David S. Hong, MD

David S. Hong, MD, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses larotrectinib (Vitrakvi) and its mechanism of action.

Currently, there are 2 NTRK inhibitors which exist and are approved by the FDA for patients with 

 fusion-positive disease. These include larotrectinib and entrectinib (Rozlytrek).

At the 2022 World Conference on Lung Cancer, 2 trials were presented which further demonstrated the favorable efficacy and survival outcomes with larotrectinib in patients with lung cancer and 

 inhibitor and it was approved for all patients who have 

 fusions regardless of age, regardless of tumor type, regardless of 

, 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. I do think at this point that 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 pooled analysis of 

 fusion patients. This 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 called the SCOUT trial [NCT02637687], and then there was the NAVIGATE study [NCT02576431], which was helped led by Dr. Drilon. Those trials, particularly the phase 2, are still enrolling patients.

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David S. Hong, MD, discusses larotrectinib and its mechanism of action.


Examining Larotrectinib in NTRK Fusion+ Lung Tumors

David S. Hong, MD, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses what he sees for the future of the NTRK inhibitor larotrectinib (Vitrakvi).

Larotrectiniib was originally approved by the FDA for patients with 

 fusion-positive lung cancer based off the findings of the phase 2 NAVIGATE (NCT02576431), phase 1 LOXO-TRK-14001 trial (NCT02122913), and phase 1/2 SCOUT trials (NCT02637687), that looked at this disease in various settings.

According to Hong, a pooled analysis of these 3 studies showed the remarkable durability of the drug, showing a median duration of response at 32.9 months, progression-free survival at 29.4 months, and in the most recent analysis, an overall survival rate around 70%. Studies are ongoing with this treatment, which is why Hong believes Larotrectinib will continue to find new roles in this, and other, patient populations.

Just like a lot of other drugs, I think larotrectiniib will be often used in the refractory setting, patients who fail chemotherapy. However, there's data that we also presented on different efficacy and different lines of therapy that suggests that patients who get this drug, even in tumor types like NSCLC, who have standard of care options in the frontline setting, do benefit from it and will have a benefit for long periods of time.

I think if you talk with a lot of [lung cancer speciclatis], for example, if you identify a patient with NTRK fusion, it's reasonable to give these patients larotrectinib even in the frontline setting. Ultimately down the line, if you think about how a lot of drugs are kind of go from refractory to frontline, [or how] eventually they will go into the adjuvant or even neoadjuvant setting, we don't have enough patients and those trials have yet to really kind of read out. But I think eventually that's what we'll move towards to.

David S. Hong, MD, discusses what he sees for the future of the NTRK inhibitor larotrectinib.

Looking at the Future of Larotrectinib in NTRK Fusion+ Lung Cancer

David Hong, MD, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, explains why larotrectinib (Vitrakvi) may be chosen over other TRK inhibitors for the treatment of 

Larotrectinib is 1 of 2 FDA-approved treatment options for TRK fusion-positive lung cancer. Findings from the phase 2 NAVIGATE (NCT02576431), phase 1 LOXO-TRK-14001 trial (NCT02122913), and phase 1/2 SCOUT trial (NCT02637687) supported the FDA approval. The other approved NTRK inhibitor, entrectinib (Rozlytrek) was supported by data from the phase II STARTRK-2 trial, the phase I STARTRK-1 trial, and the phase I ALKA-372-001 trial, anddata from the phase I/II STARTRK-NG trial.

According to Hong, although both NTRK inhibitors have a place in the field, larotrectinib appears to have more robust data.

 I think larotrectinib has the most robust data at this point, number of patients etc. and tracking it was different than the sense it's less of a nonspecific inhibitor it also targets 

 and those who are developing and larotrectinib and involved with larotrectinib will tell you that may be an advantage. But you know, what’s interesting is that the majority of patients who have 

 fusions rarely have any other alterations. They just have 

My bias, given the fact that I also helped develop this drug is that patients who have 

 of some sort, in my opinion. And larotrectinib, given the robustness of the data, and the number of patients, the response rates are a little bit better with larotrectinib. Right now, it's not clear whether progression-free survival overall survival are any better, but that's why I would consider larotrectinib.

Articles

David Hong, MD, explains why larotrectinib may be chosen over other TRK inhibitors for the treatment of NTRK fusion-positive lung cancer.

Choosing Larotrectinib vs Entrectinib to Treat NTRK Fusion+ Lung Cancer

David S. Hong, MD, deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the data supporting the use of larotrectinib (Vitrakvi) for the treatment of TRK fusion-positive lung tumors. He also explains the difference between larotrectinib another FDA-approved TRK inhibitor, entrectinib (Rozlytrek).

 So, I think larotrectinib has the most robust data at this point, number of patients, etc than entrectinib. And it was different in the sense it's less of a nonspecific inhibitor. It also targets ROS, and those who are developing and entrectinib and involved with entrectinib will tell you that it may be an advantage. But it's interesting that the majority of patients who have NTRK fusions rarely have any other alterations, they just have NTRK fusions.

 So, my bias given the fact that I also 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, the number of patients etc. Overall, 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.

David S. Hong, MD, discusses the data supporting the use of larotrectinib for the treatment of TRK fusion-positive lung tumors. He also explains the difference between larotrectinib another FDA-approved TRK inhibitor, entrectinib.

Larotrectinib Compared With Other TRK Inhibitors for TRK Fusion+ Lung Tumors

 key opinion leaders in the management solid tumor cancers consider the evolving treatment landscape for 

fusion-positive disease and share expert perspectives on the role of tyrosine receptor kinase (TRK) inhibitors for these patients. The 2 currently available TRK inhibitors, larotrectinib and entrectinib, have the potential to address important areas of unmet need, but investigators are continuing to assess how clinicians can best optimize therapeutic approaches with these agents. Ahead, David S. Hong, MD, highlights key efficacy and safety data on larotrectinib and examines how mechanisms of treatment resistance may inform future research into second-generation TRK inhibitors.

: What is the preferred method for detection of 

 fusion testing is NGS [next-generation sequencing], and preferably RNA-based [NGS]. There are a lot of commercial vendors out there that are DNA-based. I think FoundationOne is DNA-based. There are a number of them. An RNA-based NGS is preferred partly because sometimes the actual fusion partner genes can be much larger than what DNA-based NGS can pick up. Obviously, NGS is catching on at least here in the United States and more and more oncologists can order it. Usually, academic hospitals like The University of Texas MD Anderson Cancer Center have an NGS platform in-house, but there are lots of vendors out there specifically that do this. Foundation Medicine, Caris, and Tempus are all different types of vendors that can do that. In Europe there's usually an algorithm as to when you can order NGS because it’s usually socialized medicine, and they usually have to go through an algorithm where they can get FISH [fluorescence in situ hybridization] testing specifically for certain fusions. After that, if they're negative, then they can get NGS testing, but ideally RNA-based NGS testing.

: When is the best time to perform testing for NGS?

 This is a controversial question. I'm a phase 1 and early development doctor. I would argue that there is increasingly evidence that NGS testing or molecular testing in general should occur as soon as the patient is diagnosed with metastatic cancer or stage IV cancer. Now, not everybody would agree with that because some types of tumors don't really have targeted therapy. There are some diseases where I would argue that it is almost malpractice if you don't get NGS or some kind of wide-based molecular testing, such as lung cancer. We have multiple new therapies now so that if they have that alteration, they can get targeted therapy even in the frontline setting, as in lung cancer.

I think sometimes the challenge is the turnaround time of some of these NGS tests. After you get a biopsy and then send it off, it can take weeks for the turnaround time of it. Some folks would argue that it's better to get local testing, specifically targets that we know can be turned around fairly quickly in local hospitals, such as 

 testing. I would argue that, as soon as a patient is diagnosed with metastatic disease, it would be ideal to get the NGS testing.

: How does the long-term efficacy demonstrated with TRK inhibitors such as larotrectinib compare with other currently available agents?

 The latest data set that we have was from ESMO [European Society for Medical Oncology] 2021 this past year from Dr Alexander Drilon [Memorial Sloan Kettering Cancer Center, New York City, New York]. We were presented this data at ESMO looking at 

 fusion and larotrectinib. We had a total of 218 patients, and this was across a different number of prior lines of therapy. And again, this was all different tumor types across different ECOG [performance statuses], and the overall response rate remained around 75%. Our initial data cutoff showed around 80% response rates. The median duration of response was close to 49 months, median progression-free survival was 35 months, and median overall survival had not been yet reached. I would argue that there is no therapy out there, if you have metastatic cancer, that matches that.

In many ways, I would argue that, if you are a patient who is identified to have an 

 fusion, it's almost like a lottery ticket because these patients do so well on the study. The full data set did show that patients who had greater than 3 prior lines of therapy had a slightly lower median duration response or progression-free survival than somebody who had no prior therapy up-front. It's expected with the sheer burden of disease. With ECOG [performance status], there seems to be less likelihood of response, but again, that probably has to do with their overall condition and so forth. Overall, If you are able and identified to have an 

 fusion, I would argue that you need to try to get onto larotrectinib or entrectinib at some point.

: What implication might these results have for patient quality of life? How might that affect your treatment approach in some patients? What does this tell us regarding the importance of testing for 

 We've looked at this quality-of-life issue, we've looked at PROs [patient-reported outcomes] over periods of time, and it clearly shows that these patients do well on this study. From their previous state to actually going on larotrectinib, they have incredible, significant improvement in their overall quality of life. The overall adverse event profiles of these drugs are very benign. Probably the most common side effect tends to be this slight dizziness that patients develop, and over time, they actually get better. There are some grade 3 events such as an increase in LFTs [liver function tests], but usually these adverse events or side effects are manageable. You just hold the drug, you dose reduce them, and they still seem to respond to therapy, at least with larotrectinib. I don't know the data for entrectinib as well, but they're very similar drugs. I would argue that these are very well-tolerated, and their overall quality of life is very good over a period of time.

I'm an investigator, so I do mostly clinical trials, but I think that if patients are identified to have 

fusions, whether it's in the frontline setting and even the second-line setting, even though we don't necessarily have randomized data in every single tumor type, given this data at this point, I would argue that it makes sense to try these patients on TRK inhibitors compared with standard chemotherapy, which can be very toxic. In many ways, I see it as almost like a lottery ticket if you're a patient who has this 

fusion. It's worth giving larotrectinib or entrectinib a try.

You have to try to find these patients. I think we will find more and more of these patients as NGS testing becomes more common and almost reflexive, particularly in patients with metastatic cancer. I'm sure there are lots of patients out there who probably have 

 fusions who we’re not identifying. Ideally, we want to identify as many as we can.

: Regarding the on-target and off-target resistance that's been observed with the first-generation TRK inhibitors, how do these resistance mechanisms differ, and which type do you most commonly see in patients?

 There are really 4 different mechanisms of resistance. Again, the king of 

, Dr Alexander Drilon, published a great paper in 

 looking at these different types of mutations. One is something called solvent-front mutations and gatekeeper mutations. Both of these mutations, differing on where they are, and the third, called xDFG, really kind of affect that near-ATP [adenosine triphosphate] pocket. And then the last kind is the development of alternative pathways, whether it's BRAF or MET. These are alternative signaling pathways that can emerge from mechanisms of resistance.

The solvent-front mutation is probably the most common. Obviously, we don't have a huge number of patients to make that determination at this point, but several years ago we presented some of the data on selitrectinib, which was on this molecule called LOXO-195, which was initially developed by Loxo Oncology and then transitioned to Bayer. And probably the most common subset of patients who became resistant to larotrectinib and entrectinib, the first generation of NTRK inhibitors, was patients with the solvent-front mutation. The second generation tends to work in that group and tends to have efficacy, albeit not as robust as we'd hoped for compared with the first generation. Selitrectinib and also repotrectinib, which is, I think, produced by Turning Point Therapeutics, both target solvent-front and gatekeeper mutations. Selitrectinib also targets xDFG. Both of these drugs tend to have response rates around 40% to 50%, and that may again just be reflective of the disease burden in patients. The data from selitrectinib would also suggest that there was a little bit more toxicity associated with the second generation: more dizziness and ataxia associated with that based upon the April 2020 AACR [American Association for Cancer Research] presentation we gave several years ago. So we'll see what happens. There are other companies that are trying to develop second-generation inhibitors. There's a company called Pyramid Biosciences that is also developing a more brain-penetrant agent but also a molecule that exquisitely targets these solvent-front, gatekeeper, and xDFG mutations. All full disclosure, I'm involved in that trial.

There are hopes that there will be drugs for these patients who become eventually resistant to larotrectinib. The good news is that one of the challenges of these trials is these patients on larotrectinib and entrectinib are on for so long. They're benefiting, like I said; median duration of response was like 45 months, so these patients have been on for so long, and they benefit for so long from the first-generation drugs.

: How effective are the next-generation TRK inhibitors at overcoming resistance to first-generation TRK inhibitors?

 The most recent data sets were from repotrectinib, which is a ROS1/TRK inhibitor. They had a very small, limited data set. I think there were 17 patients in that ACR presentation. The overall response rate was around 45%, 43%, if you combine the phase 1 and 2 results. We will see. I think we'll see larger data sets coming out in the next year or so, and we'll see how response rates stand up. That's compared with the first-generation molecules for which you had response rates in the 80% range.

: What challenges have emerged regarding next-generation TRK inhibitors? What areas of research are further investigating overcoming TRK inhibitor-associated resistance?

 I think the main challenge of doing these trials is identifying new patients. It's been years now, and we've identified 218 patients on the first trial of larotrectinib, and I think that number will start ticking up as NGS becomes more common. But again, with the second generation, because the patients who get the first generation are rare, but also, they do so well. Finding enough patients for the second generation has been always a little bit of a challenge.

I do think that, as most things with targeted therapy, these patients, even in the second generation, may eventually become resistant. So how do we think about the next generation, or how do we improve upon the first generation even more? These are questions that we need to think through as we identify more and more of these patients.

In this companion article, David S. Hong, MD, considers the safety and efficacy of the first-generation TRK inhibitor larotrectinib and discusses how acquired resistance may affect research into second-generation agents. 

EP. 4B: Understanding Treatment Resistance in First-Generation TRK Inhibitors for the Treatment of NTRK Fusion-Positive Cancers 

The ideal preferred method of NGS testing is NGS or next-generation sequencing, and preferably RNA-based [NGS]. I would argue that there is increasing evidence that NGS testing or molecular testing in general should occur as soon as the patient is diagnosed with metastatic cancer or stage IV cancer.

The latest dataset that we have was from ESMO this past year. We presented this data at ESMO looking at TRK fusion and larotrectinib data We had a total of 218 patients, and this was across [a] different number of prior lines of therapy. And again, this [study included] all different tumor types and across different ECOGs [performance statuses], and the overall response rate remained around 75%. Our initial data cutoff showed around 80% response rates. The median duration of response was close to 49 months, median progression free survival was 35 months, and median overall survival had not been yet reached. I would argue that there is no therapy out there, if you have metastatic cancer, that matches that. If you are able [and] are identified to have [an] 

These patients do well on this study. Overall from their previous state to actually going on larotrectinib—they have significant improvement in their overall quality of life. The overall adverse event profile of these drugs [is] very benign. Probably the most common side effect tends to be this slight dizziness that patients develop, and over time, they actually get better. There are some grade 3 events such as increase in LFTs (liver function tests), but usually these adverse events or side effects are manageable. You just hold the drug, you dose reduce them, and they still seem to respond to therapy.

There are really 4 different mechanisms of resistance. One is something called solvent-front mutations and gatekeeper mutations. Both of these mutations, differing on where they are, and the third called xDFG, really kind of affect that near-ATP pocket. And then the last kind is [the] development of alternative pathways, whether it's BRAF or MET. These are alternative signaling pathways that can emerge from mechanisms of resistance.

The solvent-front mutation is probably the most common. Obviously, we don't have a huge number of patients to make that determination at this point, but several years ago, we presented some of th[ese] data on selitrectinib, which was this molecule called LOXO-195. Probably the most common subset of patients who became resistant to larotrectinib and entrectinib, the first generation of NTRK inhibitors, was [those with] the solvent-front mutation. The second generations tends to work in that [group and] tend to have efficacy, albeit not as robust as we'd hoped for, compared to the first generation. Selitrectinib and also repotrectinib both target solvent-front and gatekeeper mutations. Selitrectinib also targets xDFG. Both of these drugs tend to have response rates around 40% to 50%, and that may again just be reflective of just the disease burden in patients. The data from selitrectinib would also suggest that there was a little bit more toxicity associated with the second generation: more dizziness [and] ataxia associated with that based upon the AACR presentation we gave several years ago.

There are hopes that there will be drugs for these patients who eventually become resistant to larotrectinib. The good news is that one of the challenges of these trials is these patients on larotrectinib and entrectinib are on for so long and they benefit for so long from the first-generation drugs.

The main challenge of doing these trials is identifying new patients. It's been years now, and we've identified 218 patients on the first trial of larotrectinib, and I think that number will start ticking up as NGS becomes more common. But again, with the second generation, because the patients who get the first generation are rare, but also they do so well, finding enough patients for the second generation has been always a little bit of a challenge.

In the third video interview of the series, David S. Hong, MD, from the University of Texas MD Anderson Cancer Center discusses the safety and efficacy of first-generation TRK inhibitors and reflects on challenges affecting next-generation TRK inhibitors including research into mechanisms of treatment resistance.