry genetic alterations. [At the 2020 Winter Lung Cancer Conference], I discussed treatments for those with these alterations and presented some clinical cases [faced in practice]. We're very lucky that we have 5 drugs available to treat these patients.

Could you expand on the treatment options available to patients with ALK mutations?

According to our guidelines, alectinib is the preferred agent because it [has central nervous system activity]. When we used crizotinib, patients [will still] develop brain metastases. We use brigatinib (Alunbrig) and lorlatinib to rescue patients.

[At the conference], we discussed the problem of resistance mutations. In the same way that patients become resistant to antibiotics, patients who take any of the 5 FDA approved agents can develop resistance mutations [to these agents]. We discussed whether we should test for resistance mutations because that’s what you would do when an antibiotic fails. We do a culture and we test for resistance mutations. The controversy today is whether we should use these 5 agents empirically or whether we should select the next drug based on a patient’s resistance profile. We also discussed other issues, such as whether we should use TKIs or chemoimmunotherapy first.

Could you discuss the utility of repeat testing?

It’s very simple. The more advanced an ALK inhibitor that you use, for example alectinib and then lorlatinib, the higher the chance of developing a resistance mutation. If lorlatinib fails, patients have a higher chance, close to 50%, of developing a resistance mutation. With crizotinib, [the patient’s chance of developing a resistance mutation] may only be 24%. If a patient is taking an ALK inhibitor for 1 year and [the treatment] fails, we do a liquid biopsy. If the patient has a resistance mutation, [we’ll] know what the next agent should be. However, that’s not standard of care.

I presented a case of a patient who had 4 resistance mutations. There’s no 1 drug that can be used to rescue that patient. In the future, when liquid biopsies become more widely available, we may be testing more than once. According to the Society of Liquid Biopsy guidelines, we want to test up front, and perhaps at the time of resistance. Patients with ALK mutations [tend to] live 6 to 7 years. I have had patients who have taken all 5 pills [during that time]. That's why it’s so important to educate [patients] about resistance mutations. Not everyone has a resistance mutation. One publication reported that only 24% to 25% of patients have a resistance mutation, but it's very meaningful for the patient [to understand how the presence of such a mutation will impact treatment decisions].

We use NGS to test for resistance mutations. When we do that, we’re [looking for] fusions, and inside the fusion, a mutation. This is not only a problem for patients with ALK mutations; the same is true for those with ROS1 and NTRK fusions. I believe that it should be standard of care to [test for resistance mutations] in ALK-, ROS1-, and NTRK¬-mutated lung cancers, so we know what drug we should use next. We have to determine a more rational way to use these agents.

Where might chemoimmunotherapy be used in place of TKIs?

We’re victims of our own success. In order to give targeted therapy to patients with ALK, EGFR, BRAF, and NTRK mutations, you have to find the molecular aberration. If you do a tissue biospy, it will take 3 weeks; this is usually 2 months after we’ve discovered a mass in the patient’s lung. Sometimes, they may have seen the surgeon first which wastes time because most of these patients are stage IV, so [they’re not resectable]. There are many delays. Now, you tell them they can take a pill 3 weeks from now or receive chemoimmunotherapy the next day. Many doctors and patients will [opt] for chemoimmunotherapy. If you have a patient with a genetic alteration, you can buy them 5 years if they have an ALK mutation. You can still put them on chemoimmunotherapy with all its benefits after. That’s why we strongly [recommend] testing. You can use a liquid biopsy, which will take 8 to 9 days. If you order chemotherapy, you need to wait 8 or 9 days for the insurance approval, which is essentially same as just waiting for the liquid biopsy [results]. If the patient has an EGFR mutation, we can buy them 2 or 3 years and then use chemoimmunotherapy. If the patient has a BRAF mutation, we can buy them 6 or 7 months and then start chemoimmunotherapy.

What are some exciting ongoing trials in the ALK-positive space?

We have several agents in development. For example, here in Florida, we have repotrectinib (TPX-0005). We use repotrectinib for patients with ALK mutations who have failed conventional drugs. It's important that you enroll these patients [on clinical trials] so they can benefit from these new agents. Chemoimmunotherapy is good, but we can always delay the process and give them the benefit of that combination later [on in their treatment journey].

What is your key takeaway regarding the treatment of patients with ALK-positive NSCLC?

We need be more aware that these patients have a good prognosis. We can keep these patients alive for 6 to 7 years. We don't want to lose that opportunity because we didn’t diagnose them properly. Sometimes, there is not enough tissue available for testing, but the solution is not to just put them on chemoimmunotherapy. The solution is to do a liquid biopsy. [If the test results are negative], you may want to do another liquid biopsy—especially if your patient is a young nonsmoker with Asian heritage.

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