AstraZeneca · SE-151 85 Södertälje · Sweden
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Report from day 3 ASCO 2012
The third day began with poster session (25 posters) and later of the day was
one hour poster discussion.
The first discussion included 6 posters which was
presented by Steven M. Keller, Montefore Medical
Center
Common thread: Inadequate local therapy of early stage NSCLC
Recurrent disease following excision
-
Solution:
-Therapy enriched population likely to respond to therapy
-Maintenance therapy
Morbidity/expense of surgery
-
Solution
-Eliminate surgery
#7009 Stages I-II non-small cell lung cancer treated using either lobectomy by
video-assisted thoracoscopic surgery (VATS) or stereotactic ablative
radiotherapy (SABR): Outcomes of a propensity score-matched analysis
#7010 The SELECT study: A multicenter phase II trial of adjuvant
erlotinib in resected epidermal growth factor receptor (EGFR)
mutation-positive non-small cell lung cancer (NSCLC)
Cancers with activating EGFR mutations are exquisitely sensitive to
EGFR tyrosine kinase inhibitors (TKIs) and retrospective data suggests
adjuvant TKIs may improve outcomes in EGFR mutants. This
prospective trial investigates the safety and efficacy of adjuvant erlotinib
in EGFR mutation-positive NSCLC.
Patients (pts) with surgically resected stage IA-IIIA NSCLC harboring
activating EGFR mutations were treated with 150 mg/day of erlotinib for
2 years (y) after completion of any standard adjuvant chemotherapy
and/or radiotherapy. The trial was designed to enroll 36 patients, and
powered to demonstrate a primary endpoint of 2 y disease free survival
(DFS) exceeding 85%, which would suggest improvement over the
historically expected 70% 2 y DFS in early stage EGFR-mutant NSCLC
(J Thorac Oncol 6:569).
Reg Office AstraZeneca AB (publ)
SE-151 85 Södertälje Sweden
Reg No 556011-7482
VAT No SE556011748201
Thirty-six pts were enrolled at five sites between 1/08 and 11/09; 53%
stage I; 19% stage II; 28% stage IIIA. Toxicities were typical of erlotinib;
no grade 4 or 5 events or pneumonitis occurred. 8 pts (22%) required
one dose reduction to 100 mg/day and 5 (14%) two reductions to 50
mg/day for grade 3 or persistent grade 2 toxicities. 11 pts discontinued
before 2 full years (<1 month (mo), 1-12 mo and 12-23 mo) for toxicities
[6], patient preference , prostate cancer [1] and recurrence. After a
median follow-up of 2.5 y, the 2 y DFS from enrollment is 94% (95% CI
80%, 99%). 10 patients have recurred, 1 during erlotinib treatment and
the others after stopping erlotinib (interval before recurrence 2 mo, 6-12
mo [4], >12 mo). Genotyping on repeat biopsies from seven of the
recurrent cases is underway, as is assessment of response to
subsequent erlotinib therapy. Two pts have died of recurrence: one at
1.5 y who stopped erlotinib after 1 mo for toxicity, and one at 2 y who
progressed while on erlotinib.
Authors concluded :
-This is the first prospective study to report the efficacy of adjuvant
erlotinib in NSCLC pts with EGFR mutations.
-Primary endpoint was met: DFS 94%.
-Trial expanded to 100 pts. .
Comments:
This trial is similar to one arm of the RADIANT phase III trial
which reached the accrual goal.
#7011 Pilot SCAT trial: Spanish customized adjuvant chemotherapy (CT)
based on BRCA1 mRNA expression levels (l) in resected stage II-IIIA
non-small cell lung cancer (NSCLC) patients (p)
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#7012 Feasibility trial of adjuvant chemotherapy with docetaxel
(DOC) plus cisplatin (CDDP) followed by maintenance
chemotherapy of S-1 in completely resected non-small cell lung
cancer (NSCLC): Thoracic Oncology Research Group (TORG) 0809
Maintenance chemotherapy could prolong overall and/or progression-free
survival in advanced NSCLC.
S-1 is an oral anticancer agent comprised of tegafur, 5-chloro-2, 4dihydroxypyridine, and potassium oxonate.
The TORG 0809 study was conducted to evaluate the feasibility and efficacy of
maintenance chemotherapy of S-1 following DOC+CDDP in patients (pts) with
curatively resected stage II and IIIA NSCLC.
Pts received 3 cycles of DOC (60mg/m2 d1) plus CDDP (80mg/m2 d1), q3-4w,
and subsequently S-1 at 40mg/m2 twice a day for 14 consecutive days, q3w, for
more than 6 months (max 1 year).
Primary endpoint was determination of feasibility, which was defined as the
proportion of pts who had completed maintenance for 8 cycles of S-1 or more. If
the lower confidence interval (CI) of this proportion was 50% or more, the
feasibility of the treatment was considered confirmed. The sample size was set
to be 125.
131 pts were enrolled, of whom 129 pts were eligible and assessable. The
median age was 63 (23-74 years); PS 0: 107, 1: 22; p-stage IIA: 19, IIB: 30,
IIIA: 80; adenocarcinoma: 99, non-adenocarcinoma: 30. Of 129 pts, 109 pts
(84.5%) completed 3 cycles of DOC+CDDP. 106 pts initiated the maintenance
S-1 and 66 pts (51.2%, 95% CI: 42.5-59.8) completed 8 cycles or more S-1
treatment; this percentage was less than our previously defined criterion for
treatment feasibility, since 32 pts terminated maintenance S-1 at 3 cycles or
less. Grade 3/4 toxicities during the maintenance S-1 included anemia (7.3%),
neutropenia (3.7%), anorexia (3.7%), dyspnea (1.8%), infection with
neutropenia of grade 0 to 2 (1.8%). Febrile neutropenia was not observed. One
pt developed interstitial pneumonia and sepsis, resulting in treatment-related
death. Recurrence-free survival data will be presented.
The authors concluded:
- Though it did not meet feasibility criterion, the toxicity was acceptable.
- Modify treatment schedule for maintenance S-1 therapy and proceed with a
randomized trial.
Comments:
- Do we need another chemo alone trial in unselected
NSCLC population
- In any case, does not answer the timing question (e.g.
following adjuvant chemo or at recurrence).
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#7013 MAGE-A3 cancer immunotherapeutic in resected stage IB-III
NSCLC patients with or without sequential or concurrent
chemotherapy
A number of promising vaccine candidates based on different types of antigenic
stimulus have now been evaluated in clinical studies. These include
belagenpumatucel-L, a vaccine derived from four genetically modified,
irradiated NSCLC cell lines and target protein-specific vaccines designed to
induce responses against epidermal growth factor (EGF), melanomaassociated antigen A3 (MAGE-A3) and mucin 1 (MUC1). MAGE-A3 is a tumorassociated antigen that is not expressed in most normal cells Approximately
35–50% of lung cancers express MAGE-A3, and expression has been
associated with poor prognosis . This provided the rationale for the
development of a TCV comprising MAGE-A3 recombinant protein combined
with the AS02B immune-adjuvant. Previous trials with the MAGE-A3
recombinant (rec) protein formulated with an immunostimulant have shown
induction of specific immune responses and signals of clinical activity in
different cancer diseases. In this phase I/II study (NCT 00455572), the authors
evaluated the safety profile of the MAGE-A3 cancer immunotherapeutic (CI),
formulated with the rec MAGE-A3 protein and the AS15 immunostimulant, and
the induction of specific immune response with or without adjuvant
chemotherapy (CT).
MAGE-A3 CI was administered i.m. 8q3w in resected MAGE-A3+ stage IB-III
NSCLC patients (pts). Three cohorts (C) were evaluated:
1-Immunization with concurrent cisplatin plus vinorelbine (C1),
2-sequentially after the same CT (C2)
3-or with no CT (C3).
A total of 38/55 treated pts received the 8 doses schedule (15/19 in C1, 14/18
in C2, 9/18 in C3).
Authors concluded:
-Pts in cohorts 2 and 3 correspond to the two populations enrolled in the Phase
III MAGRIT trial evaluating the same MAGE-A3 CI.
-The phase I/II results suggest that this CI is well tolerated and induces in all
treated pts specific antibodies against MAGE-A3 after 4 doses in presence or
not of concurrent or sequential adjuvant CT.
-About 25% of the treated pts are considered as CD4 responders in presence
or not of concurrent or sequential adjuvant CT.
#7014 Quantitating pathologic response to neoadjuvant
chemotherapy in KRAS-mutated versus nonmutated lung cancers
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The second group of posters (7017-7020) was
presented by William J. Petty, Wake Forest
University
These posters were about stage III lung cancer: individualizing care.
Concerning stage III there are some issues should be point out:
There is need for improvement:
-To control cancer-related symptoms
-To reduce treatment related morbidity and mortality
-To improve the chance of cure.
-To reduce the costs of treatment
To define the populations that benefit from specific treatments
(individualized medicine)
. -this is an overarching principle that impacts every other goal.
There are many treatment modalities:
-Biomodality (concurrent chemo-radiation)
-Biomodality (chemo-surgery)
-Biomodality (surgery-chemo)
-Triomodality (chemo-radiation-surgery)
-Radiation alone
-Best supportive care alone
Patient characteristics:
Age, comorbid illness, hemoptysis, performance status, poor PFTs,
smoking
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Radiographic characteristics
Proximity to brachial plexus, tumor size, vascular involvement, number of
nodes, obstruction, central vs peripheral
Complexity of stage III NSCLC
Radiographic characteristics Patient characteristics
characteristics
Tumor
What modalities?
If chemo-radiation, which chemo regimen?
I will focus only on abstract 7020
Favorable outcomes with chemoradiation and surgery for locally
advanced non-small cell lung cancer: The BC Cancer Agency
Vancouver experience.
The role of surgery following concurrent platinum-based chemotherapy
and radiation for locally advanced non-small cell lung cancer (NSCLC)
remains controversial, with high surgical mortality rates reported in a
large randomized clinical trial. In this retrospective study, we evaluated
the safety and efficacy of concurrent chemoradiation with or without
surgery over an 11 period at the BC Cancer Agency.
Patients were identified by the Vancouver Centre Pharmacy database.
Charts were reviewed and data extracted included patient
characteristics, weight loss, performance status, and method of
mediastinal staging. Outcome measures were overall survival,
pathological response rate, and treatment-associated morbidity and
mortality.
177 patients were identified with locally advanced NSCLC (stage IIIA/B)
treated with platinum and etoposide and ≥40Gy radiation therapy, with or
without surgical resection. The majority of treatment plans were reached
by a multidisciplinary conference consensus. 74% (n=131) of patients
received chemoradiation alone (bimodality therapy) and 36% (n=46)
received chemoradiation followed by surgical resection (trimodality
therapy). Among the trimodality therapy group, 16 patients underwent
pneumonectomy and 30 lobectomy.
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Authors concluded:
- Bimodality therapy for patients with locally advanced NSCLC had
similar treatment associated mortality and survival outcomes as reported
in the literature.
-Trimodality therapy was associated with low treatment mortality rates
and favourable survival.
-These two groups cannot be directly compared in this retrospective
study. However, these results support a multidisciplinary approach to
identify and carefully select patients with locally advanced NSCLC to
undergo additional surgical resection following concurrent
chemoradiation.
Coclusions from these 4 posters:
Individualized care of stage III NSCLC:
- Patients over age 70 with adequate performance status, normal organ
function and limited comorbidities should be considered for concurrent
chemo-radiation (abstract 7017)
- Trimodality therapy continues to bersonable for carefully selected
patients with stage III NSCLC (abstract 7020)
- Patients at low risk for hemoptysis appear to have better outcomes than
patients at high risk (abstract 7018)
Use of newer agents in stage III NSCLC
- Bevacizumab consolidation is associated with a high risk of fatal
hemoptysis in patients with central tumors or squamous cell cancers
(abstract 7018)
- Cetuximab failed to improve outcomes when combined with cisplatin
(abstract 7019)
Futures directions:
-
What is the optimal chemotherapy regimen for elderly patients
with NSCLC?
Dose trimodality therapy improve the outcomes of patients with
unresectable NSCLC and limited nodal involvement?
Page 7 of 9
-
Can any of the approved or investigated targeted agents improve
the cure rates of selected patients with stage III NSCLC?
How can we rationally incorporate these agents to maximize
efficacy?
Cannot radiation schedules such hypofractionated radiation
improve outcomes?
A study presented by Camdige et al from, Philadelphia, about LDK378
which is a novel, potent and selective small molecule anaplastic
lymphoma kinase (ALK) inhibitor that does not inhibit c-MET.
First-in-human phase I study of the ALK inhibitor LDK378 in advanced
solid tumors. (Camidge et al)
LDK378 is a novel, potent and selective small molecule anaplastic
lymphoma kinase (ALK) inhibitor (IC50 0.00015 μM), that does not inhibit
c-MET (IC50 3.2 μM). Tumor regression has been observed in ALKdriven NSCLC xenografts. A first-in-human, Phase I study is being
conducted to determine the MTD and safety profile in patients (pts) with
tumors with ALK rearrangement, amplification or mutation. Other
objectives were safety, PK and antitumor activity in pts with ALK-driven
NSCLC, both naïve to ALK inhibitors and relapsed following previous
ALK inhibitor treatment, and other ALK-positive cancers.
Adult pts with advanced malignancies harboring a genetic alteration in
ALK who progressed on standard therapy or for whom there was no
effective therapy were given once daily oral LDK378 on a continuous 21day schedule. Dose escalation, starting at 50 mg/day, was guided by a
Bayesian logistic regression model (BLRM) to determine the MTD.
31 pts (primary site: lung 26 pts; breast 3 pts; other 2 pts; median age 52
years; 87% ECOG PS 0/1) were enrolled and received LDK378 at doses
of 50–750 mg/day. Median duration of treatment with LDK378 was 7
weeks (range <1–22+). At the cutoff date, 13 (42%) pts discontinued
treatment: 1 (3%) due to adverse events (AEs), and 12 (39%) due to
disease progression; 18 (58%) pts were still on treatment. The most
frequent AEs (all Gr) were nausea (45%), vomiting (36%), and diarrhea
(29%). The most frequent Gr 3/4 AEs were diarrhea and dyspnea (2 pts
[7%] each). Of 16 pts with available response data there were 4/6
responses in crizotinib (CRZ)-treated pts, and 2/10 responses in CRZnaïve pts, of whom 7 were treated below 400 mg. All responses were in
NSCLC.
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Authors concluded:
that daily oral LDK378 is well tolerated up to 500 mg/day, and escalation
continues at 750 mg/day. Preliminary responses have been seen in both
CRZ-naïve and CRZ-relapsed pts.
Best regards
Hirsh Koyi
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