Fusions of the neurotrophic tyrosine receptor kinase (NTRK)
genes 1, 2 and 3
NTRK fusions occur in many tumor types and are known to occur in less
than 1% of NSCLC. The oral TRK inhibitor FDA approved in first line or
subsequent setting for NSCLC patients harboring fusions in NTRK genes is
Larotrectinib.
The efficacy of Larotrectinib was tested in phase I/II clinical trial
that enrolled 55 patients with NTRK gene rearrangements regardless of
cancer type. The ORR was 75% (95% CI, 61 to 85). At 1 year, PFS was
55% with 71% having ongoing responses. This led to the FDA approval of
larotrectinib for NTRK-altered cancers as “tumor -agnostic” indication
based on actionable genomic insights [77].
Mutations in HER2
Approximately 2% of patients with NSCLC are found to harbor HER 2 exon-
20- insertion mutation that is detected using PCR or NGS. HER 2-
targeted antibody drug conjugate, ado-trastuzumab emtansine has shown
modest clinical efficacy in these patients. [78]
In a phase II clinical trial, 18 patients with HER 2 mutated NSCLC were
treated with ado-trastuzumab emtansine after a median of 2 prior line of
systemic therapy. These patients were found to have ORR of 44%, median
PFS of 5 months and median duration of response was 4 months, suggesting
that we can offer this treatment off label in patients HER2-positive
NSCLC refractory to other standard available therapies. [78]
In an ongoing, multicenter phase II study DESTINY-Lung01, 42 patients
with non-squamous cell lung cancerwith HER2-activating mutation were
administered
trastuzumab deruxtecan.
The ORR among these 42 patients was 62 percent with estimated median PFS
of 14 months. [79]
Given that these two drugs are FDA approved for other HER2- positive
malignancies, we can offer this treatment off label in patients with
HER2-positive NSCLC refractory to other standard available therapies.