Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Hamdi 1 , Patrick Roberts 2 , Rajesh Malik 2 , John Bisi 2 , Jessica Sorrentino 2 , Jay
Strum 2 , Emily Roarty 1 , John Heymach 1
1 Thoracic, Head & Neck Medical Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston/TX/United States of America, 2 G1 Therapeutics, North
Carolina/AL/United States of America
Background: Small cell lung cancer (SCLC) is an aggressive form of lung cancer
characterized by loss of the tumor suppressor Rb. Chemotherapy remains the
standard of care for SCLC patients but produces severe myelosuppression
that compromises patient outcomes. G1T28 is a potent and selective CDK4/6
inhibitor in development to reduce chemotherapy-induced myelosuppression
and preserve immune system function in SCLC patients. Cyclin dependent
kinases 4 and 6 (CDK4/6) phosphorylate Rb protein promoting proliferation
of specific cell types such hematopoietic stem progenitor cells (HSPCs)
by allowing cells to progress through G1 to S phase. HSPCs are exquisitely
dependent upon CDK4/6 for proliferation and become arrested in the
G1 phase of the cell cycle upon exposure to G1T28. We hypothesize that
G1T28-mediated CDK4/6 inhibition may selectively protect immune cells (Rb
intact) from chemotherapy without antagonizing the antitumor efficacy
in Rb deficient tumors, such as SCLC. G1T28 preservation of adaptive
immunity from cisplatin-induced cytotoxicity may enhance the efficacy
of chemotherapy in SCLC tumors by allowing a more robust host-immune
response. Methods: Syngeneic mouse models were established by flank
injection of KP1 and TKOTmG murine cells derived from TP53 and RB1 or TP53,
RB1 and P130 mutant mice respectively. When tumors reached 150mm 3 , mice
were randomized and treated with G1T28, cisplatin and combination of both.
Tumor volumes were measured and immune populations from tumor, spleen
and peripheral blood were analyzed by flow cytometry. Results: CDK4/6
inhibition by G1T28 protects peripheral white blood cells (lymphocytes,
monocytes and eosinophils) from cisplatin-induced cytotoxicity in the
syngeneic SCLC KP1 mouse model. Additionally, treatment with G1T28
prior to cisplatin inhibited tumor growth to a greater extent than cisplatin
alone (46% versus 12%, respectively) in the syngeneic SCLC TKOTmG mouse
model. Conclusion: G1T28-mediated CDK4/6 inhibition protects immune
cells from chemotherapy and potentiates the reduction of tumor volume
when combined with cisplatin in a syngeneic Rb deficient SCLC mouse
model. Studies are ongoing to determine if the immune protection by G1T28
is enhancing the anti-tumor activity of cisplatin in this model, as well as to
evaluate other potential mechanisms. Additionally, clinical trials testing the
combination of G1T28 with chemotherapy in patients with extensive stage
SCLC are currently in progress (1 st line, carboplatin-etoposide, NCT02499770;
2 nd line, topotecan, NCT02514447).
Keywords: G1T28-mediated CDK4/6 inhibition, immune protection, small cell
lung cancer, chemotherapy
POSTER SESSION 2 – P2.03A: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
CLINICAL TRIALS –
TUESDAY, DECEMBER 6, 2016
P2.03A-049 RESPONSE TO SALVAGE CHEMOTHERAPY FOLLOWING
EXPOSURE TO PD-1 INHIBITORS IN PATIENTS WITH NON-SMALL
CELL LUNG CANCER
Paul Leger 1 , Emily Castellanos 2 , Rathi Pillai 3 , Leora Horn 4
1 Internal Medicine, Vanderbilt University Medical Center, Nashville/TN/United
States of America, 2 Internal Medicine, Vanderbilt University Medical Center,
Nashville/United States of America, 3 Winship Cancer Institute of Emory University,
Atlanta/GA/United States of America, 4 Vanderbilt-Ingram Cancer Center, Nashville/
TN/United States of America
Background: Programmed death-1 (PD-1) inhibitors are effective second
line treatment in non-small cell lung cancer (NSCLC), however objective
responses are seen in only 20-30% of patients. While a minority of patients
achieve durable response to PD-1 inhibitors, those who progress or are
refractory receive salvage chemotherapy. We evaluate response to salvage
chemotherapy following exposure to PD-1 inhibitors. Methods: Eligible
patients were adults with NSCLC followed at the Vanderbilt Cancer Center
or the Winship Cancer Institute from 2011 to 2016 who received salvage
chemotherapy following PD-1 inhibitors (cases) versus no PD-1 inhibitors
(controls). CT-imaging of the chest/abdomen/pelvis was done within 4 weeks
of initiation of salvage chemotherapy and every 6 weeks thereafter. Revised
RECIST guidelines were used to define response to treatment. Clinical and
imaging data were abstracted from review of electronic medical records.
Multivariate logistic regression analysis was used to calculate probability
of response. Results: Three hundred patients’ charts were reviewed and
56 patients met eligibility criteria. Among evaluable patients, 28 were
males versus 28 females. Median age was 61.64 years (interquartile ranges
(IQR): 55.33–69.36) in cases versus 67.82 (IQR: 54.08-72.24) in controls.
Forty-one patients were classified as cases versus 15 controls. Thirty-six
patients received nivolumab and 5 pembrolizumab. Forty-five (80%) patients
had adenocarcinoma, 10 (18%) squamous cell carcinoma and 1 (2%) large
cell carcinoma. The median number of chemotherapy regimens prior to
salvage chemotherapy was 3 (IQR: 2-3) in cases versus 2 (IQR: 1-2) in control.
The drugs most commonly used in salvage regimens included docetaxel,
pemetrexed, paclitaxel, gemcitabine. Seven (17%) cases had partial response
to chemotherapy versus 1(6.6%) controls. Eleven (27%) cases had progressive
disease versus 6 (40%) controls. Twenty-three (56%) cases had stable disease
versus 8 (53%) controls. The odd ratio for achieving a partial response was
0.16 (95% CI: 0.08 to 0.35, P=0.000). In multiple logistic regression model, age,
gender, number of prior chemotherapy regimens, tumor histology, smoking
status, different salvage chemotherapy regimens were not associated
with the likelihood of achieving a partial response. Conclusion: The odds of
achieving a partial response to salvage chemotherapy were 6 times higher
in patients with prior exposure to PD-1 inhibitors. This observed difference
however warrants confirmation in larger cohorts. If confirmed, this difference
may represent an argument to promote immune PD-1 inhibitors as first line
regimen for the treatment of NSCLC not amenable to targeted therapy.
Keywords: PD-1, non-small cell lung cancer, salvage chemotherapy,
POSTER SESSION 2 – P2.03A: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
CLINICAL TRIALS –
TUESDAY, DECEMBER 6, 2016
P2.03A-050 ELEVATED EXPRESSION OF CCP GENES IS ASSOCIATED
WITH ABSOLUTE CHEMOTHERAPY BENEFIT IN EARLY STAGE LUNG
ADENOCARCINOMA PATIENTS
Prasad Adusumilli 1 , Raphael Bueno 2 , Robert Cerfolio 3 , David Harpole 4 ,
Takashi Eguchi 5 , Shaohua Lu 1 , Corrine Gustafson 2 , Sandra Calloway 3 , Mary-
Beth Joshi 4 , Brent Evans 6 , Elisha Hughes 7 , Kraig Yager 6 , Alison Sibley 6 , Joshua
Jones 7 , Anne-Renee Hartman 7 , Brian Allen 7
1 Memorial Sloan Kettering Cancer Center, New York/NY/United States of America,
2 Division of Thoracic Surgery, Brigham and Women’s Hospital/ Harvard Medical
School, Boston/MA/United States of America, 3 Thoracic Surgery Office, University
of Alabama at Birmingham, Birmingham/AL/United States of America, 4 Duke
University Medical Center, Durham/NC/United States of America, 5 Thoracic Service,
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York/NY/
United States of America, 6 Myriad Genetic Laboratories, Inc., Salt Lake City/UT/
United States of America, 7 Myriad Genetics, Inc., Salt Lake City/UT/United States
of America
Background: A validated RNA molecular expression signature based on cell
cycle progression (CCP) genes [CCP score] and a molecular Prognostic Score
[(mPS) combination of CCP score and pathological stage] are significant
prognostic markers of cancer-specific mortality in patients with early stage
lung adenocarcinoma. Additionally, preliminary data suggest a significant
association between CCP score and absolute benefit with platinum-based
adjuvant chemotherapy in early stage lung adenocarcinoma patients. The
aim of this study is to further demonstrate the effectiveness of CCP score
and mPS in predicting platinum-based chemotherapy benefit in a large,
multi-institutional cohort of stage IB and IIA lung adenocarcinoma patients
who underwent definitive surgical resection with and without adjuvant
chemotherapy. Methods: Formalin-fixed paraffin-embedded surgical tumor
samples from approximately 1000 patients diagnosed with stage IB and II
adenocarcinoma who underwent definitive surgical treatment with adjuvant
platinum-based chemotherapy (n = 400) and without (n = 600) will be analyzed
for 31 proliferation genes by quantitative RT-PCR. The associations of CCP
score and mPS with absolute benefit from platinum-based chemotherapy
will be separately examined using Cox proportional hazards regression
with an outcome of 5-year lung cancer survival. Results: To date, lung tumor
samples have been accrued from 388 patients treated with a platinumbased
chemotherapy and 590 untreated patients. We hypothesized that
the absolute treatment benefit will increase as CCP score or mPS increases.
Results will be shown for continuous CCP score and mPS as well as pre-defined
binary CCP score and binary mPS. Conclusion: This study will determine the
abilities of CCP score and mPS as predictive tools for absolute chemotherapy
benefit and 5-year lung cancer survival in patients with early stage lung
adenocarcinoma thereby furthering the clinical utility for these signatures
to identify patients with high risk disease who should receive adjuvant
chemotherapy.
POSTER SESSION 2 – P2.03A: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
CLINICAL TRIALS –
TUESDAY, DECEMBER 6, 2016
P2.03A-051 CMTM1_V17 PROMOTES CHEMOTHERAPY RESISTANCE
AND IS ASSOCIATED WITH POOR PROGNOSIS IN NON-SMALL CELL
LUNG CANCER
S480 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017