ALK+ NSCLC Landscape Shifting With Emerging Agents

Ranee Mehra, MD

Ongoing clinical trials and a novel agent recently submitted to the FDA could expand the armamentarium for ALK-positive non—small cell lung cancer (NSCLC). Approved agents in the setting include the ALK inhibitors crizotinib (Xalkori), ceritinib (Zykadia), and alectinib (Alecensa).

A new drug application (NDA) was submitted for brigatinib (AP26113) in August 2016 as a potential treatment for patients with ALK-positive disease. The NDA is partly based on encouraging results from the phase II ALTA study, which demonstrated a confirmed objective response rate of 54% for brigatinib at the 180 mg daily dose, including a 4% complete response rate.¹

Additionally, the Japanese-based J-ALEX study explored alectinib in the frontline setting for advanced ALK-positive patients. In findings presented at the 2016 ASCO Annual Meeting, alectinib was found to have a 66% improvement in progression-free survival versus crizotinib.²

However, members of the oncology community are eagerly awaiting the results of the global ALEX study to determine whether alectinib should, indeed, be the new frontline standard of care, explained Ranee Mehra, MD.

OncLive: What are the key takeaways for oncologists to know about ALK-targeted therapies in NSCLC?

What is the current role of targeted therapies in this setting?

Mehra, and associate professor and director, Head and Neck Oncology Therapeutics, Johns Hopkins Medicine, discussed these data and more thoughts on ALK-positive NSCLC during the 2016 OncLive State of the Science Summit on Advanced Non-Small Cell Lung Cancer, which took place on September 17 in Philadelphia. In an interview with OncLive, she provided an overview of ALK inhibition in NSCLC, an observation of the most common treatment-related adverse events, and what impact in-development agents will likely have on the expanding field.Mehra: I tried to give an overview about the current landscape regarding ALK inhibitors, so I discussed data from the 3 FDA-approved agents—crizotinib, ceritinib, and alectinib. I also shared some recent data that has been presented on some of the agents still in investigation, such as brigatinib and lorlatinib. Additionally, I reviewed the first-line data with alectinib from the J-ALEX study that were presented at the 2016 ASCO Annual Meeting.Targeted therapies for lung cancer are really for a specialized population. The testing for patients has certainly been increasing, and it is standard of care to look for molecular alterations in newly diagnosed patients. What the profile shows determines whether a targeted therapy is appropriate or not, especially in the first-line setting.

Can you discuss brigatinib, which has been submitted to the FDA for approval in ALK-positive NSCLC?

What can you share about upcoming results that the community is anticipating results of?

In the example of ALK, if there’s an ALK translocation or a positive ALK test by immunohistochemistry, those are patients who will be considered to be ALK-positive and should respond to an ALK inhibitor.Brigatinib was investigated in a phase I/II study, as well a randomized phase II trial, looking at 2 different doses of the drug. Moreover, there is a first-line study ongoing. Right now, we have to wait for the results of the trials in progress, but the preliminary results certainly showed that there was clinical activity in this population.We have seen the results from the J-ALEX study [of alectinib in the frontline setting], but there is also the ALEX study that is the North American equivalent. Especially given the positive results of the J-ALEX study, everyone is awaiting the results from the ALEX trial.

How do the side effects of these ALK-targeted therapies differ from some of the more standard treatments?

There is also an importance of understanding the role of resistance mutations, especially as the landscape of treatment for ALK-positive lung cancer is including more options, trying to understand that potentially knowing the resistance mutations can help us select which therapy to use.Many targeted therapies do not have the typical side effects that we consider with cytotoxic therapy. For instance, crizotinib is associated with increased liver function tests, perhaps some mild nausea, and an ocular toxicity where it looks like patients have floaters. Therefore, it has a very different side-effect profile.

The second-generation ALK inhibitors, such as ceritinib, had some gastrointestinal toxicity with nausea or diarrhea. With alectinib, transaminitis has been noted as an adverse event. One class effect, in general, with ALK inhibitors has been pneumonitis, and so while the incidence of this has been low, it has been reported in the clinical trials.

References

1. Kim D-W, Tiseo M, Ahn M-J, et al. Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): First report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA). J Clin Oncol. 2016;34 (suppl; abstr 9007).
2. Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. J Clin Oncol. 2016;34 (suppl; abstr 9008).

An ongoing phase III study, ALTA-1L, is comparing the 180 mg dose of brigatinib with crizotinib in the frontline setting for patients with ALK-positive NSCLC (NCT02737501).