2015年肿瘤治疗资料集中贴

Targeting KRAS mutant non-small cell lung cancer (NSCLC) with deltarasin: A small molecule inhibitor of KRAS-PDEδ interaction.
Sub-category:
Signal Transduction
Category:
Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
Meeting:
2015 ASCO Annual Meeting
Abstract No:
e13597
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr e13597)
Author(s): Jun Zhang, Ke Xu, Dong Moon Shin, Xingming Deng; Winship Cancer Inst Emory Univ School of Medcn, Atlanta, GA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA; Winship Cancer Inst At Emory Univ, Atlanta, GA; Winship Cancer Institute, Emory University, Atlanta, GA
Abstract Disclosures
Abstract:
Background: As oncogenic KRAS relies on the correct spatial localization to exert its function, disrupting the transport of KRAS to the cell membrane may provide a new approach to target KRAS mutant NSCLC. Recent study has shown deltarasin, a small molecular inhibitor, can suppress oncogenic KRAS signaling by disrupting the interaction between KRAS and its transporter PDEδ, thereby altering its localization to endomembranes (Zimmermann et al, Nature 2013). Here we investigated whether deltarain has anti-tumor effect on KRAS mutant NSCLC. Methods: NSCLC cell lines with various KRAS mutations (Calu-1, H358, H1792, H157, H460 and A549) or wild type KRAS (H292 and H1975), as well as immortalized bronchial epithelial cell line Beas2B (wild type KRAS) were used in the study. MTT and SRB assays were used to analyze cell proliferation and IC50. Flow cytometry and immunoblotting were used to investigate relevant signaling pathways as well as potential mechanisms involved in cell death. Results: Probably due to small sample size, the difference of IC50 between the KRAS mutant vs. wild type cell lines was not statistically significant. However, after we treated the cells with 5μM deltarasin for 48 hrs, 5 out of 6 KRAS mutant NSCLC lines had cell viability below 20%, but all 3 cell lines with wild type KRAS (including Beas2B) were above 20% (p = 0.0476), suggesting potential mutant-selective effect of deltarasin. When we compared KRAS mutant (H358) vs. wild type (H292) NSCLC cells in parallel, treatment with 3μM of deltarasin for 48 hrs resulted in ~ 6 times more apoptotic cells of H358 (p < 0.01), but less than 2 folds of H292 cells (p > 0.05) comparing to their baseline levels. This observation correlated to the potent inhibition of both phospho-ERK and phospho-AKT, as well as significant induction of cleaved PARP in H358 cells, which did not happen in H292 cells under similar condition. Interestingly, treatment with deltarasin didn’t change the levels of total RAS and KRAS. This is consistent with the known effect of deltarasin – it targets RAS localization rather than RAS itself. Conclusionseltarasin, a small molecule inhibitor of KRAS-PDEδ interaction, provides a unique opportunity to target KRAS mutant NSCLC.

First-in-human phase I study of EGF816, a thirdgeneration, mutant-selective EGFR tyrosine kinase inhibitor, in advanced non-small cell lung cancer (NSCLC) harboring T790M.
Sub-category:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Abstract No:
8013
Poster Board Number:
Board #335
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr 8013)
Author(s): Daniel Shao-Weng Tan, Takashi Seto, Natasha B. Leighl, Gregory J. Riely, Lecia V. Sequist, Enriqueta Felip, Juergen Wolf, James Chih-Hsin Yang, Igor Matushansky, Xiaolu Yu, Shu-Fang Hsu Schmitz, Xiaoming Cui, Dong-Wan Kim; National Cancer Centre Singapore, Singapore, Singapore; National Kyushu Cancer Center, Fukuoka, Japan; Princess Margaret Hospital, Toronto, ON, Canada; Memorial Sloan Kettering Cancer Center, New York, NY; Massachusetts General Hospital, Boston, MA; Vall d'Hebron University Hospital, Barcelona, Spain; Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital Cologne, Cologne, Germany; National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; Novartis Pharmaceuticals Corporation, East Hanover, NJ; China Novartis Institutes for BioMedical Research, Shanghai, China; Novartis Pharma AG, Basel, Switzerland; Seoul National University Hospital, Seoul, South Korea
Abstract Disclosures
Abstract:
Background: The emergence of T790M resistance mutations (mt) occurs in up to 50% of patients (pt) with NSCLC harboring a sensitizing EGFR mt treated with erlotinib or gefitinib. EGF816 is a covalent, irreversible, EGFR TKI that has nanomolar inhibitory potency against activating mt (L858R, ex19del) and T790M mt, with up to 60-fold selectivity over wild type (wt) EGFR in vitro. Methods:This multicenter, dose escalation study to determine the safety, tolerability and antitumor activity of EGF816, enrolled NSCLC pts with locally or centrally confirmed T790M status. Oral EGF816 was administered on a continuous 28-day schedule. Dose escalation started from 75 mg QD and was guided by an adaptive Bayesian logistic regression model to determine the maximum tolerated dose. Paired tumor biopsies were performed to evaluate pharmacodynamics. NCT02108964. Results: As of 26 Jan 2015, 57 pts have been treated (51 capsules, CAP; 6 tablets, TAB) across 6 cohorts (75, 150, 225, 300, and 350 mg for CAP; 225 mg for TAB). At the 4 Dec 2014 cutoff, 40 pts were evaluable for safety, median age 58.5y (range 34–76), 48% male and 80% East Asian. 2/6 pts experienced DLT at 350 mg (rash, n = 2; acute renal injury, n = 1). The most common adverse events (AE) regardless of study drug relationship were diarrhea (25%), stomatitis (22.5%), rash (17.5%) and pruritus (15%). The most common Grade 3/4 drug-related AE was rash (5%). RECIST responses and reduced pEGFR were observed at all dose levels. Amongst 22 evaluable pts, including 1 with de novoT790M mt, ORR (including unconfirmed responses) and disease control rate was 54.5% and 86.4% respectively. Only 1 pt experienced progressive disease at first evaluation – repeat testing revealed the tumor to be EGFR wt. PK shows rapid absorption with a median Tmax of 3h and dose-proportional increases in Cmax and AUC(0-tau) observed after single and multiple dosing. Conclusions: EGF816 is well tolerated with a manageable safety profile and antitumor activity against T790M mt NSCLC across all dose levels examined. Further study is ongoing to establish the optimal dose range to maximize therapeutic potential and facilitate future combinations. Clinical trial information:NCT02108964
TIGER 1: A randomized, open-label, phase 2/3 study of rociletinib (CO-1686) or erlotinib as first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC).
Sub-category:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Abstract No:
TPS8108
Poster Board Number:
Board #430a
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr TPS8108)
Author(s): D. Ross Camidge, Juergen Wolf, Jason B. Litten, Linda A Higashi, Jeffrey D. Isaacson, Tony Mok; University of Colorado Cancer Center, Aurora, CO; Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital Cologne, Cologne, Germany; Clovis Onccology, San Francisco, CA; Clovis Oncology, Englewood, NJ; Clovis Onc, Boulder, CO; Chinese University of Hong Kong, Shatin, Hong Kong
Abstract Disclosures
Abstract:
Background: Activating EGFR mutations including exon 21 L858R and exon 19 deletions (del19) are key drivers of NSCLC in 10%–15% of patients (pts) of European and 30%–35% of Asian descent.1Acquired resistance (AR) to first-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib is driven by additional EGFR mutations, with exon 20 T790M accounting for 60%–70% of cases.2Rociletinib (CO-1686) was designed to inhibit T790M as well as L858R and del19 while sparing wild-type EGFR and has demonstrated response rates up to 67% and is well tolerated in pts with AR to EGFR-TKIs during dose-finding studies.3TIGER 1 will evaluate whether rociletinib can improve progression-free survival (PFS) in the first-line setting. Novel exploratory endpoints include tumor kinetics, treatment post-progression, circulating tumor DNA, and blood-based biomarkers. Methods: Pts with histologically or cytologically confirmed metastatic or unresectable locally advanced recurrent NSCLC (no prior EGFR TKI therapy and no CNS disease), with documentation of ≥ 1 activating EGFR mutation (excluding exon 20 insertions) will be enrolled in this phase 2, open-label study (NCT02186301). Pts will be randomized 1:1 to rociletinib (625 mg) twice daily or erlotinib (150 mg) once daily until disease progression according to RECIST 1.1. Pts will be stratified by sensitizing EGFR mutation (T790M, del19, L858R, or other) and race (Asian vs non-Asian). The primary endpoint is PFS; secondary endpoints include efficacy as determined by objective response rate, duration of response, disease control rate and overall survival, and PFS in pts with baseline T790M mutations detected using allele-specific PCR. PFS and OS will be summarized with Kaplan-Meier plots. The stratified log-rank and hazard ratio will compare PFS distributions for rociletinib- vs erlotinib-treated pts. Safety will be assessed via standard adverse event reporting. Planned enrollment is for phase 2 is 200 pts up to 1000 for phase 3. Enrollment is underway with multiple patients in screening.
Herbst R et al. N Engl J Med. 2008
Yu H et al. Clin Cancer Res. 2013
Sequist LV J Clin Oncol. 2014
Clinical trial information: NCT02186301

TIGER-3: A phase 3, open-label, randomized study of rociletinib vs cytotoxic chemotherapy in patients (pts) with mutant EGFR non-small cell lung cancer (NSCLC) progressing on prior EGFR TKI therapy and doublet chemotherapy.
Sub-category:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Abstract No:
TPS8109
Poster Board Number:
Board #430b
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr TPS8109)
Author(s): James Chih-Hsin Yang, Sanjay Popat, Panos Georgiou, Emiko Miyamoto, Jeffrey D. Isaacson, Heather A. Wakelee; Department of Oncology, National Taiwan University Hospital; Graduate Institute of Oncology & Cancer Research Center, National Taiwan University, Taipei, Taiwan; Royal Marsden Hospital, London, United Kingdom; Clovis Oncology, Inc, Chelmsford, United Kingdom; Clovis Oncology, Inc, San Francisco, CA; Clovis Onc, Boulder, CO; Stanford Cancer Institute/Stanford University School of Medicine, Stanford, CA
Abstract Disclosures
Abstract:
Background: Rociletinib is a small molecule inhibitor that selectively targets mutant EGFR and has been shown in preclinical studies to inhibit L858R, del19 and T790M while sparing wild-type EGFR. TIGER-X, a phase 1/2 dose-ranging trial, has provided evidence that rociletinib is associated with durable response and is well tolerated in pts with NSCLC and positive T790M status following progression on a TKI.1 TIGER-3 is designed to investigate single agent rociletinib vs chemotherapy in pts who have failed EGFR therapy and platinum-based doublet chemotherapy; a setting of acquired resistance and a high unmet need of targeted therapeutic options. TIGER-3 will evaluate pts with T790M positive and negative status based on blood and tumor tissues, and biomarkers of response or resistance. Methods: Pts with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC, with radiological progression on the most recent therapy will be enrolled in a phase 3, randomized, open-label study (NCT02322281). Pts must have documented evidence of a tumor with ≥ 1 EGFR activating mutations excluding exon 20 insertion, and prior treatment with an EGFR TKI and platinum-containing doublet chemotherapy. Pts will be randomized 1:1 to receive rociletinib twice daily or single agent cytotoxic chemotherapy (investigator choice specified before randomization) until disease progression according to RECIST 1.1. Pts will be stratified by presence or absence of brain metastases, ECOG performance status (0 vs 1), and race (Asian vs non-Asian). The primary endpoint is progression-free survival (PFS). Secondary endpoints include objective response rate, duration of response, disease control rate, and overall survival. Kaplan-Meier methodology will assess time to event variables. The stratified log-rank and the hazard ratio (HR) will be used for comparing PFS distributions. Serial assessment of safety will be carried out based on standard adverse event reporting. Planned enrolment is 600 pts with study start planned by end of May 2015.
Sequist LV J Clin Oncol. 2014
Clinical trial information: NCT02322281

AZD9291, a mutant-selective EGFR inhibitor, as first-line treatment for EGFRmutation-positive advanced non-small cell lung cancer (NSCLC): Results from a phase 1 expansion cohort.
Sub-category:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Abstract No:
8000
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr 8000)
Author(s): Suresh S. Ramalingam, James Chih-Hsin Yang, Chee Khoon Lee, Takayasu Kurata, Dong-Wan Kim, Thomas John, Naoyuki Nogami, Yuichiro Ohe, Yuri Rukazenkov, Paul Frewer, Mireille Cantarini, Serban Ghiorghiu, Pasi A. Janne; The Winship Cancer Institute of Emory University, Atlanta, GA; Department of Oncology, National Taiwan University Hospital; Graduate Institute of Oncology & Cancer Research Center, National Taiwan University, Taipei, Taiwan; St George Hospital, Sydney, Australia; Kansai Medical University Hirakata Hospital, Osaka-shi, Japan; Seoul National University Hospital, Seoul, South Korea; Olivia Newton-John Cancer Research Institute, Heidelberg, Australia; Clinical Research Institute, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan; National Cancer Center Hospital East, Kashiwa, Japan; AstraZeneca, Macclesfield, United Kingdom; AstraZeneca, Cambridge, United Kingdom; Dana-Farber Cancer Institute, Boston, MA
Abstract Disclosures
Abstract:
Background: AZD9291 is an orally administered EGFR TK inhibitor with activity against the sensitizing EGFR mutations (EGFRm) and the T790M resistance mutation. It has demonstrated anticancer activity in patients with EGFR-TKI pre-treated EGFRm T790M positive advanced NSCLC.Methods: Treatment-na&#239;ve patients with EGFRm advanced NSCLC received AZD9291 at doses of 80 mg/day or 160 mg/day (sequential cohorts) in the first-in-human phase I study (AURA, NCT01802632). EGFRm status was tested locally at the treating site and/or confirmed by central testing (cobas EGFR mutation test). Salient eligibility included presence of measurable disease, WHO performance status of 0 or 1, and acceptable organ function. Stable brain metastases were permitted. The objective of these cohorts was to investigate safety, tolerability, and anticancer activity of AZD9291 in the first-line EGFRm treatment setting. Results: Sixty patients were enrolled (30 each in 80 mg and 160 mg dose cohorts). Patient baseline characteristics: median age 63.5; male 25%; WHO performance status 0.57%, 1.43%; Asian 72%, and white 23%; central mutation test result exon 19 del 37%, L858R 40%, other EGFR sensitizing mutations 3%, T790M 8%. At the data-cutoff of 2 December 2014, 52 out of 60 patients remain on study treatment with a median treatment exposure of 260 days and 171 days for 80 mg and 160 mg cohorts, respectively. The objective response rate was 70% (95% CI 57, 81): 80 mg, 60%; 160 mg, 80% and the median progression-free survival (PFS) has not been reached. The disease control rate was 97% (95% CI 89, 100): 80 mg, 93%; 160 mg, 100%. Overall, the 3- and 6-month PFS rates were 93% and 87%, respectively (7/60 events, 12% mature). Grade ≥ 3 AEs were reported by 33% of patients. The incidences of grade 3 skin rash and diarrhea for the two dose cohorts combined were 1/60 and 2/60, respectively. Conclusions: AZD9291 has a manageable tolerability profile and is associated with promising anticancer activity as first-line treatment of EGFRm advanced NSCLC. A Phase III study to compare AZD9291 to erlotinib or gefitinib has been initiated (NCT02296125). Clinical trial information:NCT01802632

ASP8273, a mutant-selective irreversible EGFR inhibitor in patients (pts) with NSCLC harboring EGFR activating mutations: Preliminary results of first-in-human phase I study in Japan.
Sub-category:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Abstract No:
8014
Poster Board Number:
Board #336
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr 8014)
Author(s): Yasushi Goto, Hiroshi Nokihara, Haruyasu Murakami, Toshio Shimizu, Takashi Seto, Andrew P. Krivoshik, Anne Therese Keating, Koichi Uegaki, Kentaro Takeda, Kanji Komatsu, Satoshi Morita, Masahiro Fukuoka, Kazuhiko Nakagawa; National Cancer Center Hospital, Tokyo, Japan; Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan; Kinki University Faculty of Medicine, Osakasayama, Japan; Natl Kyushu Cancer Center, Fukuoka-Shi, Japan; Astellas Pharma Global Development, Inc., Northbrook, IL; Astellas Pharma Inc., Chuo-Ku, Japan; Kyoto University, Kyoto, Japan; Izumi Municipal Hospital, Izumi City, Japan; Kinki University Facultyof Medicine, Osakasayama, Japan
Abstract Disclosures
Abstract:
Background: ASP8273 is a small molecule, irreversible tyrosine kinase inhibitor (TKI) that inhibits the kinase activity of EGFR activating mutations and T790M resistance mutation, with higher potency than wild type EGFR. Methods: NSCLC pts previously treated with at least an EGFR-TKI were enrolled into this open-label Phase I/II study which consists of a dose escalation and response expansion cohorts followed by the P2 at the RP2D. ASP8273 was administered orally once daily. All pts were assessed for AEs, PK and anti-tumor activity. In each dose-escalation cohort at least 3 pts were enrolled regardless of T790M status and in response expansion cohorts only pts with T790M were enrolled (NCT02192697). Results: As of 14 Nov. 2014, 30 Japanese pts were enrolled across 7 dose levels (25 - 600 mg) in the dose-escalation cohorts and 15 pts were enrolled in the response expansion cohorts at 4 dose levels (100 - 400 mg). Demographics of the pts were median age 65 yrs, 73% female, 62% ECOG PS1 and 51% received immediate prior EGFR-TKI. T790M status was 49% positive, 13% negative and 38% unknown, respectively. Most common AEs were diarrhea (56%), nausea (31%), vomiting (31%) and platelet count decreased (31%). A few events of rash (9%), QTc prolongation (7%), ILD-like events (2%) and no hyperglycemia have been reported. 9 DLTs were reported at doses of 400 – 600 mg (3 diarrhea, 2 colitis, 1 biliary tract infection, 2 nausea and 1 hyponatremia). Based on these safety findings, MTD was determined to be 400 mg. Median AUC and Cmax after single- and multiple-dose of ASP8273 were increased with dose, respectively. RECIST responses were observed in pts enrolled in ≥ 100 mg. 50% (18/36) of all evaluable pts and 80% (12/15) pts with T790M have achieved PRs (includes confirmed and unconfirmed PRs). 300 mg once daily was chosen as RP2D based on the available safety, PK and anti-tumor activity data.Conclusions: ASP8273 under MTD has demonstrated anti-tumor activity in NSCLC pts with tumors harboring both EGFR activating mutations and T790M resistance mutation. The phase 2 part of this study will further investigate the clinical activity of ASP8273 at the RP2D in pts with T790M. Clinical trial information: NCT02192697

Influence of dose adjustment on afatinib safety and efficacy in patients (pts) with advancedEGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC).
Sub-category:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Abstract No:
8073
Poster Board Number:
Board #397
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr 8073)
Author(s): James Chih-Hsin Yang, Myung-Ju Ahn, Nicolas J. Dickgreber, Balazs Halmos, Vera Hirsh, Maximilian J. Hochmair, Benjamin Philip Levy, Filippo De Marinis, Tony Mok, Kenneth O'Byrne, Isamu Okamoto, Martin H. Schuler, Martin Sebastian, Riyaz N.H. Shah, Eng-Huat Tan, Nobuyuki Yamamoto, Angela Marten, Dan Massey, Sven Wind, David Paul Carbone; National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan; Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea; Thoracic Oncology and Respiratory Care Medicine, Mathias Spital Rheine, Rheine, Germany; Columbia University Medical Center, New York, NY; McGill University, Montreal, QC, Canada; Otto Wagner Hospital, Vienna, Austria; Mount Sinai Beth Israel Hospital, New York, NY; Thoracic Oncology Division, European Institute of Oncology, Milan, Italy; State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, China; Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia; Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan; West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, and University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Kent Oncology Centre, Maidstone Hospital, Kent, United Kingdom; National Cancer Centre, Singapore, Singapore; Wakayama Medical University, Wakayama, Japan; Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim Am Rhein, Germany; Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, United Kingdom; Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany; James Thoracic Center, The Ohio State University Wexner Medical Center, Columbus, OH
Abstract Disclosures
Abstract:
Background: Afatinib 40 mg/day (oral) is approved for the treatment of pts with advanced EGFRm+NSCLC. Dose adjustment is recommended according to pre-defined tolerability criteria. We performed post-hoc analyses on the influence of afatinib dose reduction on adverse events (AEs), pharmacokinetics (PK) and progression-free survival (PFS) in the Phase III LUX-Lung 3 (LL3) trial, and analyzed dose reduction data collected in clinical practice. Methods: All pts treated with afatinib in LL3 were included in the analyses (n = 229). Pts experiencing drug-related grade 3 or selected prolonged grade 2 AEs on the initial 40 mg dose could dose reduce by 10 mg decrements to 30 mg or a final dose of 20 mg. Frequency and severity of the most common AEs before and after dose reduction were analyzed. Final PK data collected as part of the standard visit schedule (Day 43) were used to compare plasma afatinib concentrations in pts who reduced to 30 mg vs those remaining at 40 mg. PFS was compared between pts who dose reduced within the first 6 months of treatment and those who did not. Real-world data were collected by practicing experts. Results: Dose reductions occurred in 53% (122/229) of pts; the majority (86%) within the first 6 months of treatment. In pts who dose reduced, decreases in the incidences of drug-related all grade (grade ≥ 3) AEs were 99.2% (20.5%) to 46.7% (4.1%) for diarrhea, 88.5% (26.2%) to 38.5% (3.3%) for rash/acne, 77.0% (12.3%) to 27.9% (0%) for stomatitis, and 44.3% (16.4%) to 36.9% (4.9%) for nail effects. Dose reduction was more likely in pts with higher plasma concentrations of afatinib. On Day 43, pts who dose reduced to 30 mg ≥ 4 days previously (n = 38) had geometric mean plasma afatinib concentrations of 24.4 ng/mL, vs 23.7 ng/mL in pts who remained on the 40 mg dose (n = 126). Median PFS was 11.3 months in pts who dose reduced during the first 6 months of treatment, vs 11.0 months in pts who did not (HR = 1.25 [95% CI, 0.91–1.72]). Dose reduction outcomes from daily clinical practice will also be presented. Conclusions: Tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related AEs without reducing therapeutic efficacy. Clinical trial information: NCT00949650

A randomized, phase III study (FLAURA) of AZD9291, a novel EGFR-TKI, versus gefitinib or erlotinib in treatment-na&#239;ve patients with advanced non-small cell lung cancer and an EGFR-TKI-sensitizing mutation.
Sub-category:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Abstract No:
TPS8102
Poster Board Number:
Board #427a
Citation:
J Clin Oncol 33, 2015 (suppl; abstr TPS8102)
Author(s): Suresh S. Ramalingam, Yuri Rukazenkov, Karen Thomas, Jean-Charles Soria; The Winship Cancer Institute of Emory University, Atlanta, GA; AstraZeneca, Macclesfield, United Kingdom; Gustave-Roussy Cancer Campus, Drug Development Department, Villejuif, France
Abstract Disclosures
Abstract:
Background: EGFR-TKI is the recommended treatment for patients with advanced NSCLC who have an EGFR-TKI-sensitizing mutation (EGFRm). However, most patients develop resistance, and in ~60% of cases the EGFR T790M mutation is the cause. AZD9291 is an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M mutations. Preliminary data from a Phase I/II study demonstrated clinical activity and a manageable tolerability profile for AZD9291 as first-line treatment of patients with EGFRm advanced NSCLC. Methods: This Phase III, double-blind, randomized study (FLAURA, NCT02296125) is designed to assess the efficacy and safety of AZD9291 (80 mg qd, orally) versus standard of care (SoC) EGFR-TKI (gefitinib [250 mg qd, orally] or erlotinib [150 mg qd, orally]) in treatment-na&#239;ve patients with locally advanced or metastatic EGFRm NSCLC. Eligible patients must have pathologically confirmed adenocarcinoma harboring an EGFR Ex19del or L858R mutation, alone or in combination with another EGFRm, determined by local (accredited laboratory) or central testing. Patients ≥ 18 years of age ( ≥ 20 in Japan), WHO performance status 0–1, will be randomized 1:1 to receive either AZD9291 or SoC EGFR-TKI, stratified by mutation status (Ex19del or L858R) and race (Asian versus non-Asian), until RECIST v1.1 defined progression or a discontinuation criterion is met. Patients may continue randomized treatment beyond RECIST defined progression if they continue to show clinical benefit, as judged by the Investigator. The primary objective is to compare progression-free survival (PFS) for AZD9291 to SoC EGFR-TKI. PFS in patients with tumors harboring T790M is a key secondary objective. Additional secondary objectives include PFS by Ex19del or L858R detectable in circulating tumor DNA, objective response rate, duration of response, disease control rate, depth of response, overall survival, PK, health-related quality of life, patient satisfaction with treatment, and the safety and tolerability profile of AZD9291 compared with SoC EGFR-TKI. The study was opened to accrual in November 2014. Clinical trial information: NCT02296125

Pharmacokinetic assessment of dacomitinib (pan-HER tyrosine kinase inhibitor) in patients with locally advanced head and neck squamous cell carcinoma (LA SCCHN) following administration through a gastrostomy feeding tube (GT)
Friday, May 08, 2015, 15:04
Summary

Background Dacomitinib is an irreversible oral pan-HER tyrosine kinase inhibitor with antitumor activity demonstrated in patients with recurrent/metastatic (RM) SCCHN. A Phase I trial of dacomitinib with standard therapy in LA SCCHN is ongoing (NCT01737008). As enteral feeding is needed for many SCCHN patients, this study investigated the PK properties of dacomitinib when administered via GT (NCT01484847). Since patients with GT are difficult to recruit, this study also determined the feasibility of PK assessments using a unique design in LA SCCHN patients with GT, by giving a single dose of drug during their radiotherapy (co-administration with chemotherapy avoided).Methods Eligible patients were given a single dose of crushed dacomitinib at 45 mg in water suspension via GT. All doses were administered in fasting state and supine position. PK samples were drawn prior to dose (t&#8201;=&#8201;0), 30 min and 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 144, 168, 192 and 216 hrs post-dose, and analyzed by HPLC-MS/MS. PK parameters (mean [CV%]) of this study were compared with those of dacomitinib given orally using Student t test. Results Six patients with LA SCCHN patients were enrolled. The median age of patients was 54 years. Two different types of GT were used: 14 F Cope-loop tube (n&#8201;=&#8201;3), 20 F PEG/disc retention tube (n&#8201;=&#8201;3). PK study showed t1/2 of 58 h, Cmax of 17 ng/ml, Tmax of 8 h, AUC0-inf of 1185 ng*hr/ml, Vd/F of 3310 L and CL/F of 41 L/hr. Conclusion Compared with oral dosing of intact immediate release (IR) tablets, GT administration resulted in 34 % reduction in Cmax and 33–44 % decrease in AUC (all p <0.05) (J&#228;nne et al., Clin Cancer Res 2011). Such differences were not detected when compared with the PK properties of dacomitinib administered orally in aqueous suspension (Bello et al., Cancer Chemother Pharm 2013). These differences may be attributed to aqueous suspension of dacomitinib. Caution should be taken with GT administration of orally active small molecule targeted therapy. This study also demonstrated that PK trials in GT patients are feasible using novel designs.

ACSO 2015部分内容
一、非小细胞肺癌
（1）Rociletinib/ CO-1686
Rociletinib的3期临床（与化疗药物对比，二线治疗）在进行中，已经报批FDA，估计年底或者明年初上市。Rociletinib的3期剂量为每天二次，一次625mg，与食物同服或者饭后半小时内服用。
https://clinicaltrials.gov/show/NCT02322281
http://abstracts.asco.org/156/AbstView_156_149724.html
http://abstracts.asco.org/156/AbstView_156_149636.html
http://abstracts.asco.org/156/AbstView_156_152181.html
（2）AZD9291
AZD9291的3期临床（与特罗凯或者易瑞沙对比，一线治疗）在进行中，已经报批FDA，估计年底或者明年初上市。AZD9291的3期剂量为每天一次，一次80mg，适当时可减量到40mg每天，最大剂量为160mg每天。
https://clinicaltrials.gov/ct2/show/NCT02296125
http://abstracts.asco.org/156/AbstView_156_148945.html
http://abstracts.asco.org/156/AbstView_156_144153.html
http://abstracts.asco.org/156/AbstView_156_145109.html
（3）AZD3759
AZD3759，阿斯利康的非小肺癌脑转新药，针对egfr突变耐药病人，50mg-100mg*2每天，无明显副作用，目前1期临床（与160mg每天的AZD9291对比治疗脑转效果，入组病人为egfr耐药的脑转非小细胞肺癌）。值得关注。
AZD3759的入脑特性：具有非常高的被动渗透率（29.5x10-6 cm/sec），不是跨膜糖蛋白(Pgp)和乳腺癌耐药蛋白(BCRP)的底物，在免子、小鼠和猴子体内的Kpuu,brain和 Kpuu,CSF > 0.5。
初步临床结果：4名脑转NSCLC病人，3名50mg*2每天，1名100mg*2每天，其中2名可评估病人中，1名肿瘤缩小，1名稳定，他们的脑脊髓液中药物浓度为7.7nM和6nM，约等于AZD3759的pEGFR IC50。临床中没有发现剂量限制副作用，有2名病人1级皮疹。
注：多药转运体如 PGP、MRP、LRP 和 BCRP,能够使细胞内药物外排增加或囊泡隔离导致细胞内药物浓度降低或药物分布改变。
Kpuu：血浆分配系数。
https://clinicaltrials.gov/show/NCT02228369
http://abstracts.asco.org/156/AbstView_156_146873.html
http://abstracts.asco.org/156/AbstView_156_147526.html
AZD9291的入脑数据：
AZD9291在脑脊髓液中药物浓度约是易瑞沙的10倍。
http://www.poster-submission.com ... oster/37/26856/456P
易瑞沙和特罗凯的入脑数据：
http://repository.kulib.kyoto-u. ... 0280-012-1929-4.pdf
特罗凯在脑脊髓液中药物浓度为68.2nM（pEGFR IC50=40nM），易瑞沙为7.2nM（pEGFR IC50=33nM）。特罗凯和易瑞沙都是PGP的底物，但不是BCRP的底物。
（4）PF-06463922
PF-06463922，辉瑞的ALK/ROS1新药，半衰期20–28小时，中等强度的CYP3A4诱导剂。1期临床收入18名ALK阳性和4名ROS1阳性病人，其中17名病人脑转，19名病人至少经过一种ALK/ROS1药物治疗（crizotinib 或 ceritinib），临床剂量从100mg-200mg每天一次，有效率为40%，最常见的副作用是高胆固醇血症23%（3级以上14%），周围神经病变23%。2期临床剂量和最大耐受剂量仍待确定，目前建议使用100mg每天一次。
https://clinicaltrials.gov/show/NCT01970865
http://abstracts.asco.org/156/AbstView_156_144494.html
http://abstracts.asco.org/156/AbstView_156_143329.html
（5）Deltarasin
Deltarasin是一种小分子抑制剂，抑制KRAS-PDEδ相互作用，治疗KRAS突变新药。
http://abstracts.asco.org/156/AbstView_156_153354.html
（6）Cabozantinib/XL184/Cometriq/卡博替尼
a.Cabozantinib（60mg每天）单药或者联合特罗凯（150mg每天）对比特罗凯单药治疗egfr野生NSCLC病人，Cabozantinib单药和联合方案相对特罗凯的无进展生存期和总生存期有提高。
b. Cabozantinib（60mg每天）或Crizotinib单药治疗Met阳性的NSCLC病人，3名Crizotinib治疗的病人有效缓解（CT），1名Cabozantinib治疗的病人CT检查稳定，PET检查完全缓解。
c. Cabozantinib（60mg每天）单药治疗Ret阳性的NSCLC病人，有效缓解率33%，无进展生存期为7个月。
http://abstracts.asco.org/156/AbstView_156_147467.html
http://abstracts.asco.org/156/AbstView_156_147349.html
http://abstracts.asco.org/156/AbstView_156_152055.html
http://abstracts.asco.org/156/AbstView_156_145500.html
https://clinicaltrials.gov/show/NCT01639508
（7）司美替尼/Selumetinib/AZD6244
Selumetinib联合化疗或AZD9291或凡德他尼治疗NSCLC，具体数据等大会报告。
http://abstracts.asco.org/156/AbstView_156_142892.html
http://abstracts.asco.org/156/AbstView_156_150914.html
http://abstracts.asco.org/156/AbstView_156_148945.html
（8）INC280
INC280诺华的Met抑制剂，1期临床中。
INC280（100-600mg*2）联合特罗凯（100-150mg），18名NSCLC病人入组，其中部分病人有met阳性，8名egfr阳性，12名特罗凯耐药。主要的副作用是腹泻（47%）和皮疹（47%），乏力（40%），肝转氨酶升高（27），恶心，厌食和甲沟炎（各27%），3级以上副作用是厌食，肝转氨酶升高和中性粒细胞减少症（各7%）。12名可评估病人中，6名稳定，2名egfr突变病人肿瘤缩小10-29%。
http://abstracts.asco.org/156/AbstView_156_145819.html
二、乳腺癌
（1）Abemaciclib/LY2835219
Abemaciclib是礼来的CDK4/6抑制剂，3期临床中。
http://abstracts.asco.org/156/AbstView_156_143933.html
http://abstracts.asco.org/156/AbstView_156_143970.html
http://abstracts.asco.org/156/AbstView_156_143933.html
（2）Ribociclib /LEE011
Ribociclib是诺华的CDK4/6抑制剂，3期临床中。
http://abstracts.asco.org/156/AbstView_156_145167.html
（3）Buparlisib/BKM120
Buparlisib是诺华的PI3K抑制剂，3期临床中。
http://abstracts.asco.org/156/AbstView_156_146016.html
三、肾癌
（1）Tivozanib/TIVO-1
Tivozanib是AVEO的抗血管生成抑制剂，3期临床中，今年打算在欧洲申请批准。
http://abstracts.asco.org/156/AbstView_156_149655.html

AACR2015_CT232: PI3K抑制剂BYL719联合来曲唑治疗ER阳性/HER阴性乳腺癌不错，19%的部分应答，43%的疾病稳定，患者之前都接受过激素疗法，69%的患者之前接受过芳香化酶抑制剂治疗。

AACR2015_Abstract#CT234: Merrimack Pharmaceuticals开发了HER2靶向脂质体包裹多柔比星，始终坚信他们的MM-302联合曲妥珠单抗优于化疗联合曲妥珠单抗，这次报告的应答率是12，mPFS为7.6个月，想跟Roche搞一腿有点难。

AACR2015_Abstract#CT231: 去年Roche以17亿美元的天价收购Seragon Pharmaceuticals，为的就是他们家的选择性雌激素受体降解剂ARN-810。现在临床数据出来了，用于ER阳性/HER阴性乳腺癌，42%的患者疾病稳定6个月以上，没有应答。我是ORR强迫症，没见着应答就觉得没谱。

AACR2015_Abstract#2859: Genentech的anti-PDL1单抗MPDL3280A对三阴性乳腺癌有效，应答率为24%，24周无进展生存率为33%。

AACR2015_Abstract#2860: nivolumab联合ipilimumab对黑素瘤的效果非常好，毒性非常大，结果就是大量患者中止治疗，中止治疗的患者应答率高达惊人的67%。

AACR_Abstract#CT139: Genentech说Chk1抑制剂GDC-0425能够增强吉西他滨对p53突变肿瘤的疗效，我一看原来入组了40例实体瘤，总共3例部分应答，就1例是p53突变的三阴性乳腺癌，怎么证明这1例不是偶然呢？

AACR_Abstract#CT138: 看今年AACR、ASCO的架势，纯粹是癌症免疫疗法吹牛逼大会，在一堆的PD1、CAR-T中，我终于找到一个还不错的另类，mTORC1/2抑制剂AZD2014联合紫杉醇对卵巢癌和非小细胞肺癌效果不错，应答率分别是3/7、2/5，患者之前都已经折腾好多遍了，包括紫杉醇类似的多西他赛。

AACR_Abstract#CT137: anti-CD40激动性单抗CP-870893联合anti-CTLA4单抗tremelimumab还行但不够出彩，一个激活免疫系统，一个抑制免疫抑制系统，治疗黑素瘤应答率为27.3%，生存期为26.1个月。

AACR2015_Abstract#CT101: 黑素瘤一线疗法用什么？Merck的pembrolizumab在III期头对头试验中击败BMS的 ipilimumab，应答率高20个百分点，6个月生存率高10个百分点，BMS真是日了狗了，被Merck这么针对，去年ipilimumab去年销售额从9.6亿增至13.1亿，今年看来是保不住了。

AACR2015_Abstract#4707: Adaptimmune报告了TCR疗法治疗滑膜肉瘤的初步临床结果，8例患者中1例完全应答、3例部分应答。

AACR2015_CT107: Atara Biotherapeutics (NASDAQ: ATRA)报告了他们的EBV-CTL疗法治疗EBV-LPD的临床数据，大部分患者之前利妥昔单抗治疗失败，EBV-CTL治疗后的应答率为62-67%，大部分是完全应答。

AACR2015_CT106: Immunocore的TCR疗法IMCgp100治疗黑素瘤效果一般，15例患者中3例部分应答、1例完全应答，有点看头的是可能对PD1、ipilimumab复发的患者有效。

ASCO2015_Abstract#CT103: anti-PD1单抗pembrolizumab对PDL1阳性胸膜间皮瘤有效，该症的一线疗法是培美曲塞+顺铂，应答率为41%，总生存期大约12个月，目前没有二线疗法，pembrolizumab可作为二线疗法，应答率为24%。Aduro Biotech正在开发该症的一线疗法，应答率为69%。

ASCO2015_Abstract#CT104: anti-PD1单抗的疗效与PDL1的表达状态直接相关，以前只是简单地区分PDL1阳性、阴性，这还不够，Merck检测表达PDL1的癌细胞比例，简称PS评分（PS=50%说明有一半的癌细胞表达PDL1），PS越高效果越好，这样PDL1作为anti-PD1疗法的标志物完全确证了。


ASCO2015看点：Aduro Biotech将更新CRS-207联合化疗治疗恶性胸膜间皮瘤的II期试验结果，ASCO2014报道了16例患者的数据，应答率达到69%，而化疗的历史数据是41%。
24例数据出炉，应答率为63%，下调6个百分点，仍然看好。

ASCO2015看点：Clovis Oncology将更新lucitanib治疗FGF异常乳腺癌的II期试验结果，ASCO2014的I/IIa期结果令人印象深刻，6/12的患者实现应答。这是他们公司的第三个抗癌药，前两个都拿到了突破性药物资格，第三个没准也有希望，而且这个药的原研是咱们中国人。

ASCO2015看点：Calithera Biosciences将公布CB-839治疗实体瘤的I期临床结果，该药是first-in-class谷氨酰胺酶抑制剂，虽然I期临床的目的是探索剂量和安全性，投资人总是期待能够看到有效性。
数据不太好，25例患者没有1例应答，有7例疾病稳定

ASCO2015看点：Curis将公布CUDC-907治疗淋巴瘤和多发性骨髓瘤的I期临床结果，该药是HDAC/PI3K双靶点抑制剂。
数据不太好，25例患者没有1例应答，有7例疾病稳定

ASCO2015看点：Cerulean Pharma将公布CRLX101联合贝伐珠单抗治疗肾细胞癌的Ib/IIa期临床结果，3月份时曾宣布达到主要临床终点（50%的患者实现4个月的PFS），详细数据将呈现在ASCO2015。CRLX101是一种纳米粒药物偶联物，加载的药物是喜树碱。
CRLX101联合贝伐珠单抗治疗肾细胞癌的应答率为23%，PFS为9.9个月。

ASCO2015看点：Karyopharm Therapeutics将公布核转运蛋白XPO1抑制剂治疗胶质母细胞瘤的II期临床进展，这也是一个first-in-class，全世界只有他们一家在做这个靶点，去年4月份启动的II期临床。
Selinexor妇产科肿瘤数据不算好：DCR in evaluable pts: OC: 36%; EC: 64%; CC: 28%. ORR in evaluable pts: OC: 9%; EC: 18%; CC 7%.
Selinexor肉瘤数据不佳：Of the 33 evaluable patients, stable disease was seen in 21/33 (64%) of pts along with decrease of tumor burden (ranging from 5 – 23%) in 7 patients. There were 12 pts (36%) that progressed.

ASCO2015看点：Ignyta将公布entrectinib治疗晚期实体瘤的I/IIa期（ STARTRK-1）临床结果，这是一个TrkA, TrkB, TrkC, ROS1, ALK抑制剂，在之前的I期临床中，有1例完全应答+5例部分应答。
STARTRK-1试验中15例患者，未见应答。

ASCO2015看点：TRACON Pharmaceuticals将公布TRC105 联合帕唑帕尼治疗软组织肉瘤的Ib期临床结果，这是一个first-in-class anti-endoglin单抗，作用机制是抗血管生成，目前开发用于多个适应症。
20例患者中1例完全应答，另外有5例患者肿瘤缩小10%以上（未达到部分应答标准）。

ASCO2015看点：JUNO将公布JCAR015治疗非霍奇金淋巴瘤的I期试验结果，去年8月KITE公布了CAR-T疗法治疗该症的I期结果，7例患者中4例完全应答，相信JUNO的数据也不差。
JUNO的数据很好看，8例患者中5例完全应答，都没有复发，最好的已经维持18个月。

ASCO2015看点：Novartis将公布CAR-T疗法治疗多发性骨髓瘤的I期临床结果，希望数据同样好看。这样就意味着CAR-T疗法对白血病、淋巴瘤、多发性骨髓瘤三大血液癌症全部有效，剩下可以全力开发实体瘤CAR-T疗法了。
目前只有3例多发性骨髓瘤数据，2例完全应答，1例疾病进展。

ASCO2015看点：德克萨斯儿童医院将公布HER2/CMV双靶点CAR-T治疗胶质母细胞瘤的I期临床结果，这个应是今年的重磅，如果数据好的话，估计会场要挤爆。我更喜欢JUNO对双靶点CAR-T的设想，梦幻一般的药物设计。
不知道是好消息还是坏消息：好消息是CAR-T疗法在实体瘤上实现客观应答，1例患者肿瘤缩小62%，坏消息是15例患者中仅此1例，另外有4例疾病稳定，虽未实现应答，但存活18个月以上。个人仍然看好CAR-T在实体瘤上的应用。

ASCO2015看点：Roche将公布anti-CSF1R单抗RG7155用于实体瘤的I期临床结果，可能对Five Prime Therapeutics的股价造成影响，谁让他两搞同一个靶点呢。

PD1的10个适应症全总结：黑素瘤、非小细胞肺癌、肾细胞癌、膀胱癌、头颈癌、卵巢癌、胃癌、三阴性乳腺癌、霍奇金淋巴瘤、非霍奇金淋巴瘤。

Aurora Kinase抑制剂alisertib (MLN8237)治疗外周T细胞淋巴瘤的III期临床失败。

IDO抑制剂indoximod脑癌数据不太好，12例患者3例疾病稳定，其中1例有部分应答倾向。

ASCO2015: Keytruda联合Yervoy治疗非小细胞肺癌的I期数据出炉，11例患者中1例完全应答，4例部分应答。（Abstract 8011 ）

Keytruda联合carboplatin/paclitaxel治疗非小细胞肺癌应答率为30%，如果在其中添加培美曲塞，应答率增加至58%。（Abstract 8031）

Genentech的anti-PDL1单抗非小细胞肺癌数据爆冷，MPDL3280A组、多西他赛组总生存期分别为11.4 vs 9.5个月，未达到统计学显著差异。

MPDL3280A联合carboplatin+培美曲塞用于新诊断的非小细胞肺癌效果不错，应答率达到75%。

Merck KGaA的anti-PDL1单抗avelumab卵巢癌数据出炉，应答率为17.4%，20年没研发出抗癌药，这次总算逮到一个。

恒瑞公布HER2/EGFR抑制剂吡咯替尼治疗转移性乳腺癌的I期试验结果，36例患者ORR为47.2%，DCR为80.6 %。
neratinib + paclitaxel的ORR为75%，真想看看neratinib与吡咯替尼的对比试验。