Treatment Options for ALK+ NSCLC Continue to Grow

Joseph Leach, MD

As more systemic agents become available for the treatment of patients with ALK-positive non—small cell lung cancer (NSCLC), physicians are encouraged to test patients diagnosed with lung cancer for mutations, said Joseph Leach, MD.

For example, data from the phase III ALEX trial had a significant impact on the treatment of newly diagnosed ALK-positive NSCLC. Results showed that alectinib (Alecensa) reduced the risk of disease progression or death by 53% (HR, 0.47; 95% CI, 0.34-0.65; P <.0001) compared with crizotinib (Xalkori) at 25.7 months versus 10.4 months, respectively. Additionally, alectinib was better tolerated, with adverse events occurring in 41% of patients on the alectinib arm versus 50% for those who received crizotinib. These findings led to the November 2017 approval of alectinib as a frontline treatment for patients with ALK-positive metastatic disease.

Beyond alectinib, ceritinib (Zykadia) and crizotinib are also available as frontline therapy, while lorlatinib (Lorbrena) and brigatinib (Alunbrig) are both available in the second-line setting. The availability of these agents emphasizes the necessity of performing genetic testing on patients diagnosed with lung cancer, according to Leach.

“Our understanding of the biology and our ability to treat these specific kinds of lung cancer has exploded in the last several years. It's so important to understand the underpinnings of these cancers from a mutational standpoint because of newer treatments that are available and upcoming,” said Leach, a medical oncologist at Minnesota Oncology. “We thought [ALK and ROS1 mutations] were uncommon, but they have become increasingly important in management of lung cancer.”

In an interview during the 2019 OncLive^® State of the Science Summit^TM on Non—Small Cell Lung Cancer, Leach discussed the emergence of ALK inhibitors in lung cancer and the importance of testing for such molecular abnormalities.

OncLive: What are the key things to note with testing for ALK and ROS1 abnormalities?

Leach: The most important thing is to test for those mutations. Unfortunately, many patients don't get tested to see if they have the mutation. If you don't know whether the mutation is there or not, your patients can't have the opportunity to be treated appropriately. Every patient with stage IV lung cancer needs to be tested for the presence ALK and ROS1 mutations.

It's also important to understand how different the landscape is in terms of novel initial therapies and therapies beyond progression, especially beyond ALK mutation, where we have multiple drugs that are potentially beneficial to those patients.

How are liquid biopsies used in lung cancer and how do they compare with tissue biopsies?

Getting tissue is really problematic for some of our patients with lung cancer; they may have areas of disease that are not safely accessible. The amount of tissue you need, especially to do some of the secondary mutation testing, sometimes is not achievable. Having circulating tumor DNA to do some of this testing has allowed us, in clinical practice, to be able to identify the resistance mechanisms without needing to get tissue in those patients in whom it is unsafe to do so.

With brigatinib pending a frontline approval in ALK-positive NSCLC, could you share your thoughts on the agent?

Brigatinib is a very interesting compound and is very potent in inhibiting ALK. It was approved for patients who progressed on first-line crizotinib. We now have published data in the first-line setting comparing brigatinib with crizotinib, which showed that [brigatinib] is superior in progression-free survival (PFS). Brigatinib has activity against more secondary mutations, especially compared with drugs such as alectinib. The mutation G1202R, which is in patients who received a second-generation ALK inhibitor upfront, has become the most mechanism of resistance in patients with ALK-positive NSCLC with the mutation. Where to utilize [brigatinib] in first- and second-line [therapy] is unclear. Unfortunately, even though we have data showing superiority, [brigatinib] has not yet been FDA approved [in the frontline setting]. Some of the data and the crizotinib studies might suggest it's a little more active, but until we have FDA approval, most patients are still going to get frontline alectinib. Where brigatinib can be used now in a world where most patients are going to be getting alectinib upfront is something we need to figure out. It does have intriguing activity, and data were recently published and showed about a 40% response rate in patients who progressed on second-generation ALK inhibitors. There is much more to learn about where brigatinib sits.

Alectinib is already approved by the FDA in the frontline setting. What are your thoughts on this agent?

The ALEX trial was a game-changer in the way we think of management of newly diagnosed ALK-positive NSCLC. Alectinib was a “home run” with a median PFS of about 3 years with less toxicity, which is amazing. Given its approval, most patients are going to start with alectinib because of its activity and favorable toxicity. The other second-generation drug approved in first-line is ceritinib, but it has so much more gastrointestinal-associated toxicity. It's hard to find rationale to use it. Alectinib, until [we see the frontline] approval of brigatinib, is our go-to drug for newly diagnosed patients.

What about the latest drug to be approved, which is lorlatinib?

Lorlatinib is the newest drug, approved at the end of last year for patients who have progressed on a second-line drug, such as ceritinib or alectinib in the first-line setting. It was an important approval because we didn't have anything that we knew worked. In the data looking at patients who received prior second-line TKI therapy, it was really active. One interesting thing about that study is that 50% of patients who progressed on a second-generation ALK TKI do so because there is a secondary mutation that happens in ALK. When those are identified, it is very active, with a response of about 63%. When researchers couldn't find [a secondary mutation in ALK], it only worked about half as well. It's really important for us to understand the biology of our cancers, because it can predict the mechanism of what drugs will be most effective.

What new treatment strategies are in the pipeline?

Understanding the mechanisms of resistance is important. About half of the patients who progress on a second-generation ALK inhibitor do so because of ALK mutations. Right now, lorlatinib is a good option for them, but that means half of patients have other mechanisms, usually bypass pathways. There is work being done, but more work needs to be done as we understand these other mechanisms of resistance in combination therapy for patients who have secondary EGFR mutations, or have secondary KRAS or MET amplification. Combination therapy for those patients will be really important, and there are other potent ALK inhibitors still in the pipeline. Entrectinib (Rozlytrek) is a drug that has been really interesting in ALK so we're waiting for final data with that.

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