NcXHF

CURRENT STANDARDS AND CLINICAL TRIALS IN STAGE III NSCLC
Based on this preclinical data, a study of erlotinib or crizotinib
as induction therapy in patients with stage III NSCLC is
ongoing (NCT 01822496). Approximately 234 patients with
nonsquamous NSCLC will be stratifıed based on EGFR mutation
and ALK gene-rearrangement status and randomly assigned
to one of four arms. Patients on arm 1 and 3 receive
erlotinib or crizotinib, respectively, as induction therapy for
up to 12 weeks. Those who have no disease response after 6
weeks will undergo immediate chemoradiation. After 2
weeks of completion of induction therapy, patients receive
concurrent chemoradiation with cisplatin and etoposide or
carboplatin and paclitaxel. Patients on arm 2 (EGFR mutation
cohort) or arm 4 (ALK gene-rearranged cohort) receive
concurrent chemoradiation beginning on day 1. The primary
objective is to assess whether patients treated with targeted
agents based on molecular characteristics have a longer
progression-free survival than those treated with chemoradiation
alone.
The RAS oncogene has also been proposed to play a role in
radiation resistance. 30 Although targeting RAS activation directly
has yielded disappointing results, downstream targets
of RAS, including MEK, may be feasible. In vitro studies demonstrate
an increased radiosensitization when such downstream
pathways are inhibited. It has also been proposed that
PI3K is a mediator of RAS-induced radiation resistance. Efforts
are underway within the National Cancer Institute to
incorporate trametinib (NCT 01912625), a MEK inhibitor,
into chemoradiation in patients with KRAS mutations. Approximately
30 patients with any histology NSCLC with a
KRAS mutation in exons G12, G13, or Q61 will receive daily
oral trametinib with concurrent carboplatin, paclitaxel, and
radiation for 6 weeks followed by two cycles of consolidation
carboplatin and paclitaxel alone. The primary objective is to
determine the maximum tolerated dose of trametinib when
combined with chemoradiation. Future efforts with PI3K inhibitors
may also be worth testing.
IMMUNOTHERAPY IN STAGE III NSCLC
Targeting immune regulatory pathways has proven to be a successful
strategy in NSCLC. A phase III study comparing nivolumab
with docetaxel in patients with NSCLC was recently closed based
on the recommendations of a Data and Safety Monitoring Board
citing evidence of superior overall survival favoring nivolumab
(CheckMate-017 trial, Bristol Myers Squibb press release January
11, 2015). Consolidating chemoradiation with an immunotherapy
has been studied in stage III NSCLC. Tecemotide (L-bLP25), a
MUC1-antigen–specifıc cancer immunotherapy, was evaluated as
consolidation therapy after chemoradiation in a phase III randomized
trial. 31 In this trial, patients were allowed to receive either concurrent
or sequential chemoradiation. Although overall survival
did not statistically differ between the two groups (HR 0.88, 0.75–
1.03; p 0.123), a subset analysis of 829 patients treated with concurrent
chemoradiation favored the tecemotide arm (median
survival, 30.8 vs. 20.6 months, HR 0.78; p 0.016). Another trial
from the Eastern Cooperative Oncology Group, combining tecemotide
with bevacizumab after chemoradiation, has recently
completed accrual (NCT 00828009). Patients with stage III nonsquamous
NSCLC received concurrent chemoradiation using
weekly carboplatin and paclitaxel for 6.5 weeks. Patients with nonprogression
receive two additional cycles of consolidation chemotherapy.
On completion of consolidation chemotherapy, patients
receive a single dose of cyclophosphamide 3 days before the fırst
tecemotide and bevacizumab treatment. Patients then receive bevacizumabonday1andtecemotidesubcutaneouslyondays1,8,and
15 for cycles 1 and 2 then every other cycle beginning in course 4.
Treatment continues every 21 days for up to 34 cycles. The primary
endpointistodeterminethesafetyofbevacizumabplustecemotide
as maintenance therapy in this setting.
Evidence indicates radiation therapy induces tumor antigen
release from the dying tumor cells that can be recognized
by the immune system. 32,33 Therefore, radiation is an immune
stimulator that enhances T-cell activation and infıltration.
Furthermore, radiation has been shown to increase the
expression of PD-L1, an immune checkpoint. Combining radiation
with checkpoint inhibitors, such as PD-1 or PD-L1
inhibitors, including MED14736, pembrolizumab, and nivolumab,
are being investigated. MED14736, an antibody to
PD-L1, will be tested in a phase III industry-sponsored trial
(PACIFIC) involving 702 patients across 100 sites around the
globe (NCT 02125461). Patients with unresectable stage III
NSCLC will be treated with concurrent chemoradiation utilizing
at least two cycles of platinum-based chemotherapy. If
no evidence of progression is seen, patients will then be
treated with MED14736 or placebo (2:1 randomization) for
up to 1 year. The primary endpoint is overall survival. A
phase II single-arm study evaluating pembrolizumab as consolidation
therapy after concurrent chemoradiotherapy will
be conducted by the Hoosier Cancer Research Network
(NCT 02343952). In this trial, approximately 83 patients will
receive either weekly carboplatin/paclitaxel or cisplatin/etoposide
with 59.4 to 66 Gy radiation. Patients with nonprogressive
disease will then receive pembrolizumab every 3
weeks for up to 1 year. A safety analysis will take place after
the initial 10 patients have been treated and received at least
three cycles of pembrolizumab. Given the possibility of pneumonitis
after chemoradiation and the expected activation of
T cells with pembrolizumab, the incidence of delayed or severe
pneumonitis and/or recurrent esophagitis in the radiated
fıeld will be of special importance. The primary
endpoint is to assess the time to distant relapse. Secondary
analyses will evaluate the effect of PDL-1 status on outcomes.
In addition, a randomized trial with nivolumab after chemoradiation
is under development (personal communication,
Jeffrey Bradley, February 2015).
CONCLUSION
Therapeutic advances in the treatment of stage III NSCLC
are diffıcult to achieve. Many factors contribute to the diffı-
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