David S. Hong, MD

The next steps in understanding and NTRK are the mechanism resistances. We already have a clear idea of what the mechanism resistances are with larotrectinib and entrectinib: Patients develop what are called solvent front and gatekeeper and what are called 

 mutations that can confer resistance to the first generation of drugs. There’s an ongoing study that several colleagues around the world and I are running, which is also developed by Loxo Oncology, Inc in collaboration with Bayer AG, the trial with the molecule selitrectinib is ongoing. We are seeing robust responses in patients who have developed resistance to the first-generation molecules.

In many ways, this disease is analogous in the context of solid tumors to another disease, such as CML [chronic myelogenous leukemia], which was the first disease that we were able to target with a targeted-therapy imatinib. For patients with chronic CML who get imatinib and the next generation of molecules down the line, their life span essentially is normalized. They have the normal life span of a normal person. We’re not there with NTRK fusion–positive cancer patients, but as we become more cognizant, more patients are screened molecularly, and we identify these patients earlier, the disease course and eventually the survival course of these patients who develop solid tumor cancers and who have NTRK fusions may be similar to what we are seeing now with CML.

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David S. Hong, MD, of The University of Texas MD Anderson Cancer Center, shares his enthusiasm for ongoing research efforts to optimize treatment for patients with advanced solid tumors who harbor NTRK gene fusions.

TRK Inhibitors for Advanced Solid Tumors: Next Steps in Research

Let me comment on the presentation of our most recent data set that we presented, concerning larotrectinib in the treatment of advanced-NTRK fusion thyroid cancer, presented by my colleague at [The University of Texas] MD Anderson [Cancer Center], Dr Kevin Nead. Stepping back, 1 of the most common tumor types actually is thyroid cancer. We’ve identified NTRK fusion in not only the more common papillary phenotype but also in follicular. Close to 25% of these patients with NTRK-fusion thyroid cancers are very aggressive anaplastic phenotypes. In this data set that Dr Nead has presented, there were close to 28 patients who were analyzed from our data set, 68% being papillary, a small percentage of 7% being follicular, and close to 25% being anaplastic. The majority of these patients interestingly, will either harbor NTRK1 or NTRK3. NTRK3 fusions can often be missed unless you have an RNA-based NGS [next-generation sequencing]. The majority of these patients were iodine refractory or systemic therapy refractory and had greater than 2 to 3 lines of therapy.

The overall response rate was close to 90%. In the anaplastic, the response rate was close to 30% or 29%. One could argue that that tells you the different histologies and the different biology of the tumors. Similar to the primary CNS cohort, these patients with anaplastic are very aggressive, and a response rate of 30% is fairly remarkable because they oftentimes do not respond to standard chemotherapy or other therapies. The duration of response in this cohort was again not reached. With a median follow-up of 10.2 months, the median progression-free survival again was not reached, the median follow-up of 12.8 months, and the overall median survival was 27.8 months in this subset.

Similar to the other patients in the larotrectinib safety profile, the vast majority of the patients who had received the drug experienced grade 1 or 2 toxicities, the most common being fatigue, constipation, and some dizziness. The vast majority of these patients tolerated therapy very well. These patients with NTRK fusion and thyroid tend to be, in this context, younger patients who do not have other alterations, such as BRAF or RET alterations. If you find a patient who is younger, who does not have all other alterations, in particular in the context of anaplastic, it is worth exploring and seeing if we can identify NTRK-fusion patients. Overall, these patients—and I’ve treated a majority of these patients in this data set with larotrectinib—have remarkable responses and will stay on study for years. Several of my patients have remained on study for 5, 6 years. On this trial, 1 of my anaplastic patients, which is an aggressive tumor, was able to stay on the study for close to a year with good quality of life. If these patients with ETV6, NTRK3, or any other NTRK alteration is identified, the benefit from this therapy can be life-changing for them.

Important takeaways from recent safety and efficacy data presented on the use of larotrectinib as treatment for advanced differentiated and anaplastic thyroid cancers with NTRK gene fusions. 

TRK Inhibitors for Advanced Thyroid Cancers

Increasing evidence in the last several years shows that lung cancer in particular is a molecular disease. As we’re increasingly being able to parse out the details of lung cancer, whether it’s ALK, ROS1, EGFR, or NTRK, we’re seeing that defining these tumors is important in our patients with NTRK1 fusion. In our data set, we’ve identified close to 14 patients. The overall response rate is very similar to the overall data set that we’ve seen in the larotrectinib cohort, and that is 71%. Interestingly, the majority of these patients, close to 50%, will present with CNS [central nervous system] metastasis. For those patients who have CNS metastasis, their response rate with a brain metastases is close to 60% or 57%. Overall, the duration we’ve seen is approximately 12.9 months; follow-up has not yet been reached. The median follow-up with 14.6 months with median progression-free survival has not been reached. The median overall survival also has not been reached for the medium fallout of about 12.6 months; 91% of these patients were alive at 12 months. These were patients who were refractory to standard platinum and immunotherapy, many of whom were in the data set that my colleague Dr [Alexander] Drilon presented with greater than 3 lines of therapy.

Dr David S. Hong reacts to updated survival data associated with the use of larotrectinib as treatment for TRK fusion–positive non–small cell lung cancer.

Treatment Considerations for TRK Fusion-Positive NSCLC 

The most recent data set we’ve presented was at our ESMO [European Society for Medical Oncology Congress] presentation by Ray McDermott, but we had also presented this similar data set in the 

 paper. In the most recent updated data set, we had close to 175 patients on that trial. Similar to the first data set that we published in the 

, the overall response rate was incredibly similar. The overall response rate was close to 80% or 78%. The complete response rate was 33%. The progression-free survival was close to 36.8 months, the duration response had not been reached, and the median overall survival had not been reached. That confirms the incredible efficacy of particularly the larotrectinib molecule. For entrectinib, the most recent data set is not much different from the approval data set, so we don’t have a clear idea how to compare these at this time. But larotrectinib is showing really incredible efficacy that has been sustained from the beginning when we published the phase 1 data to close to 175 patients.

We know that larotrectinib and also entrectinib can cross the blood-brain barrier. The most recent data set that was presented was presented by my colleague, Dr [Alexander] Drilon from MSKCC [Memorial Sloan Kettering Cancer Center] at ASCO [American Society of Clinical Oncology Annual Meeting], about 2 years ago. In that data set, we had 24 patients with intracranial disease; 18 had primary CNS [central nervous system] tumors, and 6 had nonprimary CNS. The overall response rate in this data set was excellent in 5 of the valuable patients. For the solid tumors with brain metastases, we had a response rate of approximately 60%. In those patients who had primary CNS metastasis, the response rate was approximately 36%. That may just reflect the biology of fairly aggressive disease in the brain. Overall, if you ask a neuro-oncologist, they’ll tell you 36% response rate in patients with primary-refractory CNS tumors is pretty remarkable.

The significance of recent data exploring larotrectinib, a TRK inhibitor, in a subset of patients with TRK fusion–positive tumors with CNS (central nervous system) metastasis.

Larotrectinib and CNS Metastasis in TRK Fusion-Positive Tumors

The standard approved indication for NTRK fusion is broad in the sense that patients with advanced cancers with NTRK fusions, identified by usually a CLIA [Clinical Laboratory Improvement Amendments]–certified test in the United States, can receive larotrectinib or entrectinib. Both drugs can target NTRK fusion and have shown significant efficacy in patients with NTRK fusion. Most of these patients will probably also have standard of care, and the thought is that they should probably undergo standard-of-care options before you try to give to patients with NTRK fusion. In rare settings, such as patients who don’t have standard of care, it is warranted that you can prescribe either drug. Overall, my experience is that these drugs are incredibly efficacious in patients who have NTRK fusion. In my experiences, these patients, regardless of the number of prior lines of therapy, will have an incredible benefit from either larotrectinib or entrectinib. There appears to be some differences between larotrectinib and entrectinib. Larotrectinib overall has a data set that is much more mature, and a higher number of patients seem to have been enrolled in the larotrectinib data set. The overall response rate appears to be higher, at least preliminarily with larotrectinib.

The adverse-effect profile is also very similar with these 2 drugs. Both of them have the vast majority of these patients having grade 1 and 2 toxicities, and both exhibit elevation in liver function tests. The vast majority of these patients will have mostly fatigue, which was the most common adverse effect associated with larotrectinib, and dysgeusia or changes in taste, which was also associated with entrectinib. Interestingly, both of them also will have specific adverse effects that are unique to the NTRK story in the sense that they will target the NTRK pathway. Both drugs exhibit dizziness or some level of ataxia. This dizziness and ataxia tends to be self-limiting over time; patients do tend to get better. Another common adverse effect with these drugs is that patients do gain weight, and that can be related to NTRK2 or NTRKB, which can modulate appetite and can increase appetite and weight gain. Otherwise, the overall drug adverse-effect profile of these oral drugs is incredibly well tolerated. Lastly, some of these patients will develop a pain syndrome that can be associated primarily with being off the drugs for a short period of time. This pain syndrome can be either relieved by standard opioid medications or actually redosing these patients back on the drugs.

David S. Hong, MD, of The University of Texas MD Anderson Cancer Center, discusses the availability of TRK inhibitors to treat advanced TRK fusion-positive solid tumors, highlighting their safety and efficacy. 

TRK Inhibitors for Advanced Solid Tumors

Increasingly, as new targeted therapies, including NTRK inhibitors such as larotrectinib and entrectinib, have emerged, molecular testing is becoming, if not required, always necessary to treat particular patients with advanced cancer. To deal with NTRK fusion, the gold standard is next-generation sequencing [NGS]. Ideally, RNA-based next-gen sequencing, because there are certain NTRK fusions—particularly NTRK3 fusion partners—that are fairly large, and RNA sequencing will pick those up relative to DNA-based NTRK NGS. There are other ways to pick up NTRK fusions, but they are somewhat limited. There are issues behind these methods of picking up NTRK-fusion patients. IHC [immunohistochemistry] staining is available in Europe and in some institutions, but there are flaws to NTRK IHC staining for the protein. It is not always specific, particularly in certain tumor types, such as sarcoma, which is 1 of the most common subsets of tumors that we see. It’s not always as sensitive.

FISH [fluorescence in situ hybridization] is also another possibility. There’s something called “break-apart FISH,” which can pick up certain NTRK-fusion partners, but the actual 

 gene and the fusion partner need to be known to identify these patients with NTRK fusion by FISH. This can be done in certain tumor types that we know. Clear NTRK gene and the fusion partner are oftentimes seen in pediatric patients and in rare pediatric sarcomas, such as infantile fibrosarcoma. But ideally, the gold standard is next-gen sequencing with RNA-based next-gen sequencing. Foundation Medicine, for example, has that, but it’s counterintuitive. You can order a FoundationOne Heme panel, and that will be an RNA-sequencing panel that will pick up NTRK fusions. The standard FoundationOne DNA panel will also pick up the vast majority of NTRK fusions but will not always pick up everything.

Current preferences for testing patients with advanced solid tumors for NTRK gene fusions to help guide therapy based on treatment advances for TRK fusion-positive solid tumors.

David S. Hong, MD | Authors

Articles

TRK Inhibitors for Advanced Solid Tumors: Next Steps in Research

TRK Inhibitors for Advanced Thyroid Cancers

Treatment Considerations for TRK Fusion-Positive NSCLC

Larotrectinib and CNS Metastasis in TRK Fusion-Positive Tumors

TRK Inhibitors for Advanced Solid Tumors

Molecular Testing Strategies to Identify NTRK Gene Fusions