Posted: Tuesday, January 25, 2022
An Unusual Indication
In August 2019, the U.S. Food and Drug Administration (FDA) approved entrectinib for the treatment of adult and pediatric patients 12 years of age and older who have solid tumors with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation.1,2 According to the FDA’s prescribing information,3 tumors should be metastatic or inoperable (ie, surgical resection is likely to result in severe morbidity). Additionally, entrectinib may be considered after other treatments have resulted in progressive disease or when there is no satisfactory alternative therapy. Entrectinib is also indicated for adults with metastatic non–small cell lung cancer (NSCLC) whose tumors are ROS1-positive.
“I don’t think clinicians generally read the specific FDA-approved indications,” George D. Demetri, MD, Director of the Sarcoma Center at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, Boston, told JNCCN 360, as he paraphrased a comment by Richard Pazdur, MD, Director of the FDA Oncology Center of Excellence. “The situation is even worse with a drug like entrectinib that appeals to one universe (ie, lung cancer specialists looking for an ROS1 inhibitor) as well as the tumor-agnostic world of all oncology,” Dr. Demetri continued. “The latter scenario means, ‘if you’ve got the biomarker, this is definitely a drug for you.’”
The approved indication for entrectinib overlaps that of larotrectinib—it is for adult and pediatric patients (12 years and older) who have solid tumors and whose tumors harbor an NTRK gene fusion, with no known resistance mutation. “Very few clinicians understand exactly what would represent a resistance mutation in an NTRK gene. That’s a drawback,” Dr. Demetri observed. Moreover, for those whose tumors have an NTRK gene fusion, “the indication reads that there should be “progression on first-line treatment” before the patient is technically eligible for entrectinib,” he explained. “However, the prescribing information also says, ‘or have no satisfactory alternative therapy,’ which is kind of a loophole,” Dr. Demetri said.
“In my world of metastatic sarcomas—other than limited pediatric-type sarcomas—there are no data proving that chemotherapy is associated with a significant survival benefit. So, if I have a patient with a sarcoma and a proven NTRK gene fusion, I will offer an NTRK inhibitor rather than conventional empiric chemotherapy, which remains less than a satisfactory alternative in my opinion,” Dr. Demetri stated.
The peculiar thing about entrectinib, Dr. Demetri mused, is that it is also approved for the treatment of metastatic NSCLCs that are ROS1-positive.1 “What does that mean? Does it suggest a fusion? A mutation? There has to be expression of ROS1, and although there are other drugs with activity against ROS1, entrectinib seems to be the best ROS1 inhibitor.”
NTRK Gene Fusion Versus NTRK Point Mutations, Deletions, or Amplifications
Tumors with NTRK gene fusion can look like any other tumors. “There are no histopathologic or pathognomonic findings that provide clues,” Dr. Demetri pointed out. “Unless you are looking for an NTRK gene fusion with a molecular toolkit, you will not find it.”
Unless you are looking for an NTRK gene fusion with a molecular toolkit, you will not find it.
According to Dr. Demetri, clinicians are accustomed to receiving genomic reports that indicate, “a gene is mutated.” For instance, in gastrointestinal stromal tumors (GIST), “a report might note a mutation in exon 17 in which a D has been flipped for a K,” he explained.
Describing the NTRK gene fusion, Dr. Demetri noted that “NTRK genes come in three flavors: NTRK1, NTRK2, and NTRK3.”4 “They are very similar and can have many mutations that change the coding sequence. This is parallel to what happens in KIT or EGFR, where you may have a problem in the sequence of the amino acids, like the pearls on a string, metaphorically speaking,” he told JNCCN 360. With the NTRK gene, there can be some sort of change in the correct sequence of the “pearls” that results in point mutations or small deletions. “The problem is that the NTRK inhibitors don’t work in those situations,” he stressed. “That’s why they should more properly be called TRK fusion inhibitors, not TRK inhibitors.”
Another confusing issue is that genomic reports may indicate a “rearrangement in the NTRK1 gene.” For Dr. Demetri, that finding is ambiguous and may differ for each patient. “It just means that pieces of the gene have moved somewhere else in the chromosomal landscape, but it does not necessarily mean that it is productively fused to something else. You really have to understand the language of the particular molecular laboratory that you are working with,” Dr. Demetri said. Moreover, some NTRK1 rearrangements may not be oncogenic drivers.
Dr. Demetri also pointed out that many tumors have broken pieces of DNA floating around and even if an NTRK gene is amplified with extra copies, it may not be driving the tumor. “You want the laboratory to report something like, ‘the NTRK1 gene is fused to TPM3,’ which is seen in sarcomas.” A particularly interesting point, he noted, is the partner that the NTRK gene is fused to does not seem to matter. The fact that it is fused in-frame to something, so an actual protein is expressed, means it is likely the driver of that tumor. Understanding the need for that fusion as the target is critical because precision medicine is “all about using drugs for the right person with the right proven driver, which defines the ‘right’ disease.”
How Best to Identify the NTRK Gene Fusion
With diseases such as NSCLC, the practice of identifying one abnormal gene at a time is outdated, because there are many potential oncogenic drivers, such as EGFR, ROS1, ALK, RET, BRAF, MET exon 14 skipping, NTRK1/2/3, and KRAS.5 “It is best to have this information upfront at diagnosis, via comprehensive genomic profiling. It is also the most efficient use of tissue,” Dr. Demetri said.
In other diseases, such as ovarian cancer or sarcomas with another proven fusion oncogene, Dr. Demetri noted it might not make sense to look for a TRK fusion. “In GIST, for instance, you know that KIT drives the disease so you test for that. If you find it, you probably don’t need to do broad genomic profiling. However, for GISTs with normal KIT and no other obvious driver mutation, that is precisely where it makes sense to look for NTRK fusions.” Likewise, if an EGFR mutation were identified in a sample from a NSCLC, “you wouldn’t have to look for something else. However, I doubt that anyone in the lung cancer community is just testing for one biomarker,” Dr. Demetri told JNCCN 360. He did observe that a BRCA mutation is a bit of an outlier as an oncogenic driver, as it could potentially coexist with an NTRK fusion in ovarian cancer, “but BRAF in melanoma or EGFR in lung cancer would not. We have not seen TRK fusions in patients with tumors in whom powerful and proven oncogenic drivers were identified.”
We have not seen TRK fusions in patients with tumors in whom powerful and proven oncogenic drivers were identified.
Because genomic testing is expensive and not universally available, Dr. Demetri pointed out that pathologists outside of the United States sometimes use immunohistochemistry6 to search for clues. “You can use the technique to look for a lot of ‘TRK’ proteins,” he explained. Most tumors do not have large amounts of TRK proteins. “It’s not a perfect solution, in that there can be false-positives and false-negatives, but immunohistochemistry is a far more accessible and less expensive way to screen patients and choose those for whom genomic testing might have a higher probability of finding a treatable fusion,” he suggested.
Central Nervous System Activity and/or Selectivity
Entrectinib was rationally designed to distribute into the central nervous system (CNS), “which was a bold move back in the 1990s, because there were substantial concerns about whether toxicity might be a problem. Fortunately, the drug remains well tolerated,” Dr. Demetri told JNCCN 360. Entrectinib is active against metastatic TRK fusion cancers in the CNS—both primary CNS tumors and solid tumor metastases from other sites.7 Anecdotally, larotrectinib also has reported antitumor activity in the CNS, although it was not specifically designed to do so, perhaps because tumor vasculature in the CNS is abnormally ‘leaky’ without a fully competent blood-brain barrier.8,9
In contrast to entrectinib, larotrectinib is more selective for TRK proteins and does not inhibit ROS1. However, if ROS1 is present in a NSCLC, “entrectinib is a terrific treatment option,” Dr. Demetri stated. If ROS1 is not a consideration, he noted, the choice for targeting NTRK fusions might come down to out-of-pocket expenses for patients or what is available on a preferred institutional formulary. The clinical impacts of entrectinib and larotrectinib appear to be quite similar for cancers with NTRK fusions (even though they have never been directly compared in any clinical trials), so the decision comes down to what is considered to be most cost-effective.
Interpreting Clinical Trial Data
Accelerated FDA approval of entrectinib was based on pooled data10,11 from three different trials: the phase I/II ALKA-372-001, STARTRK-1 (ClinicalTrials.gov identifier NCT02097810), and STARTRK-2 (NCT02568267). These studies were conducted in 54 adults with advanced/metastatic NTRK fusion–positive solid tumors (sarcoma, lung, salivary gland, breast, thyroid, and colorectal).11 Of note, patients with or without CNS involvement by type of cancer were eligible.
Most patients (94%) received 600 mg of entrectinib orally daily until disease progression or unacceptable toxicity. After 15.5 months, the overall response rate (by blinded independent central review) was 57.4% (95% confidence interval [CI] = 43.2%–70.8%), and the complete response rate was 7.4%. The median duration of response was 10.4 months (95% CI = 7.1 months to not reported). For patients without CNS disease, the median progression-free survival was 12 months (95% CI = 8.7–15.7 months). For those with CNS disease, progression-free survival was 7.7 months (95% CI = 4.7 months to not reported). Most treatment-related adverse events were grade 1 or 2 and managed with brief dose delays or dose reduction.
Entrectinib was also studied in 51 adults with ROS1-positive metastatic NSCLC. Dosing and administration were similar to the protocols used in patients with NTRK fusion–positive tumors. In these patients with NSCLC, the overall response rate was 77% (95% CI = 64%–88%); the median duration of response was 24 months (95% CI = 11.4–34.8 months).2
“It’s important to keep in mind that all of these entrectinib data are derived from adult-alone studies,” Dr. Demetri observed. “As humans age, we develop more health issues and are likely to be sicker than children.” In contrast, he elaborated that the larotrectinib data set included many pediatric cancers, including patients with infantile fibrosarcoma (IFS)—a comparatively genomically stable disease. “Patients with IFS generally derived tremendous benefit from larotrectinib, and anecdotally they have had exceptional benefit from entrectinib, with long durations of exceptional responses,” he said.
In the entrectinib studies, the initial study population generally comprised older adults and included a good number of patients with brain metastases. Additionally, the incidence of adverse events in the entrectinib studies seems higher than with larotrectinib. “However, in my opinion” Dr. Demetri commented, “it is less likely about true differences in the tolerability profiles of the drugs and more likely a result of a somewhat older and perhaps clinically sicker population of adults.”
“Both entrectinib and larotrectinib are remarkably active in patients with the relevant oncogenic targets and are extremely well tolerated,” Dr. Demetri said. The side effects of both entrectinib and larotrectinib are “what we would expect, in view of the fact that the drugs affect proteins responsible for balance, proprioception, and appetite in adults,” he explained. These drugs stimulate appetite, and certain patients may gain weight because they eat more.”
Clinical Eligibility and Duration of Activity
For patients with relatively “genomically stable” tumors and NTRK gene fusions, such as IFS and certain other sarcomas, treatment with an NTRK inhibitor may control the disease for a year or more. This is also true in some rare histologic subtypes of common tumors, such as mammary analogue secretory carcinomas of the breast or salivary glands; some patients can stay on treatment for years. With genomically unstable tumors, eg, NSCLC, disease control can be achieved for up to a year, but they are much more mutated tumors, especially in smokers.
Resistance can develop, “so we need to remember that entrectinib and larotrectinib are defined as ‘first-generation NTRK fusion inhibitors,’” Dr. Demetri told JNCCN 360. Research on next-generation agents is rapidly advancing to understand and overcome mechanisms of resistance. Even before approval of these drugs, he observed, “we knew what the resistance mutations would be because understanding of the biology was happening so quickly. That’s why the prescribing information indicates these drugs should not be used when a resistance mutation is present.”
Most patients with NTRK gene fusions are considered eligible for treatment, even if they are quite sick. “Patients who certainly wouldn’t be able to tolerate chemotherapy can be given an NTRK inhibitor, and the responses can occasionally appear to be miraculous,” Dr. Demetri reported. However, there are rare occasions where a seriously perturbed liver or multiorgan failure might make a patient ineligible for treatment. “We’ve been very impressed with the safety profiles of both entrectinib and larotrectinib,” Dr. Demetri concluded.
We’ve been very impressed with the safety profiles of both entrectinib and larotrectinib.
On the Horizon
Noting the emergence of drug resistance, Dr. Demetri pointed to some “terrific” second-generation NTRK inhibitors in the works: selitrectinib (NCT03215511; NCT03206931) and repotrectinib (NCT03093116; NCT05004116), for example. “These small molecules are structured a little differently, so they can fit underneath “the blocking arm of a newly substituted amino acid, which might be the cause of resistance in a subclone,” Dr. Demetri explained. “If entrectinib is too bulky to fit into the pocket, the second-generation drug may be able to slip in. I have one patient with sarcoma who has benefited from a first-generation drug for about a year but then developed resistance. She was switched to a second-generation drug and has been on it for nearly 5 years, with exceptionally good quality of life and complete disease control.”
There are concerns that these powerful drugs may still be underutilized because patients with cancer are not routinely having their tumors tested with comprehensive genomic profiling. Clearly, the incidence of NTRK gene fusions (particularly in certain tumors) is very low.
“A 0.01% incidence means that you have to screen 1,000 patients to find 1,” Dr. Demetri noted. “That is one reason to have some sort of guidelines and screening approach,” he continued, “which minimizes the chance of missing those rare patients with NTRK fusion as the cancer driver.” However, NSCLC is the paradigm for adoption of some type of multigene molecular profiling, since there are multiple potential drivers that might be identified.
This model would substantially change the therapeutic approach for each patient. That’s currently less the case in other cancers, “but that’s where we are heading.”
In closing, Dr. Demetri said: “I’m very pleased that we’ve learned as much as we have about this pathway and only wish that it applied to more patients. The NTRK gene fusion is still quite rare.”
George D. Demetri, MD, is a member of the Board of Directors for Blueprint Medicines with minor equity holdings. He is also a consultant or scientific advisory board member with minor equity holding in the following companies: G1 Therapeutics, Caris Life Sciences, Erasca Pharmaceuticals, Relay Therapeutics, Bessor Pharmaceuticals, Champions Biotechnology, CellCarta, Ikena Oncology, Kojin Therapeutics, and Acrivon Therapeutics. He is also a scientific consultant (with sponsored research to Dana-Farber) to Bayer, Pfizer, Novartis, Epizyme, Roche/Genentech, Loxo Oncology, AbbVie, GlaxoSmithKline, Janssen, PharmaMar, Daiichi Sankyo, and AdaptImmune as well as a scientific consultant for GlaxoSmithKline, EMD Serono, Sanofi, ICON plc, Medscape, Mirati,WCG/Arsenal Capital, Polaris, MJ Hennessey/OncLive, C4 Therapeutics, Synlogic, McCann Health, and Rain Therapeutics. Dana-Farber has received royalty from Novartis for the use of imatinib in GIST.
- U.S. Food and Drug Administration. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc. Accessed November 12, 2021.
- Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:261–270.
- Entrectinb (Rozlytrek) full prescribing information, Genentech, revised November 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212725s005lbl.pdf. Accessed January 21, 2022.
- Westphalen CB, Krebs MG, Le Tourneau C, et al. Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population. npj Precision Oncology 2021;5:69.
- Sequist LV, Neal JW. Personalized, genotype-directed therapy for advanced non-small cell lung cancer. UpToDate, October 2021. Available at https://www.uptodate.com/contents/personalized-genotype-directed-therapy-for-advanced-non-small-cell-lung-cancer. Accessed November 12, 2021.
- Hechtman JF, Benayed R, Hyman DM, et al. Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol 2017;41:1547–1551.
- Fischer H, Ullah M, de la Cruz CC, et al. Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein. Neuro Oncol 2020;22:719–829.
- Drilon AE, DuBois SG, Farago AF, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. 2019 ASCO Annual Meeting. Abstract 2006.
- Ziegler DS, Doz F, Georerger B, et al. Activity of larotrectinib in TRK fusion cancer patients with primary central nervous system tumours. Ann Oncol 2019;30(suppl 9): IX124.
- Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. ESMO Congress 2018. Abstract 5033.
- Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271–282.