Next-Generation Agents Accelerate Advances in ALK+ and ROS1+ NSCLC

Nisha A. Mohindra, MD

With the development of selective TKIs, it’s no longer a question of whether ALK-positive and ROS1-positive non—small cell lung cancer (NSCLC) can be targeted, but rather how to select the optimal therapy among a growing roster of treatments, according to Nisha A. Mohindra, MD.

“It's really important to order molecular profiling because if patients have these aberrations, great drugs are now available and many more are in development,” said Mohindra.

For patients with ALK-positive disease, alectinib (Alecensa) has become the preferred frontline standard of care compared with crizotinib (Xalkori) and ceritinib (Zykadia). However, ensartinib, a next-generation ALK inhibitor, is currently under evaluation in the phase III eXalt3 trial (NCT02767804) and those findings could potentially shift current sequencing strategies, added Mohindra.

In the ROS1 space, crizotinib has become the frontline standard of care, having shown an unprecedented objective response rate (ORR) of 72% (95% CI, 58%-83%) and a median progression-free survival (PFS) of 19.3 months (95% CI, 15.2-39.1), according to updated findings from the phase I PROFILE 1001 trial.¹

However, in August 2019, the FDA granted an accelerated approval to entrectinib (Rozlytrek) for use in patients with ROS1-positive, metastatic NSCLC according to data from the phase II STARTRK-2, phase I STARTRK-1, and the phase I ALKA-372-001 trials, which demonstrated comparable activity to that seen with ceritinib.²

“It's tough to do cross-trial comparisons. Longer follow-up tell us more,” said Mohindra.

In an interview with OncLive^® during the 2019 State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Mohindra, an assistant professor of medicine in the Hematology/Oncology Division of Northwestern University's Feinberg School of Medicine, detailed current treatment strategies and some of the next-generation inhibitors that could shift sequencing approaches in ALK-positive and ROS1-positive NSCLC.

OncLive: What are some key updates in ALK-positive and ROS1-positive NSCLC?

Mohindra: [In my presentation,] I spoke about ALK and ROS1 fusions, the first-line data we have, and how we approach treatment at the time of progression. Many exciting [updates] are happening in this space. In the past decade, there have been several really exciting approvals.

Could you expand on some of the available agents in the ALK space?

In the frontline setting, alectinib has become a preferred agent in the United States based on data from the ALEX trial. We also have crizotinib and ceritinib in the first-line setting.

Could you discuss the promise of ensartinib?

Ensartinib is another potent next-generation ALK inhibitor. We’re hoping to see more data in the next several years with regard to how it fares in the first-line setting in comparison with crizotinib. Several ALK inhibitors are going to emerge in this space. It will be interesting to see what agent will become the first-line treatment of choice.

How has crizotinib impacted the management of patients with ROS1-positive NSCLC?

Crizotinib was evaluated in the PROFILE-1001 trial. We saw response rates in the 70% range and a PFS of at least 17 months. That was the first time a targeted agent demonstrated benefit in the ROS1 space; that really changed the way we thought about ROS1 disease.

In August 2019, the FDA granted entrectinib an accelerated approval for patients with ROS1-positive metastatic disease. Could you discuss the data we have seen with this agent?

Entrectinib is an NTRK, ROS1, and an ALK inhibitor. Three trials were done with entrectinib that included patients with ROS1 disease. We also saw an integrated analysis, which pooled the data with ROS1 patients, and about 54 patients were included. Response rates were approximately 77% with the agent, and the PFS was about 19 months. Duration of response [with the drug] was close to 25 months. Ultimately, entrectinib is another promising agent in the first-line space. Notably, entrectinib appears to have better CNS activity versus crizotinib. However, the 2 agents have never been compared head-to-head.

How are you selecting frontline therapy in ALK-positive and ROS1-positive disease?

I generally choose alectinib in the frontline [ALK-positive] setting. We saw unprecedented PFS in the ALEX trial. We haven't seen that [magnitude of benefit] with many of the targeted agents. We're learning that resistance to these ALK TKIs is complex and understanding the mechanism of resistance will play into our understanding of what the next line of treatment should be. In ROS1-positive disease, entrectinib has become an exciting option; it will likely become my preferred agent for frontline treatment.

What is known about resistance in ROS1-positive disease?

We are beginning to learn how complex resistance is. Some of the newer agents do have some efficacy in some of the more prevalent resistance mechanisms, but that space is emerging. We’re going to see a lot more data in that space. We'll need to find the right subset of patients with ROS1-resistant disease who could continue on ROS1-directed therapy.

What agents are emerging in the ROS1 space?

We’re starting to learn about repotrectinib (TPX-0005). Additionally, [we’re seeing that] lorlatinib (Lorbrena) could overcome resistance mutations in the ROS1 space. We’re also expecting more frontline data with ensartinib and lorlatinib.

References

1. Shaw At, Riely GJ, Bang YJ, et al. Crizotinib in ROS1-rearranged advanced non-small cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019;30(7):1121-1126. doi: 10/1093/annonc/mdz131.
2. De Braud FGM, Siena S, Barlesi F, et al. Entrectinib in locally advanced/metastatic ROS1 and NTRK fusion—positive non–small cell lung cancer (NSCLC): updated integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Ann Oncol. 2019;30(suppl_5). doi: 10.1093/annonc/mdz260.010.