最近酷暑难当，所以团队成员先后进入休假模式，可能去了浪漫土耳其，也可能去了东京和巴黎，要问怎么去的，大概是在梦中吧。。。祝大家假期愉快(如果有)
本期讲座的作者：
下面是正文，ppt中引用文献在最后（本号纯属学术性应用，ppt来自cco）
Tropomyosin Receptor Kinase Signaling Pathway
TRK receptors play a key role in central nervous system (CNS) development and function. [1]The TRK receptor family consists of 3 receptor tyrosine kinases, each encoded by a different NTRK gene: TRKA, which is encoded by NTRK1; TRKB by NTRK2; and TRKC by NTRK3. When stimulated by their ligands (nerve growth factor, brain-derived growth factor, and NT-4/5, respectively), the TRK receptors homodimerize and activate multiple signal transduction pathways (eg, PI3K, RAS/RAF/MEK, and phospholipase C-γ) that influence target genes involved in cell survival, differentiation, and proliferation.
Role in Normal Biology and Cancer
In normal biology, TRK receptors are expressed in neuronal tissues and function via activation by neurotrophins.[1] Each receptor has its own set of primary functions in the CNS: TRKA plays a role in pain and thermoregulation; TRKB is involved in movement, memory, mood, appetite, and weight control; and TRKC is involved in proprioception.They are rarely expressed in nonneuronal or cancerous tissues.
In their normal state, TRK receptors are activated only when stimulated by their ligand. However, when TRK fusions occur, this tight regulation is lost. Coupling of the NTRK tyrosine kinase domain with a 5’ fusion partner via genetic rearrangement to generate a chimeric TRK protein without the ligand-binding domain leads to overexpression by constitutive activation, or an always-on state, of the TRK’s kinase domain.[1] This in turn leads to increased downstream signaling and increased cell proliferation and growth.
NTRK Fusion vs NTRK Mutation
It is important to emphasize that there are different consequences of NTRK fusions compared with NTRK mutations.[1,5,6] With NTRK fusions, there is essentially a change in the location of the gene on the chromosome, and the fusion typically results in an overactive receptor. However, there is no change in DNA sequence. For NTRK, fusions are activating and predictive of a response to therapy, rendering them a target for anticancer therapy. By contrast, NTRK mutations—which do result in changes to the DNA sequence, but not to chromosome location—do not appear to be oncogenic driver events, as NTRK fusions are, and do not predict response to therapy. This is different from some other genes involved in cancers; for example, oncogenic driver mutations activating BRAF predict response to specific tyrosine kinase inhibitors (TKIs).[7]
Incidence of NTRK Fusions
NTRK fusions are rare events but have been detected across virtually all cancers. In late 2017, data were presented for more than 11,000 patients with multiple tumor types. Among these patients, the incidence of NTRK fusions was an incredibly low 0.21%.[8] To put that incidence in perspective, we consider ALK rearrangements in non-small-cell lung cancer (NSCLC) to be rare, and those occur in 4% to 5% of patients with NSCLC.[9] NTRK fusions are approximately 20-fold less common. Returning to the profiling data, NTRK fusions are a little more common in patients with glioblastoma (2.8%)—in line with their higher prevalence in rare cancers as we will discuss next—but when glioblastoma is excluded from the pan-cancer analysis, the incidence of NTRK fusions across all tumors is only 0.1%.[8]
The clinical implication is that if one is conducting molecular profiling on all patients, it is likely that hundreds, if not thousands, of people will be tested before finding an NTRK fusion. In the United States, if every patient were tested and every test was 100% accurate, the annual incidence would be approximately 1500-5000 patients with TRK fusion–positive cancer.[10] Because TRK fusions are very important targets of targeted therapy, as we will see, that means broad-based profiling is important for all patients.
TRK Fusions Observed Across Diverse Cancer Types in Both Adults and Children
As I mentioned, there is a higher prevalence of TRK fusions in certain rare cancers, such as mammary analogue secretory carcinoma (MASC; a rare salivary gland neoplasm) and secretory breast cancer in adults and infantile fibrosarcoma and congenital nephroma in the pediatric setting.[10] In these rare tumors, TRK fusions are quite common and are even recognized as diagnostic hallmarks of these cancers.[11-13] More common tumors such as brain, thyroid, lung, pancreatic, cholangiosarcoma, and colon cancers can harbor TRK fusions, but they are much less common, on the order of 0.1% to 0.2% as we discussed earlier.
Mechanism of Action: TRK Inhibitors Function at the Level of the Kinase Domain
There are now targeted therapies that specifically inhibit activated TRK receptors, whether TRKA, TRKB, or TRKC. These small-molecule TKIs can cross the blood–brain barrier and inhibit activation of TRK fusion proteins at the kinase domain.[1]
Multiple TRK Inhibitors in Advancing Stages of Development
There are multiple TRK-targeting agents in development for this very rare alteration.[14-16] Among the TRK-specific inhibitors, the farthest along in development is larotrectinib, also known as LOXO-101. Other TRK-specific inhibitors include LOXO-195, ONO-7579, and PLX7486. However, TKIs are rarely very specific, and some inhibitors target not only TRK but also ALK and ROS1. The farthest along of these are entrectinib (RXDX-101), TPX-005, and DS-6051b. In addition to their TRK-specific inhibitory effect, these agents are being developed because of their narrow range of targets.
There are also nonspecific TKIs that may, to a much less specific and much less active degree, target TRK. These include cabozantinib, sitravatinib (MCGD516), and merestinib (LY2801653). Cabozantinib is already approved by the FDA in its tablet form for advanced renal cell carcinoma[17] and in capsule form for progressive, metastatic medullary thyroid cancer.[18]
How Is FDA Approval Obtained for a Drug That Targets Such Rare Genetic Aberrations?
An important question here is: How do you design a study to evaluate the efficacy of these drugs when the targets are so rare and spread across so many different tumor types? The answer lies in basket trials, which have come of age with the advent of widely available molecular profiling.[19] In these trials, patient eligibility is agnostic to the tumor tissue of origin and rather are based on the presence of a specific molecular target. This contrasts with how cancer drugs are usually approved in relation to a particular tissue of origin.
For example, the PD-1 inhibitor pembrolizumab represents the first ever tissue-agnostic FDA approval for an anticancer medicine.[20] Pembrolizumab was approved in May 2017 for unresectable or metastatic microsatellite instability–high/mismatch repair-deficient solid tumors, which had progressed following treatment or which had no satisfactory treatment options.[20] This means that regardless of whether a patient has colon cancer, lung cancer, or any other solid tumor, if the tumor is microsatellite instability high, they can receive pembrolizumab on label. This tissue-agnostic approval serves as an example of how an agent targeting a rare alteration across multiple tumor types—such as TRK fusions—could potentially be approved by the FDA without a trial design requiring a large cohort with a single tumor type.
Detecting TRK Fusions
How do we identify TRK fusions? There are multiple ways to look for TRK fusions: next-generation sequencing (NGS), FISH, or IHC.[10,13,21,22] DNA-based detection is difficult because of the large length of NTRK introns. Although most solid tumor NGS assays can find NTRK fusions, because of their size, blood-based NGS tests cannot. This is an important point to underscore, given that many clinicians are looking toward using blood-based biopsies.
Another approach being developed for the detection of TRK fusions is to first perform IHC, which is fairly easy and cheap, as a first-order screening test to identify which patients might benefit from a broad NGS panel. If the TRK IHC is positive, the likelihood of finding a NTRK fusion by NGS increases markedly from the low levels found across the general population. If one of the TRK inhibitors under development gains FDA approval, it is conceivable that one of the TRK IHC and/or NGS-based companion diagnostics under development may be approved as a companion diagnostic.
Is Testing for NTRK Fusions Worth the Effort for Such a Rare Genetic Aberration?
If you need to test 1000 people to find 1 patient with a TRK fusion, is it worth the effort? Let me show you why I believe it is.
These CT images are from a patient who was treated with entrectinib on the STARTRK-1 clinical trial.[23,24] This patient had a heavily pretreated NSCLC, as shown in the left image at baseline, with almost complete occupation of the left lung by this cancer. After only approximately 1 week, the patient reported that the drug was working. Now, in my experience, I often have to try and temper expectations when patients report experiencing a new symptom or feeling and assume that it means the drug is working—it is rare that symptoms actually correlate with radiographic response. However, as you can see in this chronological series of CT images, after 3.5 weeks of receiving entrectinib, this patient had a 47% reduction in tumor volume. The response was both deep and durable, as shown by the right CT image at approximately 5 months after entrectinib initiation, when the patient had a 77% reduction in tumor volume, a reduction that was maintained out to nearly 1 year (a 79% reduction at Day 317). In fact, this patient continues on therapy at this time.
The biggest challenge to establishing TRK inhibitors in oncology is the rarity of the activating fusion event. However, given the November 2017 national coverage proposal by the Centers for Medicare & Medicaid Services in response to the FDA’s approval of the first breakthrough-designated NGS in vitro diagnostic capable of detecting mutations in 324 genes and 2 genomic signatures in any type of solid tumor,[25] I anticipate that there will be more uniform uptake of broad-based NGS. I also hope that similar support from insurers will follow, thereby enabling even greater access to broad-based molecular profiling.
This is important news for this target and these agents because it will take a lot of tests with basically no reimbursement for a clinician to find 1 patient out of a 1000 with an NTRK fusion. However, there will be a clear clinical impact for the 1 or 2 patients with an NTRK fusion that an oncologist will treat with a TRK inhibitor during their career. Now that I have seen a patient respond to a TRK TKI, I want to find NTRK fusions in everybody. Of course I do not, considering their rarity, but it drives home why they are worth testing for even so.
Larotrectinib (LOXO-101)
Larotrectinib, previously known as LOXO-101, is the first and most-studied selective pan-TRK TKI under investigation.[10,13] It is highly selective against TRKA, TRKB, and TRKC fusion proteins, with an in vitro IC50 that ranges from 2-20 nmol/L.[26]
In 2014, the first phase I study of larotrectinib opened to evaluate safety and pharmacokinetics of this agent in adults with solid tumors.[26] This study was followed just a year later by the phase I/II SCOUT trial for pediatric solid or primary CNS tumors.[27] Almost a year into the adult phase I study, the first patient with a TRK fusion was identified and enrolled.[26] The patient was a 41-year-old woman who had soft tissue sarcoma with a high volume of metastatic disease in the lung and a LMNA-NTRK1 fusion. She was initiated on larotrectinib in March 2015, and at first restaging after 28 days, she showed a dramatic response that was classified as a PR by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
It is important to note that, as is typical for phase I trials of targeted therapies, the phase I adult trial started out with nonselected patients, meaning patients were not required to have TRK fusions or other alterations.[26] Phase I trial populations are often “all-comer” populations—patients who have progressed on multiple therapies and have no options left. Although we certainly were looking for patients who had NTRK rearrangements or fusions, at that point, we were not certain what alterations would be activating or predictive of a response. Thus, the first 7 or so patients who received larotrectinib either had no TRK alterations or had just a TRK mutation, and they did not respond. When that first patient with TRK fusion–positive sarcoma went on the trial and we saw her restaging scans, it was earth-shattering.
In July 2016, just over a year after this first patient with a TRK fusion was initiated on larotrectinib, this agent received breakthrough therapy designation from the FDA.[28] In February 2017, enrollment was completed for the primary efficacy analysis in this phase I study.[10] Adult and pediatric patients from these 2 early-phase trials and from the phase II NAVIGATE basket trial were included in the efficacy analysis (N = 55) we will discuss next.[29]
17 Unique Cancer Types Positive for TRK Fusions Treated With Larotrectinib
As shown here, of those 55 patients who were part of the primary efficacy analysis, there were 17 different types of adult and pediatric cancer, ranging from the most common (ie, 22% with salivary or mast tumor) to infantile fibrosarcoma at 13% all the way down to single instances of several others.[10,29] This illustrates well the rarity of some of the tumor types where we observe TRK fusions and the challenge of having to evaluate agents across multiple tumor types to establish efficacy.
Clinical Activity of Larotrectinib in TRK Fusion–Positive Cancers
The data for clinical efficacy of larotrectinib were quite impressive. Among the 55 enrolled patients, the ORR was 80% with a CR rate of 16% by investigator assessment and 75% with a CR rate of 13% by independent review.[29] In a phase I population, these are very impressive results.
Larotrectinib Antitumor Activity Regardless of Tumor Type
Larotrectinib had broad activity in patients with TRK fusions. This waterfall plot of the patients in the primary efficacy analysis demonstrates the dramatic depth of responses to larotrectinib across all tumor types, where no one tumor type seemed to respond better and no tumor type did not respond.[29] Furthermore, larotrectinib was active against TRKA, TRKB, or TRKC with any fusion partner. This captures the basket trial concept of drug development.
Duration of Larotrectinib Treatment
In this primary efficacy analysis, not only did patients respond deeply, they did so with great duration: 86% of responding patients are still receiving therapy or have undergone surgery with curative intent at the time of data cutoff.[29] At 1 year, 71% of patients have ongoing responses and 55% remain free of disease progression. Furthermore, several patients were treated beyond progression with good treatment duration, meaning progression was nontargeted. Furthermore, a patient with infantile fibrosarcoma had a limb-sparing salvage surgery and then continued on larotrectinib in an adjunct fashion. Of importance, no patients had CNS progression while on this study.[10]
Preliminary results of the dose escalation cohort (N = 24) of the phase I/II SCOUT study in pediatric patients with TRK fusion–positive solid tumors, including both infantile fibrosarcoma and soft tissue sarcoma, corroborated the promising antitumor activity with larotrectinib shown in the preliminary efficacy analysis.[30] Of 15 evaluable patients with TRK fusions, 14 achieved an objective response (93%), 4 with CR and 10 with PR. The median time to response was 1.7 months, similar to what was observed above. Again, larotrectinib was active against fusions of all 3 NTRK genes. The best response in the 7 evaluable patients without TRK fusions was progressive disease.
Case Patient With Lung Cancer and SQSTM1-NTRK1 Fusion
This illustrative case was a 45-year-old woman with NSCLC and paraneoplastic hypertrophic osteoarthropathy whose cancer had an SQSTM1-NTRK1 fusion.[10] She had been previously treated with standard platinum/pemetrexed therapy. As demonstrated in the left image, the baseline scans showed a large degree of disease in the left lower lung as well as in the liver. After just 4 cycles of larotrectinib, she had a dramatic response in both the lung and liver lesions. She continues on therapy into Month 8, when the analysis had its data cutoff.
Case Patient With Infantile Fibrosarcoma and ETV6-NTRK3 Fusion
This was a 2-year-old female patient on the pediatric trial who had infantile fibrosarcoma with an ETV6-NTRK3 fusion.[10] This young patient was about to undergo an above-the-knee amputation after her disease had progressed on standard therapies. Then, the TRK fusion was discovered and she was started on the larotrectinib study. The left baseline MRI scan shows the large mass posterior to the knee. After just 3 cycles, the right MRI scan shows a dramatic reduction in tumor volume. The patient went to surgery after 4 cycles of larotrectinib and had a pathologic CR with clear margins. Within hours after waking from the surgery the next day, she was up and able to run across the room, which she had not been able to do for months.
Case Patient With Secretory Breast Cancer and ETV6-NTRK3 Fusion
This next case was a 14-year-old girl who had secretory breast cancer with an ETV6-NTRK3 fusion.[31] After receiving 4 previous lines of chemotherapy and multiple resections, she received larotrectinib under expanded access (as such, she was not included in the primary efficacy dataset). In less than 1 week, there was a dramatic response visible to the naked eye. After less than 3 weeks, the tumor had almost completely resolved. Those of us who treat cancer know that this is not a common time course of response to our usual therapies.
Adverse Events With Larotrectinib
The safety profile of larotrectinib was well characterized in this analysis of patients from the early phase I/II studies.[29] Most adverse events (AEs) were grade 1/2, and there were no grade 4/5 AEs related to treatment. Dose reductions were required in 8 of 55 patients (15%); however, all of these patients maintained their degree of response at the lower dose. Finally, no patient who had a response discontinued therapy due to a treatment-related AE.
Based on their target being located in neuronal tissue and the role of the TRK receptor in neuroregulation,[1] the major concern with TRK inhibitors is CNS toxicity. However, any-grade dizziness and fatigue were only observed in 31% and 36% of patients, respectively. There was a low rate of any-grade anemia (29%), which was probably not related to this drug.
Larotrectinib was also well tolerated in the pediatric patients from the SCOUT trial.[30] In 24 patients enrolled on this phase I study, treatment-related AEs were primarily grade 1 and 2, occurring in 21 patients (88%), with the most common being increases in liver enzymes, hematologic toxicity, and vomiting. Only 4 patients (17%) had grade 3 treatment-related AEs, 2 of which were serious: decreased ejection fraction occurring after stopping larotrectinib and while receiving anthracycline and nausea. The only dose-limiting AE leading to discontinuation was grade 3 alanine aminotransferase elevation in a single patient without a TRK fusion and with disease progression and only 1 patient had to dose reduce. No grade 4 or 5 treatment-related AEs or deaths were observed. Of note, neurologic AEs were rarely seen.
You ordered broad-based molecular profiling for your patient with metastatic sarcoma to look for NTRK fusions. The patient received a letter from the insurance company denying the claim and saying that the test should not have been ordered. The patient reaches out to ask you why you ordered this test.
Entrectinib (RXDX-101)
Another TRK-targeting agent under investigation is entrectinib. This agent is an oral, ATP-competitive TKI effective at nanomolar or lower concentrations against 5 kinases, including all 3 TRK receptors, ROS1, and ALK.[24,32] Reports have indicated that it has in vitro and in vivo activity against cancers harboring rearrangements in these 5 kinases.[33,34]
Entrectinib Antitumor Activity
Because entrectinib targets multiple kinases, its basket studies included both multiple tumor types and multiple alterations, meaning that patients with alterations in NTRKs, ROS1, and ALK were eligible. Out of 119 patients analyzed in 2 phase I studies, the Italian ALKA-372 and the STARTRK-1 study in the United States, 25 patients considered “phase II eligible” (ie, they had molecular testing and response data) were analyzed for efficacy.[24,32]
This waterfall plot shows response by rearrangement type among these phase II–eligible patients, with the blue bars representing the 3 patients with NTRK fusion–positive cancer, including NSCLC, colorectal cancer, and MASC. All 3 patients with NTRK alterations experienced a confirmed PR—a tumor reduction of at least 30% to 90%. A fourth patient with a NTRK-positive glioneuronal tumor achieved stable disease by RECIST with a total tumor burden reduction by 60% via 3-D volumetric assessment.
Entrectinib was also associated with a good duration of response. For example, the median duration of response for the ROS-rearranged cancers was 17.4 months (95% CI: 12.7 to not reached), which is similar to the duration of response associated with crizotinib.[24,32] The 4 patients with NTRK fusions also had a good duration of time on study, which for the patient with SQSTM1−NTRK1 NSCLC extended to nearly 1.5 years.
ORR With Entrectinib in NTRK-Rearranged Cancers
This analysis also reported an ORR of 100% for the 4 patients with NTRK-rearranged cancer. As with larotrectinib, there were responses to entrectinib across multiple NTRK genes (ie, NTRK1 and NTRK3) and with different fusion partners (ie, ETV6, SQSTM1, LMNA, and BCAN).[32] This is a very important point: It is the TRK fusion that is the driver mutation, and it is independent of the fusion protein and the tumor of origin.
Intracranial Response to Entrectinib
Entrectinib crosses the blood–brain barrier and has activity against disease in the brain. This was illustrated by the intracranial response observed in a patient with SQSTMI-NTRK1–rearranged NSCLC and 15-20 brain metastases at baseline that had not been previously irradiated.[32] At baseline, this patient had a mass in the left occipital lobe and in the right thalamus. After only 1 month on treatment, these had resolved, and the patient had a durable resolution through the data cutoff after 18 months.
Adverse Events With Entrectinib
The safety profile of entrectinib was well characterized in 119 patients from the early phase I studies.[32] Most of the treatment-related AEs were grade 1 or 2 and were reversible by dose modification, with dose reductions being required in 18 patients (15%). There were no grade 5 treatment-related AEs, but 1 patient discontinued due to grade 4 eosinophilic myocarditis.
LOXO-195: Next-Generation TRK TKI
For those of us who treat cancer, it is common knowledge that acquired resistance mutations eventually develop to targeted TKIs.[35] This is also true for TRK TKIs.[13] Although the oncogenic driver in these cancers is the NTRK fusion, TRK TKI resistance does arise, typically in the form of a G595R mutation in the kinase domain of the TRK receptor, which prevents binding of TRK inhibitors and thereby negates their ability to control disease.
The investigational agent LOXO-195 is a second-generation TRK TKI developed to overcome this acquired resistance to currently available first-generation TRK TKIs.[10,32] When comparing the IC50 of LOXO-195 vs larotrectinib, we see that LOXO-195 is more potent for these acquired resistance mutations. For example, the IC50 of LOXO-195 for the TRKA G595R fusion is 2 nmol/L vs 69 nmol/L with larotrectinib, and the greater potency of LOXO-195 is also seen for TRKC G595R and other resistance mutations. LOXO-195 is being developed with the intent to treat patients who will inevitably progress on larotrectinib, entrectinib, or other TRK inhibitors.
LOXO-195 in Setting of Acquired Resistance to TRK Inhibition
Patients who experienced progression on larotrectinib or entrectinib as their first TRK inhibitor were able to enroll on a follow-up first-in-human study of LOXO-195.[10,32] Among these patients, 4 out of 6 had developed a G595R mutation in TRKA. LOXO-195 was used to successfully treat 2 of the first patients who progressed on larotrectinib, an adult patient with LMNA-NTRK1–rearranged G595R colorectal cancer and a pediatric patient with ETV6-NTRK3–rearranged G623R infantile fibrosarcoma. Both patients experienced rapid responses to LOXO-195 after approximately 1 month of receiving therapy.
Actively Recruiting TRK Inhibitor Clinical Trials
For each of these agents that we just discussed and more, there are multiple clinical trials actively recruiting patients with TRK fusions, regardless of age or tumor type. If an NTRK fusion is identified in a patient, enrolling him or her on one of these trials could be a game changer.
A challenge with rare mutations is that where a patient lives can influence access to early-phase trials of agents targeting rare mutations. In my center in Nashville, Tennessee, we are fortunate to have access to our phase I program, which offers many investigational drugs for almost any mutation to be found. Unfortunately, that is not the case for many more remote centers. However, I believe that it is worth looking into studies for patients with TRK fusions as some of them may provide patients with support for travel to a participating center.
Summary
In summary, if a patient has a cancer with an NTRK fusion, the NTRK fusion should be considered the driving event of that cancer and is highly predictive of response to TRK inhibitors regardless of the cancer’s site of origin. Regarding epidemiology, TRK fusions are common in rare tumors, but rarely seen in common tumors. The TRK inhibitors larotrectinib and entrectinib are both associated with deep, durable, and rapid responses and are very well tolerated. The investigational agent LOXO-195 has shown promise against acquired resistance to larotrectinib. Finally, broad-based molecular profiling of every patient with metastatic disease will be the only way we will start finding NTRK fusions in patients on a regular basis. If an NTRK fusion is identified in a patient through NGS, I cannot recommend enough to enroll him or her on a clinical trial of this life-changing therapy.
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