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乳腺癌：
Breast Cancer - HER2/ER
Breast Cancer - Triple Negative/Cytotoxics/Local Therapy

Breast Cancer-HER2_ER.pdf (1.01 MB, 下载次数: 38)

Breast_Cancer-Triple-Negative.pdf (549.31 KB, 下载次数: 24)

肺癌：
Lung Cancer - Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers
Lung Cancer - Non-Small Cell Metastatic

Lung-Cancer_Non-small_Cell_Loc-Reg.pdf (708.76 KB, 下载次数: 60)

Lung_Cancer-Non-small_Cell_Metastatic.pdf (803.39 KB, 下载次数: 42)

消化道肿瘤：
Gastrointestinal (Colorectal) Cancer
Gastrointestinal (Noncolorectal) Cancer

Gastrointestinal_Noncolorectal_Cancer.pdf (1004.3 KB, 下载次数: 38)

Gastrointestinal_Colorectal_Cancer.pdf (942.19 KB, 下载次数: 35)

泌尿生殖系统、妇科、头颈癌
Genitourinary (Nonprostate) Cancer
Genitourinary (Prostate) Cancer
Gynecologic Cancer
Head and Neck Cancer

Head_and_Neck_Cancer.pdf (640.4 KB, 下载次数: 23)

Genitourinary_Nonprostate_Cancer.pdf (608.29 KB, 下载次数: 37)

Genitourinary_Prostate_Cancer.pdf (639.97 KB, 下载次数: 24)

Gynecologic_Cancer.pdf (712.43 KB, 下载次数: 21)

白血病、淋巴瘤、黑色素瘤、肉瘤、中枢神经系统肿瘤
Leukemia, Myelodysplasia, and Transplantation
Lymphoma and Plasma Cell Disorders
Melanoma/Skin Cancers
Central Nervous System Tumors
Sarcoma

Sarcoma.pdf (605.13 KB, 下载次数: 33)

Melanoma_Skin_Cancers.pdf (671.86 KB, 下载次数: 44)

Lymphoma_and_Plasma_Cell_Disorders.pdf (749.59 KB, 下载次数: 41)

Leuk_Myelod_and_Transplant.pdf (812.34 KB, 下载次数: 36)

Central_Nervous_System_Tumors.pdf (667.02 KB, 下载次数: 28)

儿童肿瘤、病人和生存者照料、临床药理学、免疫治疗
Pediatric Oncology
Patient and Survivor Care
Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics
Developmental Therapeutics - Immunotherapy

Pediatric_Oncology.pdf (466.68 KB, 下载次数: 35)

Patient_and_Survivor_Care.pdf (890.67 KB, 下载次数: 24)

Dvlpmntl_Therap-Immuno.pdf (849.48 KB, 下载次数: 39)

Dvlpmntl_Therap-Clin_Pharmacol_and_Exper_Therap.pdf (787.07 KB, 下载次数: 34)

老马 · 发表于 2013-5-18 11:32:52

Patterns of metastasis and survival in patients with PI3K pathway-driven stage IV
squamous cell lung cancers (SQCLC).
Paul K. Paik, Andre L. Moreira, Lu Wang, Helen H. Won, Adnan Hasanovic, Natasha Rekhtman,
Camelia S. Sima, Marc Ladanyi, Michael F. Berger, Mark G. Kris; Memorial Sloan-Kettering Cancer
Center, New York, NY; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer
Center, New York, NY
Background: The majority of actionable drivers in SQCLCs occur in the PI3K (30%) and FGFR1 (20%)
pathways. The biologic behaviors and natural histories of these oncogenic subtypes are not well
characterized. Methods: As of October 2011, all patients with SQCLCs at MSK have undergone
prospective, multiplex testing of their FFPE tumors for FGFR1 amplification (FISH), PIK3CA mutations
(Sequenom), PTEN loss (IHC), and PTEN mutations (exon sequencing), among others. Patient character-
istics, outcomes, and metastatic sites were identified. Survival probabilities were estimated using the
Kaplan-Meier method. Group comparisons were performed with log-rank tests and Cox proportional
hazards methods. Results: 68 stage IV SQCLC patients were analyzed. 39 had tissue sufficient for next-gen
sequencing. Genotypes were: FGFR1 amplified (16%); PTEN loss (24%), PIK3CA mutant (7%), PTEN
mutant (13%). Events were non-overlapping save for 2 cases with PTENnonsense mutations and PTEN loss.
The sole significant clinical difference (KPS, age, sex, lines of tx) was sex (women in PI3K group 52% vs.
in others 23%, p50.02). Metastatic patterns vs. other are shown in the Table. Median OS for PI3K vs. other:10mo (95%CI:6.5-14.3) vs. 14mo (95%CI:9.6-36.7), p50.02. Median OS for FGFR1 vs. others: 19mo
(95%CI:9-NR) vs. 10mo (95%CI:6.5-14.3), p50.3. Multivariate analysis for OS: PI3K vs. other, HR
death52.3 (95%CI:1.1-4.8, p50.03); Age $65, HR51.3 (95%CI:0.6-2.9, p50.6); KPS$70, HR50.5
(95%CI:0.2-1.7, p50.3); Male sex, HR50.7 (95%CI:0.3-1.4, p50.3). Conclusions: Patients with stage IV
PI3K-aberrant SQCLCs have poorer survival compared to other patients with SQCLCs. Brain metastases
occurred exclusively in patients with PI3K-aberrant tumors. These data suggest that PI3K pathway
activation confers a distinct biology, and that targeting this in SQCLC patients with brain metastases may
be an effective therapeutic strategy.

老马 · 发表于 2013-5-18 11:35:49

Two parallel randomized phase II studies of selumetinib (S) and erlotinib (E) in
advanced non-small cell lung cancer selected by KRAS mutations.
Corey Allan Carter, Arun Rajan, Eva Szabo, Sean Khozin, Anish Thomas, Christina E. Brzezniak,
Udayan Guha, L. Austin Doyle, Corrine Keen, Seth M. Steinberg, Liqiang Xi, Mark Raffeld,
Karen L. Reckamp, Stephen Koehler, Barbara Jennifer Gitlitz, Ravi Salgia, David R. Gandara,
Everett E. Vokes, Giuseppe Giaccone; Walter Reed National Military Medical Center, Bethesda, MD;
National Cancer Institute, Bethesda, MD; National Cancer Institute CTEP, Rockville, MD; Biostatistics and
Data Management Section, CCR, National Cancer Institute, Bethesda, MD; Molecular Diagnostics Core
Laboratory, CCR, NCI, NIH, Bethesda, MD; Medical Oncology, City of Hope Comprehensive Cancer
Center, Duarte, CA; City of Hope, Duarte, CA; University of Southern California Norris Comprehensive
Cancer Center, Los Angeles, CA; The University of Chicago, Chicago, IL; University of California, Davis
Comprehensive Cancer Center, Sacramento, CA; The University of Chicago Medicine and Biological
Sciences, Chicago, IL
Background: KRAS mutations are present in 20% of NSCLC and are associated with primary resistance
to erlotinib (E). KRAS mutations result in constitutive activation of the Ras/Raf/MEK/ERK pathway.
Selumetinib (S) (AZD6244, ARRY-142886) is a selective and uncompetitive inhibitor of MEK kinase.
Preclinical studies demonstrated increased activity in NSCLC cell lines using S1E regardless of KRAS
status. Methods: Advanced NSCLC patients with progressive disease after platinum based chemotherapy
1/- one other treatment were stratified by KRAS status, which was centrally assessed using macrodissection and pyrosequencing for all mutations involving codons 12, 13, and 61. Patients were randomized to receive either the standard of care E or a combination of S1E in KRAS wild type (wt) and S alone or S1E in
patients with KRAS mutations. Single agent E and S were administered orally at 150 mg daily and 75 mg
twice daily respectively. Combination dosing were S 150 mg every morning and E 100 mg every evening.
The primary endpoint for the KRAS wt group was PFS and for the KRAS mutant group objective response
rate. Results: From March 2010 to January 2013, 79 patients screened; 78 enrolled: KRAS mutant, 39;
KRAS wt, 40; M/F (39:39); median age: 64 years (33-84); median WHO PS 1(0-2); 66 former and 13 never
smokers; 67 adenocarcinoma, 9 squamous cell. Three patients died of complications prior to first evaluation (1 coronary disease, 1 pulmonary fibrosis, and 1 disease progression) of which none were related to S. Dose reductions occurred in 5% E, 40% S, and 56% E1S. Most grade 3/4 AEs occurred in combination therapy; diarrhea (23%), fatigue (23%) lymphopenia (13%), myositis (10%), dyspnea (10%), rash (7%). Discontinuation due to AEs was 8% all occurring in S1E cohorts.
Conclusions: This study failed to show improvement of combination therapy over single agent in KRAS wt and mutant patients. Toxicity was increased in the combination arms. Interestingly, the KRAS mutant cohort had longer PFS than KRAS wt patients, although not statistically significant (p50.11). Clinical trial information: NCT01229150.

老马 · 发表于 2013-5-18 11:38:47

Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pem-
etrexed for KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer
(NSCLC): A phase I/Ib trial.
Karen Kelly, Julien Mazieres, Natasha B. Leighl, Fabrice Barlesi, Gerard Zalcman, Michael S. Gordon,
Karen L. Reckamp, David R. Gandara, Carlos Alberto Gomez-Roca, Jaafar Bennouna, Byoung Chul Cho,
Keunchil Park, Jeffrey R. Infante, Donald A. Richards, Yuehui Wu, Daniel J. Schramek, Donna S. Cox,
Olivia S. Gardner, Vijay Gopal Reddy Peddareddigari, George R. Blumenschein; Division of Hematology
and Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA; Hôpital Larrey CHU Toulouse,
Toulouse, France; Princess Margaret Cancer Center, Toronto, ON, Canada; Aix Marseille University,
Assistance Publique Hôpitaux de Marseille, Hôpital Nord, Marseille, France; Caen University Hospital,
Caen, France; Pinnacle Oncology Hematology, Scottsdale, AZ; Medical Oncology, City of Hope
Comprehensive Cancer Center, Duarte, CA; University of California, Davis Comprehensive Cancer Center,
Sacramento, CA; Institut Claudius Regaud, Toulouse, France; Institut de Cancerologie de l’Ouest, Nantes,
France; Yonsei University College of Medicine, Seoul, South Korea; Samsung Medical Center, Sungkyunk-
wan University School of Medicine, Seoul, South Korea; Sarah Cannon Research Institute; Tennessee
Oncology, Nashville, TN; Texas Oncology, Houston, TX; GlaxoSmithKline, Collegeville, PA; Department
of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center,
Houston, TX
Background: Lung cancer patients with mutated KRAS tumors present a treatment challenge. Trametinib
1 pemetrexed (pem) enhanced growth inhibition and apoptosis compared with either agent alone in lung
cancer cell lines with WT or mutated RAS/RAF. Methods: This 2-part, multiarm, phase I/Ib, open-label
study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib 1 pem in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were stratified as KRASWT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with trametinib 1 pem at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free DNA from plasma and available archival tumor tissue. Results: As of January 2013, 42 NSCLC pts (22 WT [82% had $ 2 prior therapies], 20 KRAS [55% had $ 2 prior therapies]) have been treated at the trametinib 1 pem RP2D (1.5 mg 1 500 mg/m2). Nausea, fatigue, and peripheral edema were the 3 most frequent toxicities. 26% of pts reported grade 3-4 hematologic toxicity. Dose reduction occurred in 15 pts (33%), most often for diarrhea, decreased ejection fraction, and fatigue (all 7%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed 1 unconfirmed) was 3 partial response (PR; RR 5 15%) and 10 stable disease (SD; 50%); additionally, 3 pts had . 20% tumor shrinkage. The disease control rate (DCR) was 65%. Final response and progression-free survival (PFS) data will be reported upon maturity. In WT pts, 3 PR (RR 5 14%) and 13 SD (59%) were observed (73% DCR); preliminary median PFS was 5.8 months (95% CI, 2.8-6.7 months). Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing.
Conclusions: MEK inhibition with trametinib 1 pem demonstrates tolerability and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and warranting further study. Clinical trial information: NCT01192165.

老马 · 发表于 2013-5-18 11:39:50

Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with do-
cetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer
(NSCLC): A phase I/Ib trial.
David R. Gandara, Sandrine Hiret, George R. Blumenschein, Fabrice Barlesi, Jean-Pierre Delord,
Jeannick Madelaine, Jeffrey R. Infante, Karen L. Reckamp, Primo Lara, Christine Audebert,
Byoung Chul Cho, Keunchil Park, Fadi S. Braiteh, Robert M. Jotte, Yuehui Wu, Daniel J. Schramek,
Alexandra M. Piepszak, Olivia S. Gardner, Vijay Gopal Reddy Peddareddigari, Natasha B. Leighl;
University of California, Davis Comprehensive Cancer Center, Sacramento, CA; Institut de Cancérologie
de l’Ouest, Saint Herblain, France; Department of Thoracic Head and Neck Medical Oncology, The
University of Texas MD Anderson Cancer Center, Houston, TX; Aix Marseille University, Assistance
Publique Hôpitaux de Marseille, Hôpital Nord, Marseille, France; Institut Claudius Regaud, Toulouse,
France; Caen University Hospital, Caen, France; Sarah Cannon Research Institute; Tennessee Oncology,
Nashville, TN; Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA; Division of
Hematology and Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA; Yonsei University
College of Medicine, Seoul, South Korea; Samsung Medical Center, Sungkyunkwan University School of
Medicine, Seoul, South Korea; Comprehensive Cancer Centers of Nevada, Las Vegas, NV, and US
Oncology Research, Houston, TX; Rocky Mountain Cancer Centers; US Oncology Research, Houston, TX;
GlaxoSmithKline, Collegeville, PA; Princess Margaret Cancer Center, Toronto, ON, Canada
Background: KRAS-mutant NSCLC, usually reflecting tobacco-related carcinogenesis, represents an unmet
medical need in lung cancer therapy. Trametinib plus docetaxel (doc) enhances growth inhibition and
apoptosis of NSCLC cell lines in vitro with and without RAS/RAF mutations when compared with either
agent alone. Methods: This 2-part, multiarm, phase I/Ib, open-label study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib1doc in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were
stratified as KRAS WT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with
trametinib 1 doc at the RP2D. Primary study objectives were safety and tolerability; secondary objectives
were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free
DNA from plasma and available archival tumor tissue. Results: As of January 2013, 46 NSCLC pts (24 WT
[67% had $ 2 prior therapies] and 22 KRAS [41% had $ 2 prior therapies]) have been treated at the
trametinib 1 doc RP2D (2.0 mg 1 75 mg/m2 1 growth factors). Diarrhea, fatigue, asthenia, and nausea
were the 4 most frequent toxicities. Dose reduction occurred in 10 pts (22%), mostly for diarrhea, fatigue,
mucositis, neutropenia, and skin fissures (all 4%). Preliminary PK suggests no drug-drug interaction. In
KRAS pts, the best investigator-assessed response (confirmed 1 unconfirmed) was 3 partial response (PR;
RR 5 17%) and 8 stable disease (SD; 44%); additionally, 4 pts had . 20% tumor shrinkage. The current
disease control rate (DCR) is 61%; 4 pts have not had postbaseline scans. In WT pts, 5 PR (RR521%) and
11 SD (46%) were observed (67% DCR). Final response and progression-free survival data will be reported
upon maturity. Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are
ongoing.
Conclusions: MEK inhibition with trametinib 1 doc (1 growth factors) demonstrates tolerability
and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and
warranting further study. Clinical trial information: NCT01192165.

老马 · 发表于 2013-5-18 11:40:49

MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety
of trametinib (T) compared with docetaxel (D) in KRAS-mutant advanced non–small
cell lung cancer (NSCLC).
George R. Blumenschein, Egbert F. Smit, David Planchard, Dong-Wan Kim, Jacques Cadranel,
Tommaso De Pas, Frank Dunphy, Katalin Udud, Myung-Ju Ahn, Nasser H. Hanna, Joo-Hang Kim,
Julien Mazieres, Sang-We Kim, Paul Baas, Erica Rappold, Suman Redhu, Kevin M. Bellew,
Michael R. W. Streit, Frank S. Wu, Pasi A. Janne; Department of Thoracic Head and Neck Medical
Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; VU University Medical
Center, Amsterdam, Netherlands; Department of Medical Oncology, Institut Gustave Roussy, Villejuif,
France; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Service
de Pneumologie and GRC-04 Theranoscan, Pierre et Marie Curie Université, Hôpital Tenon, Paris,
France; European Institute of Oncology, Milano, Italy; Duke University Medical Center, Durham, NC;
Korányi National Institute of Pulmonology, Budapest, Hungary; Department of Medicine, Division of
Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
South Korea; Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN; Department of
Internal Medicine (Medical Oncology), Yonsei Cancer Research Institute, Yonsei Cancer Center, Seoul,
South Korea; Hôpital Larrey CHU Toulouse, Toulouse, France; Department of Oncology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, South Korea; Netherlands Cancer Institute,
Amsterdam, Netherlands; GlaxoSmithKline, Collegeville, PA; Dana-Farber Cancer Institute, Boston, MA
Background: KRAS mutations are detected in 25% of NSCLC, and there are no approved targeted therapies
for this subset of NSCLC. D, an approved second-line treatment for NSCLC, has a response rate of , 10%.
T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. This phase
II trial (NCT01362296) evaluated the efficacy of T vs D in pts with advanced KRAS-mutant NSCLC who
had received prior platinum-based chemotherapy. Methods: Pts were randomized 2:1 to T (2 mg QD) or D
(75 mg/m2
IV every 3 weeks) and stratified by type of mutational status and gender. Crossover to the other
arm after progressive disease was allowed. Primary endpoint was PFS in pts with KRAS-mutant NSCLC
(modified ITT; mITT). Secondary endpoints were OS, ORR, duration of response, and safety. PFS and OS
were compared using a stratified log-rank test. The trial was stopped early for futility at a planned interim
analysis; 92 PFS events were reported at the time of study termination. Results: Between September 2011
and July 2012, 134 pts were randomized to T (89) or D (45); 129 pts had KRAS-mutant NSCLC. Mean age
was 61.4 y and 53% were male. In the mITT, 61/86 pts (71%) on T and 31/43 (72%) on D had a PFS event.
HR for PFS was 1.14 (95% CI, 0.75-1.75; P 5 .5197) with a median PFS of 11.7 vs 11.4 wk for T vs D.
ORR was 12% for T (10/86) and for D (5/43). With 27 (31%) deaths on T and 15 (35%) on D, HR for OS
was 0.97 (95% CI, 0.52-1.83; P5 .934). Five fatal SAEs were reported during treatment with T but none
with D; 1 unspecified death was considered related to T. Frequent AEs reported with T were rash (59%),
diarrhea (47%), nausea (34%), hypertension (34%), and dyspnea (33%). Grade 3/4 AEs with T were
hypertension (16%/0), dyspnea (7%/3%), rash (6%/3%), diarrhea (6%/0), and asthenia (6%/0). Rate of
treatment related SAEs was 15% with T and 12% with D.
Conclusions: T did not improve PFS in pts with KRAS-mutation–positive NSCLC compared with D. However, an ORR of 12% for T in KRAS-mutant NSCLC suggests that an effort to better identify responsive mutations is warranted. The safety profile did not favor T, but is, in general, consistent with the overall T safety profile. Clinical trial information NCT01362296.

老马 · 发表于 2013-5-18 11:48:21

Retrospective evaluation of RET biomarker status and outcome to vandetanib in
four phase III randomized NSCLC trials.
Adam Platt, Paul Elvin, John Morten, Qunsheng Ji, Emma Donald, Chris Womack, Xinying Su, Li Zheng,
Amanda Gladwin, James Robert Vasselli, Jin Soo Lee, Richard H. De Boer, Roy S. Herbst, The RET
Analysis Team; AstraZeneca, Macclesfield, United Kingdom; Innovation Cancer Center, AstraZeneca R&D,
Shanghai, China; AstraZeneca, Wilmington, DE; National Cancer Center, Gyeonggi, South Korea;
Department of Hematology & Medical Oncology, Western Hospital, Victoria, Australia; Yale Cancer
Center, New Haven, CT
Background: The prevalence of the tumorigenic KIF5B:RET fusion gene in NSCLC tumors has been
estimated at 0.2–6% (Jiu et al 2012; Lipson et al 2012). We retrospectively analyzed tumor samples from
4 Phase III NSCLC trials of vandetanib, a TKI that selectively targets RET, VEGFR and EGFR signaling,
to determine the prevalence of RET fusions and other RET biomarkers, and any potential association with
outcome to vandetanib (V). Methods: The studies evaluated were ZODIAC (NCT00312377; docetaxel 6
V 100mg), ZEAL (NCT00418886; pemetrexed 6 V 100mg), ZEPHYR (NCT00404924; V 300mg vs
placebo) and ZEST (NCT00364351; V 300mg vs erlotinib). RET biomarkers evaluated included RET
fusions (including KIF5B:RET) and RET gene copy number (assessed by a 4-probe FISH assay), as well as
RET protein expression (by IHC). Results: Of 4089 patients randomized across the 4 studies, 1291 and 1234
had tumor samples available for FISH and IHC analysis, respectively, with evaluable data obtained for 944
and 1102. RET fusions (in .10% of tumor cells) were detected in 7 of 944 samples (vandetanib, n53;
comparator, n54), at a prevalence of 0.7% (95% CI, 0.3–1.5%). None of the 3 vandetanib-treated RET
fusion-positive patients had an objective RECIST response, although there was radiologic evidence of tumor
shrinkage in 2. Overall, 2.8% (n526) of samples had RET amplification (innumerable RET clusters, or $7
copies in .10% tumor cells), 8.1% (n576) had lower RET gene copy number gain (4–6 copies in $40%
tumor cells) and 8.3% (n592) were RET expression positive (signal intensity 11 or 111 in .10% of
tumor cells). There was no difference in ORR between vandetanib and comparator for the RET
amplification-positive subset (both 8.3% [1/12]), the RET copy number gain subset (9.8% [4/41] vs 9.1%
[3/33], respectively) or the RET protein expression-positive subset (15.2% [7/46] and 13.6% [6/44],
respectively).
Conclusions: The prevalence of RET fusions was estimated at 0.7%. There were too few
vandetanib-treated patients with RET fusions to make any firm conclusion regarding association with
efficacy. Evidence from the other RET biomarkers tested suggested that these do not infer a differential
advantage in patients treated with vandetanib. Clinical trial information: NCT00312377; NCT00418886;NCT00404924

老马 · 发表于 2013-5-18 11:50:41

Occurrence of HER2 amplification in EGFR-mutant lung adenocarcinoma with
acquired resistence to EGFR-TKIs.
Giuseppe Altavilla, Carmela Arrigo, Chiara Tomasello, Mariacarmela Santarpia, Patrizia Mondello,
Sara Benecchi, Vincenzo Pitini; Medical Oncology University of Messina, Messina, Italy; Medical
Oncology, Messina, Italy
Background: Patients with EGFR-mutant lung adenocarcinoma develop progression of disease on TKIs
therapy after a median of 12 months;this acquired resistance is mainly due to a secondary mutation in EGFR (T790 M) in about 50% of patients, amplification of MET in 15%, PIK3CA mutations in 5%, an unknown mechanism in almost 30% and a SCLC transformation in some pts. Recently, Takezawa and colleagues pointed out that HER2 amplification is a mechanism of acquired resistance to EGFR inhibition in
EGFR-mutant lung cancers without EGFR T790M mutation. To aid in identification and treatment of these
patients we examined a cohort of patients whose cancers were assessed with tumor biopsies at multiple times before and after their treatment with TKIs. Methods: 41 lung adenocarcinomas pts. (20 male, 21 female, median age 55 years) with EGFR mutations at 19 or 21 exons received TKIs as first line of treatment. 31 pts. (75%) showed a clinical response and relapsed after a mTTP of 12 months. At the time of relapse a new biopsy was performed, histologic samples were reviewed to re-confirm the diagnosis, EGFR, MET and HER-2 amplification were identified by FISH, while EGFR mutations have been tested by DNA sequencing.
Results: At the time that drug resistence was acquired all 31 pts. retained their original activating EGFR
mutations, 16 pts. developed EGFR T790M resistance mutation with pronunced EGFR amplification in 5,
4 pts. developed MET amplification, 3 pts. were found to have a diagnosis of small cell lung cancer. HER2
amplification was observed in four pts. (13%), with dramatic progression and a median OS of 5 months after treatment with CDDP 1 pemetrexed. Notably all 4 cases were EGFR T790M negative.
Conclusions:
Among pts. with acquired resistence to EGFR TKIs the presence of HER2 amplification defines a clinical
subset with a more adverse prognosis and rapid progression. Interestingly, recent data suggest that afatinib combined with cetuximab could have promising activity in pts. with acquired resistance due to HER2 amplification.

老马 · 发表于 2013-5-18 11:56:47

Final overall survival (OS) results of a noncomparative phase II study of bevaci-
zumab (B) plus first-line chemotherapy or second-line erlotinib (E) in nonsquamous
NSCLC (ns-NSCLC) patients with asymptomatic untreated brain metastases (BM)
(BRAIN).
Benjamin Besse, Sylvestre Le Moulec, Hélène Senellart, Julien Mazieres, Fabrice Barlesi, Eric Dansin,
Gilles Robinet, Maurice Perol, Denis Moro-Sibilot, Jean-Charles Soria; Institut Gustave Roussy, Villejuif,
France; Val-de-Grâce Hospital, Paris, France; Institut De Cancérologie De l’Ouest, Site René Gauduch-
eau, Nantes, France; Toulouse University Hospital, Toulouse, France; Aix Marseille University, Assistance
Publique Hôpitaux de Marseille, Marseille, France; Centre Oscar Lambret, Lille, France; Institut de
Cancerologie CHU Morvan, Brest, France; Centre Léon Bérard, Lyon, France; Centre Hospitalier
Universitaire Grenoble, Thoracic Oncology Unit, Grenoble, France
Background: The non-comparative BRAIN study (NCT00800202) is the first trial to evaluate efficacy/
acceptable safety of B in pts with ns-NSCLC and untreated BM. We report final efficacy/safety results.
Methods: Eligible pts (stage IV ns-NSCLC; PS 0–1; untreated, asymptomatic BM ineligible for
surgery/radiosurgery) received until unacceptable toxicity/disease progression: 1st-line B #6 cycles
(15mg/kg q3w) plus carboplatin (AUC 6 q3w) and paclitaxel (200mg/m2 q3w; B1CP; n567); or 2nd-line
B plus E (150mg/day; B1E; n524). Primary endpoint is 6-month progression-free survival (PFS).
Six-weekly assessments included mandatory brain MRI. The trial could be halted if there were .3 (B1CP)
or .2 (B1E) brain hemorrhages (ICH). Results: Baseline (BL) characteristics are reported. With a median
follow-up of 16.3 (B1CP) and 11.8 months (B1E), efficacy data are summarized. Adverse events (AE)
were comparable with those in previous trials of B. Only 1 grade $3 bleeding AE (grade 3, extracranial site;B1E) and only one ICH event (grade 1, resolved; B1CP) occurred. Most frequent cause for B withdrawal was progression: intracranial only in 20.9% (B1CP) and 16% (B1E); extracranial only in 50.7% (B1CP) and 54.2 % (B1E).
Conclusions: The final BRAIN results demonstrate promising efficacy and acceptable safety of B with 1st-line chemotherapy or 2nd-line E in ns-NSCLC pts with asymptomatic untreated BM. Clinical trial information: NCT00800202.

老马 · 发表于 2013-5-18 12:06:47

Multitargeted antiangiogenic tyrosine kinase inhibitors in advanced non-small cell
lung cancer: A meta-analysis of randomized controlled trials.
Wenhua Liang, Li Zhang; Cancer Center, Sun Yat-Sen University, Guangzhou, China; Sun Yat-sen
University Cancer Center, Guangzhou, China
Background: Novel multitargeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have showed
promising advantages in combination with chemotherapy or as monotherapy in treatments of advanced
non-small cell lung cancer (NSCLC). Since the efficacy and safety of these small molecules have been
evaluated by several phase II/III randomized controlled trials (RCTs), we seek to summarize the current
evidences by performing a meta-analysis. Methods: PubMed, EMBASE, the Cochrane Library as well as
the ASCO and ESMO databases were searched for eligible literatures. We defined the experimental arm as
MATKI-containing group while the control arm as MATKI-free group. The endpoints being evaluated
included overall survival (OS), progression free survival (PFS), objective response rate (ORR) and disease
control rate (DCR), as well as adverse events (AEs). Pooled hazard ratios (HRs) for survival outcomes and
odds ratio (ORs) for dichotomous data, with 95% confidence intervals (CI) were calculated using REVMAN
5.0. Subgroup analysis was conducted according to each agent respectively. Results: Five agents
(vandetanib, sunitinib, cediranib, sorafenib, motesanib) with comparable data could be analyzed. Fifteen
phase II/III RCTs that involved a total of 8854 participants were included. Compared to MATKI-free group,
MATKI-containing group was associated with significant longer PFS (HR 0.824, 95% CI 0.759 to 0.895,
P,0.001), superior ORR (OR 1.27, 95% CI 1.13 to 1.42, P,0.0001) and DCR (OR 1.14, 95% CI 1.04 to
1.25, P50.006). However, although some improvement in OS was observed, the benefit did not reach
statistical significance (HR 0.962, 95% CI 0.912 to 1.015, P50.157). In terms of subgroup results, sorafinib
was revealed to yield no improvement in all endpoints. The specific AEs in patients who received these
agents were rash, diarrhea and hypertension.
Conclusions: Regimens consisting of multitargeted antiangiogenic TKIs were superior to those without these agents in terms of tumor response and PFS in patients with advanced NSCLC. However, no significant benefits in OS were observed. In addition, sorafinib seemed to has no substantial efficacy for NSCLC patients.