First-generation TRK inhibitor in a patient with highly aggressive caecal and gastric adenocarcinoma with lung metastases

History, presentation and diagnosis
A 75-year-old male with shortness of breath and mild chronic cough was ad­mitted to hospital in September 2022. He had multiple comorbidities, including di­abetes, fatty liver, hypertensive nephrop­athy, postinfectious pulmonary fibrosis, and haemolytic anaemia (managed with azathioprine). Upon admission, the pa­tient was not experiencing anorexia or weight loss, and his Eastern Coopera­tive Oncology Group performance status (ECOG PS) was 0. (Table 1)

PET-CT showed ≥7 hypermetabolic lesions (≤2.0 cm each; maximum stan­dardized uptake values [SUV_max], 2.4–7.4) in the right lower and middle lobes of the lung, with metabolic activity in consolida­tion (SUV_max, 3.0) in the right lower lobe and lymph nodes (LNs; <1 cm; SUV_max, 3.3) in the subcarinal and right thorac­ic inlet. In the gastrointestinal (GI) tract, metabolic activity was detected in a cae­cal mass measuring 3.7 x 3.7 x 3.8 cm (SUV_max, 9.3), regional pericolic LNs (in­cluding an enlarged node with a maxi­mum diameter of 2.4 cm and SUV_max of 4.0), and the stomach region (SUV_max, 4.0). (Figure 1A)

Further examination of the GI tract showed caecal and gastric adenocarci­noma of unknown stage with signet-ring-cell characteristics. Transbronchial biopsy and immunohistochemistry (IHC) revealed lung carcinoma metastasizing from GI pri­mary, with positivity for CK7, CK19, CK20 and CDX2. Blood test showed elevated carcinoembryonic antigen (CEA; 15.0 ng/ mL), mild anaemia (haemoglobin [Hb], 10 g/L), and renal impairment (creatinine clearance, 50 mL/min). Genetic testing showed UGT1A1 deficiency, while micro­satellite status was stable. (Table 1)

The patient was diagnosed with cae­cal and gastric signet-ring-cell adenocar­cinoma and lung metastases.

Management
Three weeks after being admitted to hospital, the patient became bedridden and dependent on supplemental oxygen at 4 L/min. Subsequently, he developed progressive respiratory failure despite concomitant antibiotics and required ad­mission to intensive care unit for high-flow oxygen support. (Table 1)

Due to respiratory failure and renal im­pairment, the patient received one cycle of first-line treatment with reduced-dose FOLFOX (oxaliplatin, 100 mg/m²; flu­orouracil, 2,250 mg/m²; leucovorin, 700 mg/m²) in late September 2022, while awaiting genetic test results. However, this treatment did not lead to improvement in progressive respiratory failure. In addition, subacute intestinal obstruction was identified in week 2 of the treatment cycle. Abdominal X-ray showed multiple air-fluid levels in dilated bowels, whereas chest X-ray revealed progressive bilateral lung mottling with lymphangitis carcino­matosis. The patient required parenteral nutrition. His ECOG PS deteriorated to 3. (Table 1)

Amplicon-based, RNA-based hotspot next-generation sequencing (NGS) revealed an EML4 exon 2–NTRK3 exon 14 fusion in both caecal and gastric tumour tissues, and a KRAS^V41I mutation in the caecal tumour tissue. (Table 1)

Considering the patient’s genetic pro­file and disease status, in early October 2022, a consensus was reached within our oncology team to start second-line treatment with larotrectinib (100 mg BID, capsule form), a first-generation tropo­myosin receptor kinase (TRK) inhibitor indicated for adult and paediatric patients with metastatic or unresectable solid tu­mours harbouring NTRK fusions without a known acquired resistance mutation, when no satisfactory therapies are avail­able.¹ (Table 1)

One week after starting larotrectinib, our patient’s lung function improved, and supplementary oxygen was reduced to 2 L/min. By week 2, he was completely weaned off oxygen support. As his intes­tinal obstructions resolved in week 3, he was able to consume solids and was put on a low-residue diet. (Table 1)

During week 2 of larotrectinib treatment, laboratory investigation showed grade 2 asymptomatic elevation of alanine transaminase (ALT) without increased bilirubin. Antibiotics were pre­scribed, and larotrectinib was temporarily withheld until ALT elevation was reduced to grade 1. After 5 days, larotrectinib was reintroduced at a reduced dose of 50 mg BID for 1 week. Upon discussion with the patient’s family, larotrectinib was escalated to the standard dose of 100 mg BID. (Table 1) Neither ALT elevation nor other adverse events (AEs) were observed thereafter.

Despite treatment interruption, the patient achieved partial response (PR). Repeat PET-CT in November 2022, after 4 weeks of larotrectinib, showed that half of the pulmonary lesions had resolved, with the primary caecal lesion reducing in size from 3.8 x 3.7 x 3.7 cm to 3.1 x 1.9 x 3.1 cm. Metabolic activity of the caecal lesion, gastric lesions and pericolic LNs remained stable. (Figure 1B) CEA level decreased from 15.0 ng/mL to 6.5 ng/mL, while Hb level remained at 10 mg/L throughout treatment. (Table 1) After dis­cussion with the surgeon and anaesthesi­ologist, palliative resection of the primary caecal tumour was not recommended due to the patient’s respiratory status and comorbidities.

In mid-December 2022, the patient developed anorexia cachexia syndrome, with an increased CEA level of 12 ng/mL. He continued to receive second-line larotrec­tinib at the standard dose in mid-January 2023. Throughout the treatment, the patient did not develop recurrent respiratory failure or significant intestinal obstruction until 3 days before his death. (Table 1)

Discussion
Rare but actionable NTRK fusions have been identified in various solid tu­mours, including colorectal cancer (CRC), lung cancer and sarcomas.^2,3 At our cen­tre, NTRK fusions are found in some patients with lung cancer or sarcoma. This 75-year-old patient is one of our first GI adenocarcinoma and CRC cases with an NTRK fusion.

In Chinese patients with CRC, 0.7–1.0 percent exhibit NTRK fusions.^4,5 Previ­ous research showed that NTRK fusions tend to be mutually exclusive with other genetic driver mutations in CRC, including KRAS and BRAF mutations, and are associated with high tumour muta­tion burden and DNA mismatch repair–deficiency/microsatellite instability (MSI)–high status.^5,6

Phenotypic features may vary in CRC patients with NTRK fusions. For example, our patient’s tumour had microsatellite-stable status at initial diagnosis. However, his primary GI tumour was signet-ring-cell adenocarcinoma, an aggressive CRC subtype that led to the rapid deteriora­tion of his condition.⁷ Given the high risk of imminent fatal complications in case of first-line therapy failure, it was important to explore treatment alternatives based on the patient’s genetic profile.

Genetic testing for actionable mutations
Genetic testing has become a useful tool for guiding treatment decisions by identifying actionable genetic alternations, including KRAS, NRAS and BRAF muta­tions, and NTRK fusions.⁸ At our centre, 10–20 percent of CRC patients undergo genetic testing. This relatively low rate of genetic testing is due to the rarity of ac­tionable mutations and costs associated with targeted therapy. However, engaging in open and comprehensive discussion with patients and their family members is crucial for making informed decisions re­garding utility of genetic testing and avail­ability of treatment options. If the patients agree, genetic testing can be performed at diagnosis.

Multiplex tests, such as RNA-based NGS, are the preferred approach for specific, sensitive and simultaneous detec­tion of multiple actionable mutations.^2,9 Tumour biopsy tissue, which is the gold-standard specimen for genetic test­ing, is usually available in CRC patients.⁸

Treatment options for TRK fusion solid tumours
According to international expert con­sensus recommendations from the Ja­pan Society of Clinical Oncology (JSCO), European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), Japanese Society of Medical Oncology (JSMO), and Taiwan Oncology Society (TOS), TRK inhibitors, namely larotrectinib and entrectinib, are recommended for patients with TRK fu­sion solid tumours when no other satis­factory treatment options are available (level of evidence, III; grade of recommen­dation, A).¹⁰

Genetic testing of our patient’s pri­mary GI tumour tissues revealed EML4::NTRK3 fusion, an NTRK fusion previously reported in CRC.¹¹ Multiple comorbidities and UGT1A1 deficiency rendered our pa­tient unfit for escalation of chemotherapy or use of irinotecan-based therapy.^9,12 Because of genetic test results and limited therapeutic options, he was treated with larotrectinib.^1,10

Larotrectinib’s efficacy
The use of larotrectinib in adult and paediatric patients with TRK fusion solid tumours, including GI cancers, is sup­ported by evidence from a pooled analy­sis of three phase I/II clinical trials (namely, LOXO-TRK-14001, SCOUT and NAVI­GATE) with a mixed population across 25 tumour types (n=244).¹³

As of data cut-off on 20 July 2021, the primary endpoint of overall response rate (ORR) by independent review com­mittee assessment was 69 percent. Median time to response (TTR) was 1.8 months. At a median follow-up of 28.3 months, median duration of response (DoR) was 32.9 months.¹³

In the expanded dataset analysis of the phase II NAVIGATE trial, among 33 evaluable patients with TRK fusion GI cancer, the ORR was 33 percent. The median TTR for all GI patients (n=34) was 1.9 months. At a median follow-up of 26.4 months, median DoR was 7.3 months. In patients with CRC (n=19), the ORR was 47 percent. At a median follow-up of 17.8 months, the 12-month DoR rate in the CRC subset was 67 percent. (Table 2) These results indicate rapid response with larotrectinib in pa­tients with TRK fusion GI cancers, including CRC.¹⁴ 

Larotrectinib was also shown to extend survival in patients with TRK fusion GI cancers. Among these patients, me­dian progression-free survival (PFS) was 5.4 months at a median follow-up of 5.4 months, while median overall survival (OS) was 12.5 months at a median follow-up of 7.7 months. Similarly, in the CRC subset, median PFS was 5.5 months at a median follow-up of 5.6 months, and median OS was 12.5 months at a median follow-up of 7.8 months.¹⁴ (Table 2)

Although clinical trial results indicate a relatively shorter DoR in the GI cancer cohort vs the overall study population, the use of larotrectinib was crucial for our patient who had highly aggressive, metastatic signet-ring-cell adenocar­cinoma with NTRK fusion with a poor prognosis.^8,13,14 Without appropriate treatment, his life expectancy would have been limited to days or weeks.

Despite the aggressive nature of his disease and failure of first-line treatment, larotrectinib rapidly and remarkably improved our patient’s respiratory and GI symptoms within 3 weeks. Notably, he achieved PR at week 4 and did not experience recurrent symptoms for nearly 14 weeks. With an OS of 14 weeks since starting larotrectinib, he was able to spend meaningful time with his family.

Larotrectinib’s safety profile
In a pooled analysis of larotrectinib’s safety data, AEs were primarily grade 1–2. The most common grade 3 or 4 treatment-related AEs were increased ALT (n=8; 3 percent), anaemia (n=6; 2 percent) and decreased neutrophil count (n=5; 2 percent).¹⁵ No new safety signals were identified in longer-term follow-ups in both the overall population and GI can­cer cohort.^13,14

Overall, our patient tolerated laro­trectinib well. At week 2 of treatment, he had asymptomatic grade 2 elevated ALT, which improved to grade 1 after a 5-day dose interruption. Larotrectinib was re­sumed at a reduced dose of 50 mg BID for 1 week before being escalated to the standard dose of 100 mg BID. It is important to assess patients’ liver function prior to initiating larotrectinib and regularly thereafter. Caution should be exercised if larotrectinib is administered to patients on CYP3A inhibitors.¹

Dizziness, weight gain and paraesthe­sia are on-target AEs associated with TRK inhibitors’ mechanism of action, namely, the inhibition effect on TRK receptors in the nervous system. Neurological AEs are occasionally observed in patients receiving TRK inhibitors, including larotrectinib, and should be regularly monitored.^15,16

Final thoughts
In CRC, upfront genetic testing for actionable mutations should be considered because effective treatments, such as larotrectinib, are available for patients with TRK fusion cancers. This elderly pa­tient with metastatic TRK fusion GI can­cer demonstrated a rapid and substantial response to larotrectinib within 3 weeks, with no symptomatic AEs. Further re­search is warranted to investigate the effectiveness of larotrectinib in various ge­netic profiles, including NTRK and KRAS comutation.