Entity-independent cancer therapy: a glimpse of the future?

Since 2020, two TRK inhibitors have been approved in Switzerland for tumor diagnosis, i.e. independent of tumor entity. They are designed to treat any solid tumor with NTRK gene fusions, and thus could lead the way in regulatory policy – particularly helping those suffering from rare cancers.

With larotrectinib and entrectinib, two substances are now available in Switzerland that can be used independently of the tumor entity – i.e. “tumor-agnostically” [1]. Both agents are inhibitors of tropomyosin receptor kinases (TRK). The prerequisite for their use is the detection of NTRK (neurotrophic tyrosine receptor kinase) gene fusion. Although these gene fusions are rare, they occur in a wide range of tumors – and can now be targeted. The data for both entrectinib and larotrectinib are promising, and both agents have been shown to be effective and tolerable in various studies [2-7]. Thus, not only is testing for NTRK gene fusions gaining importance, but a new wind may be blowing in regulatory and trial policy. A wind that carries the focus away from tumor entities and toward molecular, potentially cross-entity targets.

TRK, NTRK: Who is who?

Tropomyosin receptor kinases (TRK) are essential for nervous system function. Among other things, they regulate synaptic strength and plasticity and influence the differentiation of neurons. However, the fusion of the gene underlying the TRK protein, the NTRK (neurotrophic tyrosine receptor kinase) gene, with another gene is problematic. This can lead to cancer. Excitingly, the oncogenic potential is independent of which other gene the fusion occurred with. It causes overactivity of NTRK and production of oncogenic aberrant TRK fusion proteins, which are considered to be potent drivers of various tumor diseases [8].

To be precise, three genes exist that encode tropomyosin receptor kinases – and accordingly, three different tropomyosin receptor kinases exist: TRKA, TRKB and TRKC [8]. All three are inhibited by both larotrectinib and entrectinib. This inhibition should slow the growth of TRK fusion tumors. A plan that seems to be working, according to current data. Overall, NTRK gene fusions are rare, and yet they are very common in some rare tumor types. Approximately 0.2% to 18% of all solid tumors are affected (Table 1) [9]. Near pathognomonic aberrant TRK fusion proteins include secretory salivary gland carcinomas and infantile fibrosarcomas [8].

The active ingredients under the microscope

Entrectinib, like larotrectinib, primarily targets TRK, and yet differences exist in the targets as well as in the approval. While larotrectinib, which was approved first, inhibits TRK exclusively, entrectinib engages additional targets such as the tyrosine protein kinase ROS1 and the anaplatic lymphoma kinase ALK [1]. Accordingly, entrectinib is also approved as monotherapy for the treatment of ROS1-positive metastatic non-small cell lung cancer (NSCLC). Both agents may be used entity-independently in solid tumors with NTRK gene fusion without a known NTRK resistance mutation. Prerequisites are an advanced, non-resectable situation and lack of alternatives. While entrectinib from 12 years, larotrectinib is already accessible to younger patients [1].

A pooled analysis of multiple studies evaluated the efficacy and tolerability of entrectinib in 54 adult patients with partially pretreated TRK fusion tumors [2]. Sarcomas, NSCLC, mammary, and thyroid tumors were among those represented in the population; overall, the evaluation included 10 different entities and 19 histologic types. An objective response rate (ORR) of 57% and a median duration of response (DoR) of 10 months observed. Overall survival (OS) was 21 months, progression-free survival (PFS) was 11.2 months. Previously untreated patients appear to have the greatest likelihood of response at approximately 80% [4]. Data published at the ESMO Congress 2020 also raise hope, suggesting efficacy in CNS metastases [5].

The approval of larotrectinib is based on pooled data from three studies. In total, the active ingredient has been used for the treatment of over 20 entities used, including sarcomas, infantile fibrosarcomas, thyroid and salivary gland tumors, and lung carcinomas. An analysis published at ESMO Congress 2020, which included 175 patients were included shows a rapid and sustained response [6]. The ORR of the overall population was 78%, with pediatric patients responding particularly well to treatment with an ORR of 92%. Affected individuals with brain metastases also responded to therapy with an ORR of 71%. The median PFS was 36.8 months. At this year’s ASCO annual meeting, new data were recently presented with a longer median follow-up of 22.3 months and one to 206 Patient expanded data set presented [10]. The ORR remained 75%, and that of patients with brain metastases was 73%. The median duration of response was 49.3 months, median PFS 35.4 months. Overall survival data remained immature, with a 3-year overall survival rate of 77%. Promising – albeit still very early – data specific to primary CNS tumors and lung carcinomas with NTRK gene fusion were also published at the ASCO annual meeting [11,12].

Overall, both substances have proven to be well tolerated, with treatment discontinuation due to adverse drug reactions occurring in about 2% of cases [2,10]. The most common serious side effects are cytopenias such as anemia and neutropenia, and liver elevations. In addition, both agents sometimes lead to high-grade weight gain, gastrointestinal side effects, fatigue, and myalgias [1].

Of opportunities and challenges

Despite all the euphoria, it must be borne in mind that the pivotal studies for both larotrectinib and entrectinib were conducted without controls, i.e. single-arm. The reason: the absolute rarity of NTRK fusion tumors. In an attempt to increase the validity of previous findings on the efficacy of larotrectinib, the so-called “Growth Modulation Index” (GMI) was used. This describes the ratio of PFS under larotrectinib and time to treatment failure under the previous therapy for each individual patient – so in a sense, patients serve as their own control. By definition, clinically relevant activity is present from a GMI of 1.33. Updated results of the analysis were presented at this year’s ASCO Annual Meeting [13]. Seventy-four percent of patients showed a GMI ≥1.33. This result was independent of the line of therapy in which study participants received larotrectinib. Accordingly, the use of larotrectinib was considered superior to the previous line of therapy in nearly three-quarters of cases – and thus extremely effective.

Great ambiguity still exists in the area of testing. Who should be tested for NTRK gene fusions? According to the tumor diagnostic approval, the answer should be: All! However, since this is neither practical nor financially feasible, a clinically applicable and equitable consensus must be found here. In general, patients with advanced pathology and no known molecular driver will particularly benefit from testing. This is because in those cases where, for example, an ALK, ROS or BRAF mutation is present, on the one hand, other therapeutic options exist and, on the other hand, the probability of a relevant NTRK mutation is low. If panel testing is already routinely performed, as in NSCLC, it may be worthwhile in the future to include NTRK in the analysis. The bottom line remains that it is important to be familiar with the genetic landscape of the various entities – even more so given the relatively new phenomenon of tumor-agnostic approvals. This is because testing is of course particularly worthwhile when NTRK fusion genes are clustered, as in salivary gland tumors or infantile fibrosarcomas.

In addition to entrectinib and larotrectinib, other TRK inhibitors are in development. These include VMD-928, a compound specifically targeting TRKA, currently in Phase II testing, and LOXO-195 [14]. However, it is not only TRK inhibitors that lend themselves to tumor diagnostic applications, as demonstrated by the entity-independent approval of the checkpoint inhibitor pembrolizumab in the United States. In particular, patients with rare diseases could increasingly benefit from this approach in the future.

Literature:

Medicinal product information of Swissmedic. www.swissmedicinfo.ch (last accessed 07/17/2021)
Doebele RC, 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(2): 271-282.
Dziadziuszko R, et al: Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2021; 39(11): 1253-1263.
Liu SV, et al: Entrectinib in patients with ROS1/fusion-positive non-small cell lung cancer (NSCLC) or NTRK/fusion-positive solid tumors: analysis of response by line of therapy. Abstract 540P, ESMO Virtual Congress 2020.
John T, et al: Intracranial efficacy of entrectinib in patients with NTRK fusion-positive solid tumors and baseline CNS metastases. Abstract 364O, ESMO Virtual Congress 2020.
McDermott R, et al: Survival benefits of larotrectinib in an integrated dataset of patients with TRK fusion cancer. Abstract 1955P, ESMO Virtual Congress 2020.
Italiano A, et al: Growth modulation index (GMI) of larotrectinib versus prior systemic treatments for TRK fusion cancer patients. Abstract 542P, ESMO Virtual Congress 2020.
Cocco E, Scaltriti M, Drilon A: NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018; 15(12): 731-47.
Solomon JP, et al: NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol. 2020; 33(1): 38-46.
Hong DS, et al: Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer. Journal of Clinical Oncology. 2021; 39(15_suppl): 3108.
Perreault S, et al: Efficacy and safety of larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system tumors. Journal of Clinical Oncology. 2021; 39(15_suppl): 2002.
Lin JJ, et al: Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer. Journal of Clinical Oncology. 2021; 39(15_suppl): 9109.
Hong DS, et al: Intra-patient comparison from larotrectinib clinical trials in TRK fusion cancer: An expanded dataset. Journal of Clinical Oncology. 2021; 39(15_suppl): 3114.
Chung V, et al: First-time in-human study of VMD-928, an oral allosteric TrkA selective inhibitor targeting TrkA protein overexpression, in patients with solid tumors or lymphoma. Journal of Clinical Oncology. 2021; 39(15_suppl): 3081.
Stransky N, et al: The landscape of kinase fusions in cancer. Nature communications. 2014; 5: 4846.
Bourgeois JM, et al: Molecular Detection of the ETV6-NTRK3 Gene Fusion Differentiates Congenital Fibrosarcoma From Other Childhood Spindle Cell Tumors. The American Journal of Surgical Pathology. 2000; 24(7): 937-946.
Wu G, et al: The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nature Genetics. 2014; 46(5): 444-450.