Larotrectinib Demonstrates Robust Responses in TRK Fusion-Positive Lung Cancer

David Hong, MD

The treatment landscape for NTRK fusion-positive disease has been evolving with developments of new tyrosine receptor kinase (TRK) inhibitors for this patient population.

Currently, 2 TRK inhibitors, larotrectinib (Vitrakvi) and entrectinib (Rozlytrek), are approved by the FDA. Each drug shows the ability to address important areas of unmet need, in TRK fusion-positive lung tumors.

According to David S. Hong, MD, recent efficacy and safety data on larotrectinib has been robust, even when compared to entrectinib. Multiple studies, including the phase 2 NAVIGATE (NCT02576431), phase 1 LOXO-TRK-14001 trial (NCT02122913), and phase 1/2 SCOUT trial (NCT02637687) sought to evaluate larotrectinib as an NTRK inhibitor.

In each trial, adult and/or pediatric patients with fusions in the NTRK1, NTRK2, and NTRK3 genes, were treated with larotrectinib. While patients with various cancer types, including lung, thyroid, salivary, and colorectal cancers were enrolled on these trials, Hong discusses only those with advanced lung cancer.

Based on SCOUT, NAVIGATE, and LOXO-TRK-14001,larotrectinib was approved by the FDA for all solid tumors harboring an NTRK fusion in adults and children with metastatic disease or those who cannot receive surgery and have no satisfactory alternative treatments in 2018.

While results from these studies confirm the long-term response and efficacy of larotrectinib in patients with lung cancer who harbor NTRK fusions, further research is needed to assess the ways in which one can best optimize therapeutic approaches with each agent.

In an interview with Targeted Oncology​​yTM, David S. Hong, MD, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed an updated analysis of larotrectinib and the data supporting the agent for the treatment of TRK fusion-positive lung tumors.

Can you discuss larotrectinib? What sets it apart from other TRK inhibitors?

Larotrectinib was the first approved NTRK inhibitor and it was approved for all patients who have and TRK fusions regardless of age, regardless of tumor type, regardless of NTRK fusion partner. There are 3 NTRK genes, NTRK1, NTRK2, NTRK3, and there are multiple different partners. It was an accelerated approval for a breakthrough indication that led to the first small molecule inhibitor that was a tumor agnostic approval. At this point, I think it is the most potent NTRK inhibitor out there.

We did a recent analysis and with Alexander Drilon, MD, we looked at the long term efficacy and safety of larotrectinib. In this pool, the analysis of transfusion patients was from 3 trials that ultimately led to the approval. There was the adult phase 1, which I led, and there was the pediatric phase 1 and 2 is called the SCOUT trial [NCT02637687], and then there was the NAVIGATE study [NCT02576431], led by Dr. Drilon. Those trials, particularly the phase 2, are still enrolling patients.

What were the updated findings from this recent analysis?

In this most recent analysis, we looked at close to 244 patients. In those 244 patients, we looked at response rates, progression-free survival, duration of response, and overall survival. It's always amazing to me when I see this updated data, how durable and how beneficial this drug is in these patients. The overall response rate remained very high, close to 70%, 69%, with complete response rates of over 21%. The median duration of response was 32.9 months, with median progression-free survival at 29.4 months, and the overall survival had yet to be reached across all different pathologies.

In the phase 1 trial and all the other studies of about 269 patients, the vast majority of adverse events had only been grades 1 and 2. About 20% of the patients had grade 3 treatment related adverse events, mostly related to elevated liver function tests, which were usually reversible once the drugs were held, and dose reduced. This was pretty much the same thing that we saw with larotrectinib with the initial approval at 55 patients.

In this expanded analysis, larotrectinib continued to show robust and durable objective responses with patients with TRK fusions and a favorable long term safety profile. It speaks to the fact that with next generation sequencing [NGS] being the common test that we can get in our patients that it behooves every oncologist to try to find these patients through NGS testing.

With these updated results in mind, how do you think larotrectinib stands up to something like entrectinib (Rozlytrek)?

I think larotrectinib has the most robust data at this point, number of patients, etc. Entrectinib is different in the sense that it's less of a nonspecific inhibitor and it also targets ROS. Those who are developing and involved in entrectinib will tell you that that may be an advantage. What is interesting is that the majority of patients who have NTRK fusions rarely have any other alterations.

My bias, given the fact that I helped develop this drug, is that patients who have NTRK fusions should be getting an NTRK inhibitor of some sort. In my opinion, larotrectinib, given the robustness of the data and the number of patients, the overall response rates are a little bit better with larotrectinib right now. It's not clear whether progression-free survival or overall survival are any better, but that's why I would consider larotrectinib.

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How do you think larotrectinib will be used in the future?

Like a lot of other drugs, I think larotrectinib first will be often used in the refractory setting and patients who have failed chemotherapy. But there's data that we also presented on different efficacy of different lines of therapy that suggests that patients who get this drug, either in tumor types, like non–small cell lung cancer who have standard care options in the frontline setting do benefit from it and will have benefit for long periods of time.

If you identify a patient with an NTRK fusion, it's reasonable to give these patients larotrectinib even in the frontline setting. Ultimately down the line, a lot of drugs go from refractory to frontline, and then eventually they will go into the adjuvant or even neoadjuvant setting. We don't have enough patients, and those trials have yet to be read out. I think eventually that's what we will move towards.

Are there any other disease subgroups that might benefit from larotrectinib?

The central nervous system [CNS] is a component of it. We didn't present the data at ASCO this year, but there are clearly patients who have either primary CNS, or who also have brain metastases who are benefiting from larotrectinib. A highlight of entrectinib is that it seems to be brain penetrating, but we know that both molecules can penetrate the brain.

Some of these patients, particularly the pediatric patients with infantile fibrosarcoma, who got the drug had significant tumor shrinkage and they were able to go in and resect the tumor out in a way, almost like in a neoadjuvant setting. Primarily, as more patients are becoming or getting NGS earlier in the staging, I think we will identify these patients that may benefit from these drugs earlier, as soon as they're identified within transfusion.