Press Release
– Three oral presentations given at CSCO for fruquintinib, savolitinib and theliatinib –
– Plenary keynote presentation for FRESCO Phase III trial details analysis showing consistent survival benefit in all key subgroups –
London: Friday, September 29, 2017: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) announced that new clinical data on three of its novel tyrosine kinase inhibitors, fruquintinib, savolitinib and theliatinib, were presented at the 20th Annual Meeting of the Chinese Society of Clinical Oncology (“CSCO”), held in Xiamen, China, from September 26 to 30, 2017.
The three oral presentations were as follows:
| Session: | Plenary Keynote Presentation |
| Presenter: | Shukui Qin |
| Date: | Wednesday, September 27 |
| Presentation Slides: | www.chi-med.com/csco-2017-fresco/ |
FRESCO is the Phase III trial assessing fruquintinib in patients with colorectal cancer (“CRC”) in China. Overall results presented earlier at the American Society of Clinical Oncology annual meeting in June 2017 showed that the trial met all primary and secondary efficacy endpoints. Fruquintinib is a novel vascular endothelial growth factor (“VEGF”) receptor kinase inhibitor.
Dr. Qin, Director of the PLA Cancer Center and Deputy Director of the 81st Hospital in Nanjing, presented data from prespecified subgroup analyses of overall survival (“OS”) and progression-free survival (“PFS”), which showed that the benefits of fruquintinib were generally consistent amongst all subgroups including, but not limited to, the following important subgroups:
1. Significant improvements in OS and PFS were demonstrated irrespective of whether patients had received prior anti-VEGF therapy or anti-epidermal growth factor receptor (“EGFR”) therapy. Median OS for those who had not received such prior therapies (250 of 416 patients enrolled, i.e. 60%) was 10.4 months for the fruquintinib group, versus 6.9 months for the placebo group, with a hazard ratio of 0.63 (95% CI 0.46–0.86; p= 0.010). Median PFS for this group was 3.8 months for the fruquintinib group versus 1.8 months for the placebo group, with a hazard ratio of 0.28 (95% CI 0.21–0.37; p < 0.001).
2. Significant OS and PFS improvements were demonstrated particularly amongst K-RAS wild-type patients (i.e. without mutation of the K-RAS gene). Median OS for patients that were K-RAS wild-type (231 of 416 patients enrolled, i.e. 56%) was nearly five months longer in the fruquintinib group at 10.7 months, versus 6.1 months for the placebo group, with a hazard ratio of 0.56 (95% CI 0.40–0.78; p< 0.001). K-RAS mutant patients (44%) also demonstrated OS and PFS improvements, with median OS of 8.2 months in the fruquintinib group and 7.0 months in the placebo group, with a hazard ratio of 0.75 (95% CI 0.53–1.07; p = 0.114).
The FRESCO plenary presentation received the “2017 First Prize, CSCO Outstanding Research Paper Award” by the Academic Committee of CSCO based on votes by the committee members.
| Session: | Precision Therapy for Late-Stage Gastric Cancer |
| Presenter: | Jifeng Feng |
| Date: | Thursday, September 28 |
| Presentation Slides: | www.chi-med.com/csco-2017-savolitinib-ph1b-gastric/ |
Dr. Feng, Chief Physician of the Jiangsu Cancer Hospital, presented results from the Phase Ib clinical trial of the safety and anti-tumor activity of savolitinib in aberrant c-MET advanced gastric cancer patients. Savolitinib is a highly selective c-MET kinase inhibitor.
The study cohort included 31 locally advanced or metastatic gastric cancer patients who had failed at least two lines of therapy. C-MET status was determined using fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC). The primary endpoint was to evaluate the safety and tolerability of savolitinib, with secondary endpoints including objective response rate (“ORR”), disease control rate (“DCR”), PFS and determining the pharmacokinetic profile.
As of June 15, 2017, of the 441 patients screened, 58 patients (13.2%) were determined to have aberrant c-MET, of which 22 (5.0%) were MET gene amplified. 31 patients were enrolled. Amongst the efficacy evaluable MET gene amplified patients, ORR was 42.9% (3/7) and DCR was 85.7% (6/7), with ORR of 13.6% (3/22) and DCR of 40.9% (9/22) amongst the overall efficacy evaluable aberrant c-MET set. As of the database cut-off, the longest PFS was in excess of two years.
Savolitinib monotherapy was determined as safe and well tolerated in patients with advanced gastric cancer. Grade 3 or above adverse events occurring in at least two patients included abnormal hepatic function in 12.9% (4/31), each of gastrointestinal bleeding or decreased appetite in 9.7% (3/31 each), and each of diarrhea or gastrointestinal perforation in 6.4% (2/31 each).
The study concluded that savolitinib monotherapy demonstrated promising anti-tumor efficacy in gastric cancer patients with MET gene amplification, and the potential benefit to patients with MET gene amplification warrants further exploration.
| Session: | Esophageal Cancer |
| Presenter: | Jifang Gong |
| Date: | Thursday, September 28 |
| Presentation Slides: | www.chi-med.com/csco-2017-theliatinib-ph1/ |
Dr. Gong of the Beijing Cancer Hospital presented results from the Phase I trial of the safety and anti-tumor activity of theliatinib. Theliatinib is a novel EGFR inhibitor designed with strong affinity to the wild-type EGFR kinase, and has been shown to be five to ten times more potent than erlotinib, which holds importance because tumors with wild-type EGFR activation have been found to be less sensitive to current EGFR inhibitors. This is notable in certain cancer types such as esophageal cancer, where 8-30% have EGFR gene amplification and 30-90% have EGFR over-expression.
Up to 500mg QD was determined to be safe and well-tolerated, with no dose-limiting toxicities (DLT) and no clear maximum tolerated dose (MTD). Pharmacokinetic exposure increased with dose, with a 300mg QD or more considered to be sufficient to inhibit EGFR phosphorylation. Amongst the 21 patients that received 120mg to 500mg QD, there were only four adverse events of grade 3 or above: gastrointestinal bleeding, decreased white blood cell count, anemia or decreased platelet count (1/21 = 4.8% each). There were no incidences of grade 3 or above rash or diarrhea. Amongst seven esophageal cancer patients, five had measurable lesions and could be evaluated for response. All five had stable disease. Of the efficacy evaluable patients in the 120mg to 500mg cohorts, 44.4% (8/18) had stable disease after 12 weeks.
The study concluded that further study of theliatinib at 400mg QD amongst esophageal cancer patients with EGFR activation was warranted.
In addition to the oral presentation, Yongxin Ren et al published preclinical study data regarding EGFR as a target for advanced esophageal cancer treatment using theliatinib. The summary abstract is available at www.chi-med.com/csco-2017-theliatinib-preclinical/.
Fruquintinib (HMPL-013) is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR receptor (“VEGFR”) 24 hours a day via an oral dose, with lower off-target toxicities compared to other targeted therapies. VEGFR is known to play a pivotal role in tumor-related angiogenesis, and inhibition of VEGFR represents an important therapeutic strategy in blocking the development of new blood vessels essential for tumors to grow and invade. Fruquintinib’s tolerability, along with its clean drug-drug interaction profile demonstrated to date, may enable rational combination with other cancer therapies such as in our ongoing clinical trials of fruquintinib in combination with chemotherapy and targeted therapy.
Fruquintinib is currently under joint development in China by Chi-Med and its partner Eli Lilly and Company. The New Drug Application (NDA) for fruquintinib in CRC was accepted by the China Food and Drug Administration (CFDA) in June 2017. In addition, fruquintinib is being studied in China in a Phase III pivotal trial in non-small cell lung cancer (NSCLC), known as FALUCA; and a Phase II study using fruquintinib combined with Iressa® (gefitinib) in the first-line setting for patients with advanced or metastatic NSCLC. Other studies currently being planned, and soon to be initiated, include a Phase III study in gastric cancer in combination with paclitaxel in China, new studies in the United States, and certain exploratory studies in combination with other oncology agents.
Savolitinib (AZD6094/HMPL-504) is a potential first-in-class selective inhibitor of c-MET (also known as mesenchymal epithelial transition factor) receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumors. It was developed as a potent and highly selective oral inhibitor specifically designed to address issues observed in the clinic with other selective c-MET inhibitors, such as renal toxicity.
Savolitinib was discovered by Chi-Med and is being developed in collaboration with AstraZeneca PLC. Savolitinib is currently being studied in Phase Ib/II and III studies in multiple tumor types worldwide including kidney, lung and gastric cancers, both as a monotherapy or in combination with other targeted and immunotherapy agents. A global Phase III registration study in papillary renal cell carcinoma (PRCC) was initiated in June 2017. Later in 2017, Phase II data is expected to be be presented at a major scientific conference on savolitinib in combination with Tagrisso® and Iressa®, in both second- and third-line NSCLC.
Theliatinib (HMPL-309) is a novel molecule EGFR inhibitor under investigation for the treatment of solid tumors. Tumors with wild-type EGFR activation, for instance, through gene amplification or protein over-expression, have been found to be less sensitive to currently marketed EGFR inhibitors. Theliatinib has been designed with strong binding affinity to the wild-type EGFR kinase and has been shown to be five to ten times more potent than erlotinib. Theliatinib may benefit patients with esophageal and head and neck cancers, tumor-types with a high incidence of wild-type EGFR activation.
Chi‑Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products. Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.
Chi‑Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001). For more information, please visit: www.chi‑med.com.
Tagrisso® and Iressa® are trademarks of the AstraZeneca PLC group of companies.
This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect Chi-Med’s current expectations regarding future events, including its expectations for the clinical development of fruquintinib, savolitinib and theliatinib; plans to initiate clinical studies for fruquintinib, savolitinib and theliatinib; its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of drug candidates fruquintinib, savolitinib and theliatinib to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions, to gain commercial acceptance after obtaining regulatory approval, the potential markets of fruquintinib, savolitinib and theliatinib for targeted indications and the sufficiency of funding. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM. Chi-Med undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.
Mark Lee, SVP Corporate Finance & Development
+852 2121 8200
Anthony Carlisle, Citigate Dewe Rogerson
+44 7973 611 888 (Mobile)
anthony.carlisle@cdrconsultancy.co.uk
Brad Miles, BMC Communications
+1 (917) 570 7340 (Mobile)
bmiles@bmccommunications.com
Susan Duffy, BMC Communications
+1 (917) 499 8887 (Mobile)
sduffy@bmccommunications.com
Matt Beck, The Trout Group
+1 (917) 415 1750 (Mobile)
mbeck@troutgroup.com
David Dible, Citigate Dewe Rogerson
+44 7967 566 919 (Mobile)
david.dible@citigatedr.co.uk
Richard Gray / Andrew Potts
+44 (20) 7886 2500
Press Release
– Data to show potential of savolitinib to treat EGFR-TKI resistance in both Iressa® and Tagrisso® refractory patients with MET amplification –
– Results to further validate Chi-Med’s scientific strategy of designing highly selective small molecule TKIs that can be safely and effectively used in combination regimens –
– Updated data through August 2017 will be reviewed on-site in three oral presentations –
London: Friday, September 29, 2017: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) today announces that non-small cell lung cancer (“NSCLC”) proof-of-concept clinical data on two of its novel tyrosine kinase inhibitors (“TKI”), savolitinib and fruquintinib, will be presented at the 18th World Conference on Lung Cancer (“WCLC”), to be held in Yokohama, Japan from October 15 to 18, 2017. The three oral presentations cover the following studies in epidermal growth factor receptor (“EGFR”)-mutant NSCLC patients:
The proof-of-concept TATTON B study demonstrated promising safety, tolerability, and efficacy of this combination. Data was not yet mature at abstract data cut-off (April 2017). The presentation will include data up to and including August 2017, including further patient enrolment, response confirmations, and duration of response results.
| Title: | OA 09.03 – TATTON Ph Ib Expansion Cohort: Osimertinib plus Savolitinib for Pts with EGFR-Mutant MET-Amplified NSCLC after Progression on Prior EGFR-TKI |
| Presenting Author: | Myung-Ju Ahn |
| Authors: | Ji-Youn Han, Lecia V Sequist, Byoung Chul Cho, J.S. Lee, Sang-We Kim, W. Su, C. Tsai, James Chih-Hsin Yang, Helena Yu, L. Horn, K. Lee, V. Haddad, M.M. Frigault, G. Ahmed, L. Yang, D. Ghiorghiu, Geoffrey R. Oxnard |
| Time & Location: | Tuesday October 17, 2017, 11:20AM – 11:30AM, Room 301 + 302 |
| Session: | OA 09 – EGFR TKI Resistance (ID 663) |
This proof-of-concept study in China demonstrated promising safety, tolerability, and efficacy of this combination. Data was not yet mature at abstract data cut-off (March 2017). The presentation will include data up to and including August 2017, including further patient enrolment, response confirmations, duration of response results, and confirmation of T790M status for each patient.
| Title: | OA 09.06 – A Phase Ib Trial of Savolitinib plus Gefitinib for Chinese Patients with EGFR-Mutant MET-Amplified Advanced NSCLC |
| Presenting Author: | Jin-Ji Yang |
| Authors: | Jian Fang, Y. Shu, J. Chang, G. Chen, J. He, W. Li, X. Liu, N. Yang, Caicun Zhou, J. Huang, L. Yang, A.A. Handzel, M.M. Frigault, G. Ahmed, C. Egile, S. Morgan, Yi-Long Wu |
| Time & Location: | Tuesday October 17, 2017, 11:55AM – 12:05PM, Room 301 + 302 |
| Session: | OA 09 – EGFR TKI Resistance (ID 663) |
This proof-of-concept study in first-line EGFR-mutant NSCLC demonstrated no unexpected toxicities and a manageable preliminary safety profile of this combination. Data was not yet mature at abstract data cut-off (June 2017). The presentation will include data up to and including August 2017, including further patient enrolment, safety and efficacy results.
| Title: | JCSE 01.12 – A Phase II Study of Fruquintinib in Combination with Gefitinib in Stage IIIb/IV NSCLC Patients Harboring EGFR Activating Mutations |
| Presenting Author: | Shun Lu |
| Authors: | J. Zhou, X. Niu, M. Chen, Y. Hua, W. Su |
| Time & Location: | Sunday October 15, 2017, 10:35AM – 10:50AM, F203 (Annex Hall) |
| Session: | JCSE 01 – Joint IASLC / CSCO / CAALC Session: Immunotherapy for Management of Lung Cancer: Ongoing Research from East and West (ID 630) |
| Poster Note: | The study detailed in oral presentation JCSE 01.12 will also be presented as poster P3.01-070 as part of the Advanced NSCLC poster session on Wednesday October 18, 2017 at 9:30AM, in Exhibit Hall (B + C). |
Once presented, the presentations will be available at www.chi-med.com/news/. Further information about WCLC is available at www.wclc2017.iaslc.org.
Savolitinib (AZD6094/HMPL-504) is a potential global first-in-class inhibitor of c-MET (also known as mesenchymal epithelial transition factor) receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumors. It was developed as a potent and highly selective oral inhibitor specifically designed to address issues observed in the clinic with first-generation c-MET inhibitors, including renal toxicity.
Savolitinib was discovered by Chi-Med and is being developed in collaboration with AstraZeneca PLC. AstraZeneca PLC and Chi-Med are currently testing savolitinib in multiple tumor types worldwide including kidney, lung and gastric cancers, both as a monotherapy or in combination with other targeted and immunotherapy agents.
Fruquintinib is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR 24 hours a day via an oral dose, without known off-target toxicities. Its tolerability, along with its clean drug-drug interaction profile, enables rational combination with other cancer therapies such as in our ongoing clinical trials of fruquintinib in combination with chemotherapy and targeted therapy.
At an advanced stage, tumors secrete large amounts of VEGF, a protein ligand, to stimulate formation of excessive vasculature (angiogenesis) around the tumor to provide greater blood flow, oxygen, and nutrients to the tumor. VEGF and VEGFR play a pivotal role in tumor-related angiogenesis, and the inhibition of the VEGF/VEGFR pathway. This represents an important therapeutic strategy in blocking the development of new blood vessels essential for tumors to grow and invade.
Fruquintinib is currently under joint development in China by Chi-Med and its partner Eli Lilly and Company (“Lilly”). Chi-Med and Lilly jointly announced top-line results from the FRESCO CRC trial on March 3, 2017. In addition, fruquintinib is being studied in China in a Phase III pivotal trial in NSCLC, known as FALUCA; and a Phase II study using fruquintinib combined with Iressa® (gefitinib) in the first-line setting for patients with advanced or metastatic NSCLC. Other studies currently being planned, and soon to be initiated, include a Phase III study in gastric cancer in combination with paclitaxel in China, new studies in the United States, and certain exploratory studies in combination with other oncology agents.
Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products. Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.
Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001). For more information, please visit: www.chi-med.com.
Tagrisso® and Iressa® are trademarks of the AstraZeneca PLC group of companies. Tarceva® is a trademark of the Astellas Pharma Inc. group of companies.
This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect Chi-Med’s current expectations regarding future events, including its expectations for the clinical development of fruquintinib and savolitinib, plans to initiate clinical studies for fruquintinib and savolitinib, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of drug candidates fruquintinib and savolitinib to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions, to gain commercial acceptance after obtaining regulatory approval, the potential market of fruquintinib and savolitinib for a targeted indication and the sufficiency of funding. In addition, as certain studies rely on the use of Iressa® (gefitinib) as a combination therapeutic with fruquintinib and Tagrisso® (osimertinib) or Iressa® (gefitinib) as a combination therapeutic with savolitinib, such risks and uncertainties include assumptions regarding the safety, efficacy, supply and continued regulatory approval of Iressa® and Tagrisso®. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM. Chi-Med undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.
Mark Lee, SVP Corporate Finance & Development
+852 2121 8200
Anthony Carlisle, Citigate Dewe Rogerson
+44 7973 611 888 (Mobile)
anthony.carlisle@cdrconsultancy.co.uk
Brad Miles, BMC Communications
+1 (917) 570 7340 (Mobile)
bmiles@bmccommunications.com
Susan Duffy, BMC Communications
+1 (917) 499 8887 (Mobile)
sduffy@bmccommunications.com
Matt Beck, The Trout Group
+1 (917) 415 1750 (Mobile)
mbeck@troutgroup.com
David Dible, Citigate Dewe Rogerson
+44 7967 566 919 (Mobile)
david.dible@citigatedr.co.uk
Richard Gray / Andrew Potts
+44 (20) 7886 2500
London: Friday, September 29, 2017: For information purposes, Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) hereby notifies the market that as at September 29, 2017, the issued share capital of Chi-Med consisted of 60,750,132 ordinary shares of US$1.00 each, with each share carrying one right to vote and with no shares held in treasury.
The above figure of 60,750,132 may be used by shareholders as the denominator for the calculations by which they could determine if they are required to notify their interest in, or a change to their interest in, Chi-Med under the Financial Conduct Authority’s Disclosure Rules and Transparency Rules.
For illustrative purposes only, the 60,750,132 ordinary shares would be equivalent to 60,750,132 CREST depositary interests (each equating to one ordinary share) which are traded on AIM or, if the CREST depositary interests were converted in their entirety, equivalent to 121,500,264 American depositary shares (each equating to one-half of one ordinary share) which are traded on Nasdaq.
About Chi-Med
Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products. Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.
Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001). For more information, please visit: www.chi-med.com.
CONTACTS
Mark Lee, SVP Corporate Finance & Development
+852 2121 8200
Anthony Carlisle, Citigate Dewe Rogerson
+44 7973 611 888 (Mobile)
anthony.carlisle@cdrconsultancy.co.uk
Brad Miles, BMC Communications
+1 (917) 570 7340 (Mobile)
bmiles@bmccommunications.com
Susan Duffy, BMC Communications
+1 (917) 499 8887 (Mobile)
sduffy@bmccommunications.com
Matt Beck, The Trout Group
+1 (917) 415 1750 (Mobile)
mbeck@troutgroup.com
David Dible, Citigate Dewe Rogerson
+44 7967 566 919 (Mobile)
david.dible@citigatedr.co.uk
Richard Gray / Andrew Potts
+44 (20) 7886 2500
Jifeng Feng, Baorui Liu, Tianshu Liu, Nong Xu, Jianming Xu, Yunpeng Liu, Yuxian Bai, Jin Li, Wei Li, Chunmei Bai, Tao Zhang, Ruihua Xu, Da Jiang, Jianwei Lu, Jia Wei, Yuehong Cui, Jifang Gong, Haiping Jiang, Yuling Chen, Xiujuan Qu, Hong Sui, Weijian Guo, Chang Wang, Lin Zhao, Dandan Yu, Fenghua Wang, Mingxia Wang, Lin Shen
Venue: Chinese Society of Clinical Oncology Annual Meeting
Session: Precision Therapy for Late-Stage Gastric Cancer
Presenter: Jifeng Feng
Date: Thursday, September 28, 2017
Lin Shen, Li Zhang, Hongyun Zhao, Wenfeng Fang, Jifang Gong
Venue: Chinese Society of Clinical Oncology Annual Meeting
Session: Esophageal Cancer
Presenter: Jifang Gong
Date: Thursday, September 28, 2017
Shukui QIN*, Jin LI*, Yuxian BAI, Yanhong DENG, Lei YANG, Zhen-Dong CHEN, Haijun ZHONG, Rui-Hua XU, Hongmin PAN, Weijian GUO, Yongqian SHU, Ying YUAN, Jianfeng ZHOU, Nong XU, Tianshu LIU, Dong MA, Changping WU, Ying CHENG, Jian-Ming XU, Donghui CHEN, Wei LI, Sanyuan SUN, Zhuang YU, Peiguo CAO, Lin SHEN, Haihui CHEN, Jiejun WANG, Shubin WANG, Hongbing WANG, Songhua Fan, Ye Hua, Weiguo Su
Venue: Chinese Society of Clinical Oncology Annual Meeting
Session: Plenary Keynote Presentation
Presenter: Shukui Qin
Date: Wednesday, September 27, 2017
Rongxin Ren, Shiming Fan, Linfang Wang,Min Cheng, Dongxia Shi, Wei Zhang,Renxiang Tang, Ying Yu, Longxian Jiao, Jun Ni, Haibin Yang, Huaqing Cai,Feng Zhou, Weihan Zhang, Weiguo Qing, Weiguo Su
Purpose: Esophageal cancer (EC) is a high prevalence cancer type in China, which lacking effective targeted therapy. Accordingly to past studies, over 50% EC patients are with over-expression of EGFR, and this is usually associated with poor prognosis. Unlike colorectal cancer, K-Ras mutations are quite rare in EC, so EGFR may become one of the targets for esophageal cancer treatments. However, clinical trials with anti-EGFR antibodies or small molecule EGFR inhibitors (gefitinib, erlotinib, icotinib) have showed disappointing anti-tumor effects. The possible causes might be: 1. Clinical trial enrollments lacking EGFR screening or EGFR enrollment criteria need further optimization. For example, gefitinib ph3 III Trans-COG retrospective analysis suggested that, for patients with EGFR gene amplification or increased copy numbers, overall survival of the gefitinib treatment group is significantly longer than the placebo group; 2. Relevant EGFR small molecule inhibitors need to be improved in terms of affinities and inhibition activities to the wild-type EGFR. Theliatinib is a novel small molecule EGFR inhibitor, with high affinity and potent inhibitory activity to the wild-type EGFR. This study use pre-clinical molecular, cell and animal models to explore the inhibition to the wild-type EGFR, and relevance between esophageal cancer treatment efficacy and EGFR expression level.
Methods: Use z-lyteTM method to determination theliatinib, erlotinib and gefitinib’s inhibition constants to the wild-type EGFR kinase, “Ki”, compare their targeted inhibition activities on EGFR-dependence cell lines and cytotoxicity effectiveness on the tumor cells. On several nude mice transplanted PDX (patient derived xenograft) models, which are derived from esophageal cancer patient tissue, study the expression levels of EGFR genes, proteins and theliatinib’s anti-tumor efficacy. Also investigated other relevant genes or protein abnormalities that might affect the activities of EGFR pathway.
Results: Theliatinib’s Ki to the wild-type EGFR inhibition is 0.05 nM, is 7 ~ 10 times of gefitinib and erlotinib; on multiple EGFR-dependent cell lines, theliatinib’s EGFR phosphorylation and cytotoxicity activity is 3 ~ 6 times stronger than similar compounds. On two EGFR gene amplification and EGFR protein over-expression PDX models, theliatinib at oral clinically relevant dose, can make tumor volume decreasing by > 30%; In several models with high EGFR protein expression (immunohistochemical H score > 250) but no EGFR gene amplification, theliatinib shows tumor growth inhibition rate up to 67% ~ 100%. While for models with low EGFR protein expression (immunehistochemical H score < 200), the inhibition effect of tumor growth is not significance. In multiple models above, at clinically relevant doses, theliatinib shows significantly stronger anti-tumor efficacy than gefitinib (P < 0.05). In addition, if esophageal cancer patients with EGFR over expression, who also have over expression of FGFR1, PIK3CA mutation or PTEN deletion, will reduce theliatinib’s antitumor efficacy.
Conclusion: EGFR may be a feasible target for esophageal cancer treatment, which is worthy further clinical researches. Explorations with EGFR screening criteria and other biomarkers influencing EGFR inhibition efficacy that can bring benefit to patients, is critical to successful of clinical trials. Theliatinib clinical trial in advanced esophageal cancer (NCT02601274) is ongoing.
Keywords: esophageal cancer, EGFR, targeted therapy, theliatinib, PDX model
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