ASCO2013摘要

A phase Ib safety and tolerability study of a pan class I PI3K inhibitor buparlisib
(BKM120) and gefitinib (gef) in EGFR TKI-resistant NSCLC.
Daniel Shao-Weng Tan, Kiat Hon Lim, Wai Meng Tai, Aziah Ahmad, Summer Pan, Quan Sing Ng,
Mei-Kim Ang, Apoorva Gogna, Yuen Li Ng, Bien Soo Tan, Haur Yueh Lee, Sakktee Sai Krisna,
Dawn PX Lau, Liz Zhong, Gopal Iyer, Balram Chowbay, Alvin ST Lim, Angela Takano, Wan-Teck Lim,
Eng-Huat Tan; National Cancer Centre, Singapore, Singapore; Department of Pathology, Singapore
General Hospital, Singapore, Singapore; Singhealth Investigational Medicine Unit, Singapore, Singapore;
Department of Radiology, Singapore General Hospital, Singapore, Singapore; Department of Dermatology,
Singapore General Hospital, Singapore, Singapore; Cytogenetics Laboratory, Singapore General Hospital,
Singapore, Singapore
Background: Overcoming EGFR TKI resistance (R) is a major clinical challenge; reported mechanisms
include EGFR T790M mutation (mt), MET amplification (amp) and PIK3CA mt. As the PI3K pathway is
a central convergent signaling node, we hypothesized that addition of buparlisib (BKM) could overcome
EGFR TKI-R. Methods: Patients (pt) resistant to EGFR TKI (Jackman JCO 2010) were enrolled to
determine safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of BKM-gef. Using a “313”
design, escalating doses of BKM were added to pt progressing on gef (Gp A). Pt not on gef preceding
enrolment received a 2 wk run in (Gp B). Given the favorable CNS penetration of BKM, a CNS gp with
brain metastases only was included. Pt had pretreatment biopsies and sequential PET-CT scans (baseline &
d28). Results: 15 pt have been treated at 3 dose levels: BKM 80 mg/d (n56), 100 mg/d (n56), 80 mg 5d
on 2d off (5/2, n53), with gef 250 mg/d. Gp A (n59, 1 CNS), B (n56, 1 CNS), F:M (9:6), median age 63
(47-73) and majority .3 lines of therapy. DLT was G3 diarrhea observed in 2/6 pt at BKM100. Common
adverse events (AE, all grades) include rash (80%), diarrhea (73%), fatigue (60%), anorexia (47%),
mucositis (40%). Notably, 40% of pt had late (beyond DLT period) G3 toxicities such as rash and diarrhea.
MTD is BKM 80/d and gef 250/d. To improve the overall safety profile, an intermittent schedule of BKM80
5/2 was also found to be feasible. In gp B, PET-CT done after 2 wk run-in of gef, 3/4 evaluable pt
demonstrated reduction in SUVmax of which 1 had PR. With addition of BKM, reduction in SUVmax
(.25%) was seen in 4/10 pt (gp A & B). Median PFS 2.8 m (95%CI 2.3 – 8.1), two pt in CNS gp had PFS
of 2.8 and 10.7 m. Molecular analyses revealed 6/12 (50%) harbored T790M mt, 2/5 (40%) MET amp, 0/12
PI3KCA mt. In gp A, 4/9 pt (2 T790M; 1MET amp) had clinical responses, including slight tumor shrinkage
and reduced pleural effusion, but required dose reductions due to AE. PK profiles are being analyzed.
Conclusions: MTD is gef 250-BKM 80/d. Antitumor activity has been observed with addition of BKM in
EGFR TKI-R pt. In view of late toxicities and long t½ of BKM, exploring alternative schedules is warranted.
A dose expansion cohort at MTD is currently ongoing. Clinical trial information: NCT01570296.

Erlotinib beyond progression study: Randomized phase II study comparing chemo-
therapy plus erlotinib with chemotherapy alone in EGFR tyrosine kinase inhibitor
(TKI)-responsive, non-small cell lung cancer (NSCLC) that subsequently progresses.
Balazs Halmos, Nathan A. Pennell, Gregory Alan Otterson, Shirish M. Gadgeel, Tarek Mekhail,
Michael Robert Snell, J. Phillip Kuebler, Pingfu Fu, Neelesh Sharma, Afshin Dowlati; New York-
Presbyterian Hospital, Columbia University, New York, NY; Cleveland Clinic Taussig Cancer Institute and
Case Comprehensive Cancer Center, Cleveland, OH; Department of Internal Medicine, The Ohio State
University Comprehensive Cancer Center, Columbus, OH; Karmanos Cancer Institute, Wayne State
University, Detroit, MI; Florida Hospital Cancer Institute, Orlando, FL; MetroHealth Medical Center,
Cleveland, OH; Columbia Oncology Associates, Columbus, OH; Case Comprehensive Cancer Center,
University Hospital of Cleveland Medical Center, Cleveland, OH; University Hospitals Seidman Cancer
Center, Case Comprehensive Cancer Center, Cleveland, OH; University Hospitals Seidman Cancer Center,
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH
Background: In EGFR-TKI responsive NSCLC, at progression only some tumor clones might carry
resistance mechanisms. This provides a rationale for maintenance therapy with TKIs on progression and is
supported by “tumor flares” noted in patients taken off of TKI therapy. Methods: Randomized, phase II
study of chemotherapy (pemetrexed or docetaxel) versus chemotherapy plus erlotinib (ERL) in patients with
progressive NSCLC following clinical benefit from erlotinib for . 12 weeks. In Arm A Pemetrexed or
Docetaxel were given at standard doses every 3 weeks to a maximum of 8 cycles. In Arm B chemotherapy
was given with ERL at 150 mg oral daily dose on days 2-19 of each cycle. The primary endpoint was that
continuation ERL in this patient population could extend PFS by 50%, from 3 to 4.5 months. The original
enrollment goal was 39 pts per arm to allow 80% power to detect such a difference. Results: 46 patients
were randomized (Arm A: 24; Arm B: 22). Early termination was due to slow enrollment. Patient
characteristics were well balanced except for more females on Arm A (p50.075). The median PFS on Arm
A was 5.4 months and for Arm B was 4.6 months (p50.569). The median overall survival (OS) on Arm A
was 18.7 months and for Arm B 14.7 months (p50.295). Multiple Cox regression analysis showed an
impact of female gender on OS (HR 0.1) but not PFS (HR50.49). EGFR status was available on 39/46
patients. 17 patients in Arm A and 14 Arm B were mutation positive. In analyzing mutation 1 only patients,
no difference in PFS (p50.332) or OS (p50.346) was seen amongst the 2 groups. In the mutation 1 patients
the 6 months PFS for Arm A was 39% and for Arm B was 32%. More toxicity was seen on Arm B as
compared to Arm A. Irrespective of causal attribution, 1 grade 5 event occurred on Arm A as opposed to
2 events on Arm B. A total of 7 grade 3/4 events occurred on Arm A while 24 occurred on Arm B.
Conclusions: No benefit was seen with the continuation of ERL in addition to chemotherapy as compared
to chemotherapy alone in patients who had previously benefited from ERL but then showed progression.
The combination arm showed significantly more toxicity. Clinical trial information: NCT00660816.

Pulsed dosing of erlotinib for central nervous system (CNS) progression in EGFR-
mutant non-small cell lung cancer (NSCLC).
David Michael Jackman, Stacy L. Mach, Jennifer C. Heng, Michael S. Rabin, David Allen Barbie,
Leena Gandhi, J Paul Marcoux, Daniel Botelho Costa; Dana-Farber Cancer Institute, Boston, MA; Beth
Israel Deaconess Medical Center/Harvard Medical School, Boston, MA
Background: Lung cancer is the most common cause of CNS metastases. Options for CNS progression are
limited, particularly with leptomeningeal metastases (LM). High dose EGFR-TKIs have been used in this
setting. This is a retrospective series of our experience with pulsed high dose erlotinib for these patients.
Methods: Eligible pts with EGFR-mutant NSCLC were identified through our institutions’ databases and
had received pulsed high dose erlotinib for CNS progression. Patients had received erlotinib 1000-1500 mg
once weekly. The primary endpoint was CNS response; secondary endpoints included toxicity, systemic
response, CNS progression-free survival, and overall survival. Results: Between 10/2010 – 10/2012, 10
eligible pts received pulsed dose erlotinib for CNS progression. The median age was 60 yrs; 8/10 were
female, 7/10 were never-smokers, with a median of 2 pack-years. All pts had lung adenocarcinoma, and 9/10
had received prior EGFR-TKI. Median duration of prior TKI was 19 months. 6 received prior erlotinib, 1
received prior dacomitinib, and 2 received prior erlotinib followed by dacomitinib. The overall CNS
response rate was 10% (1/10); 2 others achieved CNS stability. Median overall survival was 1.7 months
(range 0.6 – 7.0). There was no clear correlation between outcomes and underlying EGFR genotype; type,
duration, or dose of prior EGFR-TKI; or extent of CNS involvement. Conclusions: While there has been
evidence of higher penetration of EGFR-TKI’s into cerebrospinal fluid with pulsed high doses of
EGFR-TKI’s, the clinical efficacy of this strategy remains limited.

BATTLE-2 program: A biomarker-integrated targeted therapy study in previously
treated patients with advanced non-small cell lung cancer (NSCLC).
Vassiliki Papadimitrakopoulou, Ignacio Ivan Wistuba, J. Jack Lee, Anne S. Tsao, Neda Kalhor,
Frank V. Fossella, John Heymach, Christine M Alden, Scott N. Gettinger, Kevin R. Coombes,
Pierre Saintigny, Ximing Tang, Emily Duffield, Julie Boyer, Suzanne E Davis, Garth Powis,
David J. Mauro, Eric H. Rubin, Waun Ki Hong, Roy S. Herbst; Department of Thoracic Head and Neck
Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; The University of
Texas MD Anderson Cancer Center, Houston, TX; Department of Biostatistics, The University of Texas MD
Anderson Cancer Center, Houston, TX; Yale University, New Haven, CT; Yale Cancer Center, New Haven,
CT; Merck & Co, Inc, North Wales, PA; Merck Sharp & Dohme, North Wales, PA
Background: New strategies incorporating a personalized medicine approach for NSCLC treatment are
increasingly explored and were pioneered in the prospective, biomarker-driven clinical program titled
Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-1) (Kim et
al Cancer Discov 2011;1:44). Effective therapeutic strategies for mutant KRAS and other biomarkers of
resistance in refractory NSCLC remain an unmet medical need. The BATTLE-2 clinical study is using
EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection
for these therapies, with a long-term goal to significantly improve the survival of NCSLC patients (pts)
(ClinicalTrials.gov NCT01248247). Methods: This is a four-arm, open-label, multi-center, biopsy-driven,
adaptive randomization, phase II clinical trial in refractory NSCLC pts (failed at least 1 prior line of
therapy). After a study-entry tumor biopsy, pts are adaptively randomized, based on KRAS status, to 4 trial
arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib,
and sorafenib. The primary objective is 8-week disease control rate (DCR). Baseline tumor testing includes
KRAS and EGFR mutations and EML4/ALK translocation, the latter two being exclusion criteria. The trial
is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed
8-week DCR and KRAS status while predictive biomarkers are being developed. In Stage 2, the AR model
is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based
on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers
(“signatures”) follows a rigorous, internally and externally reviewed statistical analysis. All Stage 1 and 2
randomization biomarker assays are CLIA-certified. 219 pts have been enrolled and 124 pts randomized.
100 pts are evaluable for the 8-week DCR endpoint. Accrual updates, demographics, and further details will be presented at the meeting. Supported by NCI R01CA155196-01A1. Clinical trial information:
NCT01248247.

A phase III comparative study of nivolumab (anti-PD-1; BMS-963558; ONO-4538)
versus docetaxel in patients (pts) with previously treated advanced/metastatic
nonsquamous non-small-cell lung cancer (NSCLC).
Scott N. Gettinger, Julie R. Brahmer, Naiyer A. Rizvi, Neal Ready, Laura Quan Man Chow, Scott J. Antonia,
Marc E. Buyse, Jacek Jassem, Friedrich Graf Finckenstein, Lucio Crinò, Thomas James Lynch; Yale
Cancer Center, New Haven, CT; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
University, Baltimore, MD; Memorial Sloan-Kettering Cancer Center, New York, NY; Duke University
Medical Center, Durham, NC; University of Washington, Seattle, WA; H. Lee Moffitt Cancer Center &
Research Institute, Tampa, FL; International Drug Development Institute, Louvain la Neuve, Belgium;
Medical University of Gdan´sk, Gdan´sk, Poland; Bristol-Myers Squibb, Princeton, NJ; Azienda Ospedaliera
di Perugia, Perugia, Italy
Background: Lung cancer is the leading cause of cancer mortality globally. Non-squamous NSCLC
represents up to 75% of NSCLC cases with most pts diagnosed with advanced disease, which progresses
rapidly following failure of 1st
-line platinum-based doublet (Pt-doublet) chemotherapy. Benefit from current
therapies has reached a plateau with median overall survival (OS) for late stage NSCLC pts of 10-12 months.
Standard 2nd-line therapy (single-agent chemotherapy; eg. docetaxel) results in OS of 8 months. Expression of programmed death-1 (PD-1), an immune checkpoint receptor that negatively regulates T-cell activation, is associated with poor prognosis in NSCLC. Nivolumab, a PD-1 receptor blocking antibody, prevents activation of PD-1 by its known ligands, PD-L1 and PD-L2, and demonstrated durable antitumor activity in NSCLC pts in a phase 1 study (Topalian ST, et al. N Engl J Med 2012). We present a phase III study comparing OS benefit of nivolumab vs docetaxel in pts with metastatic/recurrent non-squamous NSCLC.
Methods: In this study, 574 pts will be randomized 1:1 to receive nivolumab 3 mg/kg IV q 2 weeks (wks)
or docetaxel 75 mg/m2 q 3 wks until disease progression or unacceptable toxicity. Pts will include those
having progressed during/after Pt-doublet 6 bevacizumab (bev) for advanced disease as well as pts with
EGFR-mutant or ALK-rearranged NSCLC who have progressed following treatment with a tyrosine kinase
inhibitor (TKI) and a Pt-doublet 6 bev. Prior maintenance therapy with erlotinib, pemetrexed and/or bev is
allowed. Pts will be stratified by prior use of maintenance therapy and receipt of 1 vs 2 (Pt doublet and TKI) prior lines of therapy. Response will be assessed (modified RECIST 1.1) at 9 wks following treatment
initiation and every 6 wks thereafter until disease progression. The primary objective is to compare the OS
of nivolumab vs docetaxel treated pts. Secondary objectives include comparison of objective response rates, progression-free survival and disease related symptom progression, and evaluation of clinical benefit of nivolumab vs docetaxel in PD-L11 vs PD-L1- tumor subgroups. Clinical trial information: NCT01673867.

A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538)
versus docetaxel in patients with previously treated advanced or metastatic squa-
mous cell non-small cell lung cancer (NSCLC).
Hossein Borghaei, Thomas James Lynch, Naiyer A. Rizvi, Laura Quan Man Chow, Robert Reilly,
Lucio Crinò, Marc E. Buyse, Rana Ezzeddine, Brian Joseph Lestini, Julie R. Brahmer; Fox Chase Cancer
Center, Philadelphia, PA; Yale School of Medicine, New Haven, CT; Memorial Sloan-Kettering Cancer
Center, New York, NY; University of Washington, Seattle, WA; St Mary Medical Center, Langhorne, PA;
Azienda Ospedaliera di Perugia, Perugia, Italy; International Drug Development Institute, Louvain la
Neuve, Belgium; Bristol-Myers Squibb, Wallingford, CT; Bristol-Myers Squibb, Princeton, NJ; Sidney
Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD
Background: NSCLC is the leading cause of cancer death worldwide, exceeding breast, colon and prostate
cancer combined. Most patients (pts) are diagnosed with advanced/recurrent disease. NSCLC therapies have
incrementally improved overall survival (OS), but benefit has reached a plateau (median OS for late stage
pts is just 1 yr). Squamous cell carcinoma (SCC) represents one quarter of NSCLC cases and has limited
treatment options. Pemetrexed and bevacizumab are not approved in SCC, and molecularly targeted
therapies have limited application. Single-agent chemotherapy is standard of care following progression
with platinum-based doublet chemotherapy (Pt-doublet), resulting in median OS of approximately 7 months.
Immune checkpoint blockade in NSCLC may promote tumor regression by reversing tumor-induced
immunosuppression and restoring the antitumor immune response. Programmed death-1 (PD-1), an immune
checkpoint receptor that negatively regulates T-cell activation, is upregulated in tumor infiltrating
lymphocytes; expression of its ligand PD-L1 has been associated with poor prognosis in NSCLC.
Nivolumab, a PD-1 receptor blocking antibody, showed encouraging antitumor activity in SCC pts in a
phase 1 study, with objective responses (ORs) in 4 pts (27%) and stable disease $24 weeks in 1 pt (7%)
(3 mg/kg; n515) (Gettinger S et al; ESMO 2012 [Abstr 1237PD]).We describe an ongoing open-label phase
3 study to compare the clinical benefit of nivolumab vs docetaxel in advanced/metastatic SCC pts following
failure of Pt-doublet. Methods: A total of 264 pts will be randomized 1:1 to nivolumab monotherapy 3
mg/kg IV every 2 weeks or docetaxel 75 mg/m2
every 3 weeks until disease progression or unacceptable
toxicity. Pts will be stratified by prior paclitaxel use and geographic region. Tumor response will be assessed
using modified RECIST 1.1. The co-primary objectives are OR rate and OS. Secondary objectives include
progression free survival, clinical benefit in PD ligand 1 (PD-L11) and PD-L1– subgroups (archived tissue
required for entry), durability of and time to OR, and pt proportion with symptom improvement. Clinical
trial information: NCT01642004.

谢谢老马！

不错的东西 可惜看不懂 要是有中文的就好了

不要急，下个月国内网站就有会陆续翻译。

老马兄弟是医生吧？这么专业的英文也能读懂哦。佩服！