patients with BRAF mutations in this case series
was NR, while it was 37 months for patients with
EGFR mutations (P = 0.73) and NR for patients
with ALK rearrangements (P = 0.64). 9
For patients with BRAF V600E–mutant
NSCLC who have progressed on platinum-based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK
inhibitor) may represent a new treatment paradigm. This was illustrated in a phase 2, nonran-domized, open-label study. A total of 57 patients
were enrolled and 36 patients (63.2% [95% CI
49.3% to 75.6%]) achieved an overall response
by investigator assessment, the trial’s primary
end point. Disease control rate was 78.9% (95%
CI 66.1% to 88.6%), with 4% complete response, 60% partial response, and 16% stable
disease. PFS was 9. 7 months (95% CI [ 6. 9 to
19. 6 months]). The safety profile was comparable to what had been observed in patients with
melanoma treated with this regimen. More specifically, 56% of patients on this trial reported
serious AEs, including pyrexia (16%), anemia
(5%), confusional state (4%), decreased appetite (4%), hemoptysis (4%), hypercalcemia
(4%), nausea (4%), and cutaneous squamous
cell carcinoma (4%). In addition, neutropenia
(9%) and hyponatremia (7%) were the most
common grade 3-4 AEs. 16
The case patient has experienced disease pro-
gression after 1 line of platinum-based chemo-
therapy, so the combination of dabrafenib and
trametinib would be a robust systemic treatment
option. Dabrafenib as a single agent has also
been studied in BRAF V600E–mutant NSCLC
in a phase 2 trial. The overall response by inves-
tigator assessment among 84 patients was 33%
(95% CI 23% to 45%). 14 Vemurafenib, another
oral BRAF TKI, has demonstrated efficacy
for NSCLC patients harboring BRAF V600E
mutation. In the cohort of 20 patients with
NSCLC, the response rate was 42% (95% CI
20% to 67%) and median PFS was 7. 3 months
(95% CI 3. 5 to 10. 8 months). 13 Patients with
non-V600E mutations have shown variable
responses to targeted therapies. MEK TKIs may
be considered in this setting; however, the de-
tails of this discussion are beyond the scope of
The management of advanced NSCLC with
driver mutations has seen revolutionary changes
over the past decade. Tremendous research
has been done in order to first understand the
molecular pathogenesis of NSCLC and then
discover driver mutations that would lead to development of targeted therapies with clinically
significant efficacy as well as tolerability. More
recently, increasing efforts have focused on how
to conquer acquired resistance in patients with
disease progression after first-line TKIs. The
field of EGFR-mutant NSCLC has set a successful
example, but the work is nowhere near finished.
The goals are to search for more driver mutations and to design agents that could potentially
block cell survival signals once and for all.
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2. Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med
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3. Alberg AJ, Brock MV, Ford JG, et al. Epidemiology of lung cancer:
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4. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics
Review, 1975-3013, based on November 2015 SEER data submission,
posted to the SEER website, April 2016. Bethesda (MD): National
Cancer Institute; 2016.
5. National Comprehensive Cancer Network. NCCN Clinical Practice
Guidelines in Oncology. Non-Small Cell Lung Cancer: 1–190.
6. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the
epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–39.
7. Soda M, Choi YL, Enomoto M, et al. Identification of the transform-
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