NTRK fusion-positive non-small-cell lung cancer: the decisions you may face

Cancer page →Second-opinion finder →

1 treatment setting, 1 with more than one named option. Each section lays out the options the standard of care names, what each is for, the trials behind them with their recorded results, the side effects and cautions on record, and questions to ask. Built from the cancer page's standard-of-care rows; nothing here is advice for your case.

Second line

Advanced, first line or after chemotherapy

6 optionsCompare side by side →

Larotrectinib or entrectinib under their tumour-agnostic approvals; repotrectinib after resistance to either; chemoimmunotherapy as for driver-negative disease before or after.

Guideline

NCCN Guidelines: Non-Small Cell Lung Cancer

The options, in plain words

LarotrectinibApprovedSmall-molecule pan-TRK inhibitor (first generation)

The first drug approved for a gene fusion regardless of where the cancer started; it works in about 75% of NTRK-fusion cancers, from infant fibrosarcoma to salivary and thyroid cancers.

EntrectinibApprovedSmall-molecule TRK/ROS1/ALK TKI (CNS-penetrant)

Entrectinib (Rozlytrek) is a pill for NTRK-fusion cancers and ROS1 lung cancer that reaches brain metastases.

RepotrectinibApprovedSmall-molecule kinase inhibitor (ROS1 / NTRK)

A ROS1 and NTRK pill that also works after other ROS1 drugs fail, with dizziness as its signature side effect.

PembrolizumabApprovedMonoclonal antibody (anti-PD-1)

Pembrolizumab is a PD-1 blocking antibody approved in more than 40 settings, from melanoma and lung cancer to the first tumour-agnostic approval for mismatch-repair-deficient tumours in 2017, and before and after surgery in triple-negative breast cancer. A subcutaneous form arrived in 2025, and it is the backbone partner for ADCs and personalised neoantigen vaccines.

CarboplatinApprovedCytotoxic chemotherapy (platinum)

Carboplatin is a platinum chemotherapy that crosslinks DNA; it is part of the standard pre-surgery regimen for triple-negative breast cancer.

PemetrexedApprovedCytotoxic (antifolate)

Pemetrexed is the chemotherapy that, with a platinum drug, became the first approved treatment for mesothelioma in 2004, and is still the backbone today.

Also referenced:Tumour-agnostic (tissue-agnostic) approval

The evidence behind it

NAVIGATE Phase 2 NCT02576431 2018215 peopleevidence 55
Tests Larotrectinib
TRK fusion-positive solid tumours in adults and children, any tumour type: larotrectinib single-arm basket trial
ORR 75% by independent review in the first 55 pooled patients across 17 tumour types.
Objective response rate (independent review, pooled with LOXO-TRK-14001 and SCOUT) (%): Larotrectinib 75 (n=55) · source
Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme Phase 2 NCT02568267534 peopleevidence 34
Tests Entrectinib
An Open-Label, Multicenter, Global Phase 2 Basket Study of Entrectinib for the Treatment of Patients With Locally Advanced or Metastatic Solid Tumors That Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements
No headline result recorded yet.

The main trade-offs on record

Entrectinib all recorded rates →

Avoid grapefruit.
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.

Pembrolizumab all recorded rates →

Side effect	Any grade	Grade 3+
Hypothyroidism (immune-mediated) · Pooled monotherapy data, >2,800 patients	8%	-
Pneumonitis (immune-mediated) · Pooled monotherapy data, >2,800 patients	3.4%	-
Colitis (immune-mediated) · Pooled monotherapy data, >2,800 patients	1.7%	-
Hepatitis (immune-mediated) · Pooled monotherapy data, >2,800 patients	0.7%	-

No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.

Rates from the label or pivotal trial as recorded on the product page; each grade 3+ figure links to its source.

Carboplatin all recorded rates →

Dose by Calvert formula using GFR (see the calculators).

Pemetrexed all recorded rates →

Not recommended for CrCl below 45.

Questions to ask about this decision

Between Larotrectinib, Entrectinib, Repotrectinib and the other options, which do you recommend for me, and what about my case would make you choose differently?
Why: Guidelines list several reasonable options; the choice turns on details of your tumour, your health and your priorities.
What is each option trying to achieve: cure, long control, or relief of symptoms, and over what time?
Why: The aim shapes how much side effect and disruption is worth accepting.
How closely do I match the people in NAVIGATE and Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme, and does that change what the results mean for me?
Why: Trial populations are selected; age, fitness, prior treatment and biomarkers all affect how far results carry.
Which side effects of Pembrolizumab are most likely for me, which are reversible, and which would make us stop?
Why: The recorded rates below come from labels and trials; your own risk depends on dose, other medicines and your health.
What happens if I delay, or decline this step for now? Is the decision reversible?
Why: Some decisions can wait for a second opinion or a trial slot; others cannot. Knowing which is part of the choice.
Does your recommendation follow the current guideline (NCCN Guidelines: Non-Small Cell Lung Cancer), and if it departs from it, why?
Why: Departures from guidelines are sometimes right for an individual; they should be explained.
For my situation (advanced, first line or after chemotherapy), which of the standard options do you recommend and why?
Why: Guideline options include: Larotrectinib or entrectinib under their tumour-agnostic approvals; repotrectinib after resistance to either; chemoimmunotherapy as for driver-negative disease before or after.
Am I a candidate for Larotrectinib, Entrectinib, Repotrectinib or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of NAVIGATE and Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Add these to your appointment list, or take the full question set for this cancer.

How to read this page. Options and results come from OnCo records with their sources; the settings are the standard-of-care rows on the cancer page, and the lines of therapy are on the sequencing grid. Where a setting names one path, the choice is usually about timing, trials and where to be treated: see expert centres. OnCo is orientation, not medical advice.

Living with cancer·Standard of care