Larotrectinib and Entrectinib: A Golden Ticket for Adult and Pediatric Patients with NTRK Gene Fusion?

Hansen Ho, PharmD BCOP
Oncology Pharmacist
Associate Clinical Professor
UCSF Helen Diller Comprehensive Cancer Center
UCSF School of Pharmacy, Department of Clinical Pharmacy
San Francisco, CA

A new class of anticancer agents has joined pembrolizumab as tissue-agnostic treatment options for solid tumor cancers. Pembrolizumab, an immune checkpoint inhibitor that targets the programmed cell death-1 (PD-1) pathway, was the first U.S. Food and Drug Administration (FDA)–approved tissue-agnostic agent targeting tumors with high microsatellite instability or DNA mismatch repair deficiency (dMMR) as a surrogate marker for high-somatic mutations.^1,2 Pembrolizumab’s tissue-agnostic approval added to the solid-tumor armamentarium based only on a tumor marker. Larotrectinib and entrectinib, which are tropomyosin receptor kinase (TRK) small-molecule inhibitors, are the second class of tissue-agnostic anticancer agents approved by the FDA, specifically for adult and pediatric patients with NTRK gene fusion.^3,4 The NTRK genes NTRK1, NTRK2, and NTRK3 encode TRK proteins TRKA, TRKB, and TRKC, respectively. TRK expression is primarily limited to embryogenesis and regulation of the central nervous system (CNS).⁵ Somatic gene fusions involving the NTRK family of genes and subsequently downstream TRK fusion protein overexpression are implicated in driving proliferation in multiple solid tumors.

In common cancers, NTRK gene fusions are extremely rare, occurring in 0.1%–2% of patients as determined by highly sensitive next-generation sequencing (NGS).⁶ However, there is widespread variability in this incidence and bias, depending on the type of test used for NTRK gene fusions, with colorectal, appendiceal, and lung cancers and cancers such as sarcomas, melanomas, cholangiocarcinomas, and gliomas reportedly having an incidence of <5%. In certain exceedingly rare tumors, such as pediatric infantile fibrosarcomas, adult salivary gland tumors, and secretory breast cancers, the incidence of NTRK gene fusion is much higher, greater than 75%.⁶ Other rare tumors, such as thyroid carcinomas, congenital mesoblastic nephromas, and spitzoid melanomas, have reported incidences of 5%–75%, illustrating testing bias and variability in clinical laboratory technique.⁶ Detecting a NTRK gene fusion signal can currently be challenging, but its identification can give patients a long-term benefit.

Larotrectinib

Larotrectinib was approved on the basis of three phase 1 studies, the LOXO-TRK-14001, SCOUT, and NAVIGATE trials, involving 55 adults and children with TRK fusion–positive tumors.⁷ Eligible patients had locally advanced or metastatic disease and had exhausted standard-of-care treatments. Of the 55 patients, 17 unique cancer diagnoses were identified, with the majority of patients (n = 30) having salivary gland carcinomas, soft tissue sarcomas, or pediatric fibrosarcomas. In addition, only one patient had evidence of CNS metastasis in the pooled data. At primary data cutoff, the overall response rate by independent radiologic review was 75% (95% confidence interval [CI], 61–85).⁶ A total of 13% of patients had a complete response (CR), 62% had a partial response (PR), 13% had stable disease (SD), and 9% had progressive disease (PD).⁷ The median duration of response (DOR) and progression-free survival (PFS) had not been reached after the median follow-up duration of 8.3 and 9.9 months, respectively.7 At 1 year, 71% of responses were ongoing, and 55% of responding patients remained progression free. At data cutoff, 86% of the patients with a response were continuing to receive treatment or had undergone curative surgery.7 Acquired resistance was detected in 19 patients receiving larotrectinib from kinase domain mutations, which may have important implications in the development of second-generation NTRK inhibitors.⁷

Updated data presented at the European Society for Medical Oncology Congress 2019 that now includes 153 patients continued to demonstrate a high overall response rate (ORR) of 79% (95% CI, 72–85), with 16% with a CR and 63% with a PR.8 Median DOR was 35.2 months (95% CI, 22.8 to not evaluable [NE]), median PFS was 28.3 months (95% CI, 22.1 to NE), and median overall survival (OS) was 44.4 months (95% CI, 36.5 to NE).⁸ Additional subgroup analysis showed a response rate of 75% in solid tumors with brain metastasis demonstrating CNS activity.⁹

An examination of adverse events from the LOXO-TRK-14001, SCOUT, and NAVIGATE trials showed that, overall, larotrectinib was well tolerated. The most common adverse reactions (all grades ≥ 20%) include fatigue, nausea, dizziness, vomiting, anemia, increased aspartate aminotransferase (AST)/alanine aminotransferase (ALT), cough, constipation, and diarrhea.¹⁰ Dose modifications were required in 37% of patients because of increased AST/ALT and dizziness.¹⁰

Entrectinib

Entrectinib was approved on the basis of early-phase pooled analysis of three studies, the STARTRK-1, STARTRK-2, and ALKA-372-001 trials, composed of 54 adult patients with NTRK fusion–positive metastatic or advanced tumors with or without brain metastasis. Results demonstrated a high ORR of 57.4% (95% CI, 43.2–70.8) with 7.4% of patients achieving a CR.4 Median DOR was 10.4 months (95% CI, 7.1 to not reached [NR]), PFS was 11.2 months (95% CI, 8–14.9), and median OS was 20.9 months (95% CI, 14.9 to NR).¹¹

In adult patients with brain metastasis (n = 12) across the three studies, ORR was consistent with patients without brain metastasis at 50%, with median PFS of 7.7 months (95% CI, 4.7 to NR).¹¹ In addition, intracranial ORR was 54.5% in patients with baseline CNS disease, demonstrating entrectinib’s activity across the blood-brain barrier.¹¹

Approval of entrectinib for pediatric patients was based on early results from the phase 1/1b study STARTRK-NG that enrolled 29 patients with primary CNS tumors, neuroblastomas, and other solid tumors with NTRK fusions, ROS1 fusions, or ALK fusions. Of six patients with CNS tumors, one patient achieved a CR, three patients achieved a PR, and two patient responses were yet to be confirmed.¹² Of eight patients with extracranial solid tumors, six patients responded, including two ALK-fusion patients who obtained a CR and PR, three NTRK-fusion patients who obtained a PR, and one ROS1-fusion patient who obtained a PR. Median time to response was 57 days (30–58 days).¹² The median duration of therapy was 85 days (6–592 days) for all patients, 56 days (6–338 days) for nonresponders, and 281 days (56–592 days) for responders.¹²

Adverse events with entrectinib were seen in NTRK fusion, ROS1 mutation–positive, and ALK mutation–positive patients. Examining the safety profile from STARTRK-1, STARTRK-2, STARTRK-NG, and ALKA-372-001 trials showed that entrectinib was well tolerated.⁹ The most common toxicities (all grades ≥ 20%) include fatigue, edema, pyrexia, constipation, diarrhea, nausea, vomiting, dizziness, dysgeusia, dysesthesia, and myalgias. Dose reductions were required in 29% of patients because of dizziness, fatigue, anemia, increased creatinine, and weight gain.¹³

NTRK Gene Fusion Testing

The major hurdle in treating patients with larotrectinib or entrectinib is appropriately detecting patients with NTRK gene fusions. Approaches that may be used to directly or indirectly detect the presence of gene fusion include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction (RT-PCR), and RNA or DNA NGS.¹⁴ IHC, FISH, and RT-PCR are low cost and readily available but are associated with a higher proportion of false-positive and false-negative results. IHC enables detection of TRK overexpression as a surrogate marker for NTRK fusion proteins, leading to possible detection of nonpathogenic fusions.¹⁴ FISH and RT-PCR require a known target sequence to detect NTRK 5' fusions, which may lead to missing novel NTRK fusions and subsequently result in false negatives.¹⁴ NGS provides a precise method of detecting known and novel NTRK gene fusions, but its availability varies by region.¹⁴ Testing algorithms are still in development; a staged strategy has been proposed. Tumors with a high frequency of NTRK gene fusions, such as pediatric infantile fibrosarcomas and secretory breast cancers, can be screened with IHC or FISH and reflex to NGS to account for false-negative results.^14,15 The treatment of tumors with a low frequency of NTRK gene fusion, such as colon cancer or lung cancer, should proceed directly to NGS.¹⁴

Conclusions

Positive early-phase studies have demonstrated high response rates and durable responses with larotrectinib and entrectinib in adult and pediatric patients with NTRK gene fusions. Similar to the results of microsatellite instability–high or dMMR testing, a positive signal can provide an extra line of therapy for patients with solid tumors. In the future, long-term follow-up and further studies are needed to determine differences in safety and efficacy between larotrectinib and entrectinib. Adult and pediatric pharmacists in all solid-tumor subspecialties should assess for the opportunity to advocate for NTRK gene fusion testing to potentially find a golden ticket for patients on their last line of treatment.

References

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