ALKA-372-001, STARTRK-1, and STARTRK-2 Trials

Lyudmila A. Bazhenova, MD: Entrectinib approval was certainly welcome because it gives our patients another option. Entrectinib approval was based on the combined analysis of 3 trials, which are called ALKA-372-001, STARTRK-1, and STARTRK-2. It is a very effective drug, and a response rate of 78% is excellent. In addition, entrectinib has confirmed CNS (central nervous system) efficacy, which is important for our patients with oncogenic-driven cancers.

Jonathan W. Riess, MD: In terms of the management of ROS1-positive non–small cell lung cancer that's metastatic, there's been the development of several exciting therapies. As mentioned, crizotinib has been around for several years and does have good activity. Entrectinib has recently been approved as well. The approval was based on a pooled analysis of 3 studies with entrectinib, as it's also an NTRK and ALK inhibitor and was studied in a cross section of these patients.

When looking at patients with ROS1 in the ALKA-372-001, STARTRK-1 and STARTRK-2 studies, overall response rates were over 70%, and median duration of response came out to be 24.6 months. The major advantage of entrectinib is that it does have additional CNS activity and penetration. There are potential adverse effects: weight gain; neutropenia; some nervous system disorders, such as paresthesias; GI (gastrointestinal) upset with nausea; myalgia; dysgeusia; and attention disturbance.

Overall, it's an excellent option for patients with ROS1 rearranged non–small cell lung cancer. In terms of the pharmacodynamics and pharmacokinetics of entrectinib compared with crizotinib and ceritinib, I think the big advantage is CNS activity, and we've seen that. We've seen CNS activity play a role, for example, with alectinib and brigatinib versus crizotinib in ALK rearranged non–small cell lung cancer, as well as osimertinib compared with erlotinib and gefitinib in eGFR mutated lung cancer, where those have become first-line treatments.

One could look at entrectinib in a similar way. It is a selected ATP (adenosine triphosphate)-competitive inhibitor of TRK, ROS1, and ALK and does have great potency in terms of its pharmacokinetics and pharmacodynamics, with maximal concentration reaching 2 to 4 hours. Half-life is about 21 hours in the fed state, so it can be taken with food. It is a good option for these patients.

Balazs Halmos, MD: Coming now to entrectinib, a recently developed and very potent NTRK and ROS1 inhibitor, we’ve seen great success with this agent in both NTRK fusion-positive and ROS1-fusion positive cancers, including a fair number of lung cancers. This is an agent that’s also very selective. It doesn’t have a lot of off-target adverse effects. It’s a very safe molecule. It’s also designed to be CNS-penetrant, which is very important in the treatment of these patients.

Non–small cell lung cancer has a great predilection for CNS metastases, in particular eGFR-, ALK-, and ROS1-positive cancers have a great likelihood of ultimately metastasizing to the CNS. Having targeting agents with CNS penetrants is critical, and entrectinib is a molecule that fits the profile and has shown great efficacy in the combined analysis of the phase 1 and phase 2 studies, showing a PFS (progression-free survival) of 19 to 20 months. It’s shown a great benefit in the overall group of patients,specifically patients with CNS disease, with a response rate surpassing 50% in the CNS and a substantial duration of response, maybe a year or so in the CNS as well. This is a highly promising agent for the management of ROS1 translocation-positive non–small cell lung cancers.

I think we’re fortunate to be able to witness the treatment of patients with this targeted agent. ALK and ROS1-positive cancers stand out as having great benefits from ALK- and ROS1-targeting drugs. Crizotinib is sort of the historical molecule that we’ve used for these patients with great success. In fact, some of the longest responders among advanced lung cancers tend to be patients with ROS1 translocation-positive disease. Entrectinib seems to have a profile analogous to crizotinib in terms of overall benefit and has the advantage of the CNS penetration. That’s significant for this subset of patients, so it’s a favorable asset to entrectinib and offers a great alternative for our patients with ROS1 fusion-positive non–small cell lung cancer.

Lyudmila A. Bazhenova, MD: The overall response rate to entrectinib in the entrectinib trials was 78%. Responses were durable, with median duration of response of almost 25 months. It's important that responses were seen in patients with and without brain metastases. The median progression-free survival was 19 months. We also saw that entrectinib appears to have a very good CNS penetration, with intracranial overall response rate of 55%. Entrectinib is well tolerated.

Even though nearly all the patients in that trial experienced adverse events, the majority of them were grade 1 or 2. There are certain adverse events that are expected for NTRK inhibitors, and those are called on-target treatment-emergent adverse events, which we think are due to inhibition of TRK. Those are dizziness, sometimes perioral numbness. Interestingly enough, TRK TKIs (tyrosine kinase inhibitors) also cause weight gain in our patients due to inhibition of the TRK pathway.

Despite the fact some of the patients had adverse events, discontinuation was very rare in that trial. Only 3% of the patients discontinued the drug due to adverse events. About one-third of the patients required dose interruption, and 20% required dose reduction. Evidence of serious adverse events was also very low, about 9%. Overall, entrectinib is well tolerated by our patients.

I have experience with entrectinib, and I have given it for both ROS1 rearranged as well as NTRK rearranged cancers. My experience is very similar to what has been described. Dizziness is something we commonly see, as well as perioral numbness. Another interesting adverse effect that we see with NTRK inhibitors is if you hold the drug for one reason or another, your patient will experience pain. It's important to be aware of withdrawal symptoms and manage that pain with any kind of pain medication.

Jonathan W. Riess, MD: Intracranial response is important, particularly in patients with CNS disease or in oncogene-driven lung cancers that have a propensity to develop CNS disease. It can be a sanctuary site for recurrence as well. It's a very good option for patients with ROS1 rearranged non–small cell lung cancer, particularly regarding the CNS activity as a potential sanctuary site.

Like I said with alectinib and brigatinib in ALK rearranged lung cancer, and osimertinib in eGFR mutated lung cancer, the longer you can forestall metastases to the brain, the better off you are. The other thing is for small asymptomatic brain metastases: If you can forestall radiation to the brain, these are patients who will sometimes live 4 to 6 years or longer. If you do brain radiation upfront, particularly whole-brain radiation, you're risking some serious neurocognitive toxicities down the road. If you give a TKI that has CNS activity, you'd be able to forestall that and potentially save the patient from some life-impactful toxicities down the road.

Balazs Halmos, MD: Entrectinib is a molecule, a drug that’s easy for patients to take. It has a simple administration schedule, 600 mg once daily, if I remember correctly. It can be taken with or without food. The adverse effect profile is very favorable. Whenever we look at studies of these targeted compounds, it’s nice to see the number of patients who needed to dose reduce due to adverse effects. It’s also important to look at the number of patients who had to stop the drug due to adverse events. Those percentages are very low with entrectinib. It’s a very well-tolerated compound.

It’s important to remember that it also blocks the NTRK pathway, and that’s an important pathway in the CNS. That explains some of the unique adverse effects of the molecule, as well as any molecule blocking the TRK pathway. There can be CNS adverse effects, such as dizziness, and neuromuscular adverse effects, such as neuropathies, polyphagia, and potentially weight gain. These patients have a very good appetite, which is nice on a certain level, but it can sometimes yield to significant weight gains.

Transcript Edited for Clarity