Vincent K. Lam, MD
In a recent phase II study, the next-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) lorlatinib induced an objective response rate (ORR) of 90% in treatment-naïve patients with ALK
-positive non–small cell lung cancer (NSCLC).
OncLive: Please provide an overview of your presentation.
I discussed the latest developments for patients with ALK- and ROS1-positive NSCLC. We are seeing that treatment development is much better with the ALK-targeted therapies compared with ROS1
. Overall, it is an exciting time.
What potential is there with entrectinib as a treatment for patients with ROS1-positive NSCLC?
falls behind compared with ALK
development. It is important to keep in mind that not all ALK inhibitors work for ROS1
-positive NSCLC, such as alectinib. In terms of the ROS1
data, the furthest along is lorlatinib. The phase II trial in the ROS1
cohort showed good response for patients who have been previously treated or are treatment naïve. These results are similar to what we are seeing with ALK.
Other ROS1 inhibitors are entrectinib or ensartinib. Entrectinib also showed very promising data at the recent World Conference on Lung Cancer in Yokohama, with about 70% response rate and excellent CNS activity in a Phase 1/2 treatment naïve ROS1 cohort. However, it is does not seem to be effective for the solvent-front mutations that may be seen in crizotinib-resistant patients. TPX-005 is another promising ROS1 inhibitor that may be more effective in terms of targeting these solvent-front mutations, which are problematic for [first-generation] agents.
What is the role of lorlatinib in ALK-positive tumors?
Lorlatinib is a potent third-generation ALK inhibitor that has been granted FDA breakthrough status for the treatment of ALK
-positive patients, particularly after prior exposure to TKIs, specifically with crizotinib (Xalkori). Its main benefit, or value, is that it does treat G1202R solvent-front mutations, which is a difficult area for other second-generation TKIs.
There has been a phase II trial that has generated nice data for lorlatinib. That trial is broken into various expansion cohorts based on what type of prior TKI or chemotherapy exposure the patient has seen.
In that trial, we see the treatment-naïve patients have an ORR of around 90% and a median progression-free survival (PFS) that had not been reached with the recent data that was presented at the 2017 World Conference on Lung Cancer. Most importantly, the crizotinib-resistant patients saw an ORR of around 30% or higher with a median PFS of 6 months.
There is still work to do, but it is promising that we will have an agent in the third-generation [space] that can address these resistance mutations.
What are some of the most pressing unmet needs for patients with ALK-positive NSCLC?
We have made progress in terms of TKI development. The median PFS is somewhere on the order of 26 months with alectinib in the first-line setting. Brigatinib (Alunbrig) is expected to have even better results, with phase I data suggesting that the PFS in the frontline setting may be 30 to 34 months.
However, we are going to run into the challenge where all of the TKIs will stop working at some point. The phase II study investigating lorlatinib is instructive in seeing how the response rate goes down as a patient is exposed to second-generation inhibitors or more than 2 TKIs—ending up with an ORR around 30% and a median PFS of 5.5 months.
That is the biggest hurdle. We need to figure out how to improve the development of third- and fourth-generation TKIs to affect a durable response but to also explore rationale combinations. Additionally, we need to address the ALK
-independent resistance mechanism which is already in trials or under development.
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