ESMO Asia 2016 Industry Satellite Symposium December 2016, Singapore. Advances in gastric cancer

Transcription

1 ESMO Asia 2016 Industry Satellite Symposium December 2016, Singapore Advances in gastric cancer Chair: Ian Chau With Mitsuru Sasako, Kei Muro and Yung-Jue Bang Saturday 17th December, 12:45-14:15 Hall 404, Suntec Singapore Convention and Exhibition Centre Scientific summary SINGAPORE 2016 This programme is made possible thanks to independent educational sponsorship from Eli Lilly and Company.

2 Contents 3 Welcome message 4 Faculty biographies 7 The surgical treatment pathway Mitsuru Sasako 11 Optimising patient care in metastatic gastric cancer Kei Muro 15 Future directions in metastatic gastric cancer Yung-Jue Bang Springer Healthcare IME 2

3 Welcome message Dear Colleagues, Thank you for attending the independent satellite symposium entitled Advances in gastric cancer at the ESMO Asia 2016 Congress. The ESMO Asia 2016 Congress aimed to facilitate information exchange between Asian and European oncology professionals across continents, and provided an ideal backdrop for this symposium where we fostered the sharing of experiences among those in the gastric cancer field. The aim of the symposium was to discuss the latest surgical and oncology treatments for gastric cancer in the context of an increasingly complex treatment landscape including patient and tumour characteristics, clinical guidelines, and novel clinical data. We hoped that by sharing the challenges facing clinicians both in Asia and Europe, our expert Faculty could provide insights to aid the delegates in their clinical practice. During this session, the expert Faculty guided us through this complexity by placing the latest developments in gastric cancer in the context of treatment. They then provided their insights into how we could best understand the latest developments in gastric cancer treatment in a multidisciplinary care team. We hope that you found this symposium educational and that it furthered your understanding of this evolving field. Yours faithfully, Ian Chau Ian Chau- Chair Springer Healthcare IME 3

4 Faculty biographies Ian Chau (Symposium Chair) Royal Marsden Hospital, UK Dr Chau holds the position of Consultant Medical Oncologist within the Gastrointestinal and Lymphoma Units at the Royal Marsden Hospital and Honorary Senior Lecturer at the Institute of Cancer Research, London & Surrey. He qualified from the United Medical & Dental Schools of Guy s and St. Thomas Hospitals, University of London, before undergoing medical oncology specialist training and a clinical research fellowship at the Royal Marsden Hospital. His main research interests are clinical trials and translational research in gastrointestinal cancers and lymphoma. He is the Chief or Principal Investigator of multiple phase I, II and III clinical trials evaluating novel treatment strategies and agents in various cancer signalling pathways. Dr Chau serves or has served on the American Society of Clinical Oncology (ASCO) Scientific Program Committee, European Society of Medical Oncology (ESMO) Congress Steering Committee, ESMO Educational Committee and UK National Cancer Research Institute (NCRI) Colorectal Cancer and Pancreatic Cancer Clinical Study Groups. He is on the Trial Management Groups and Trial Steering Groups of multiple national and global phase II-III gastrointestinal cancer and lymphoma trials. Dr Chau has given invited lectures in over 30 countries, and has served on international drug development advisory boards. He has peer reviewed publications in The New England Journal of Medicine, The Lancet, The Lancet Oncology, Journal of Clinical Oncology and other leading oncology/biomedical journals. Springer Healthcare IME 4

5 Mitsuru Sasako Hyogo College of Medicine, Japan Dr Sasako graduated from the Faculty of Medicine at Tokyo University in 1976 and later obtained his PhD from the same institution. He spent one year as foreign assistant of the 5th University of Paris between 1984 and 1985 before moving to the National Cancer Center Hospital Tokyo in He was appointed as Boerhaave Professor of Leiden University in In 2007, he relocated as Professor of Surgery, Hyogo College of Medicine. In 2016, he was appointed as Professor of the Department of Multidisciplinary Surgical Oncology of the same college. Dr Sasako specialises in upper gastrointestinal oncology surgery. He has carried out numerous clinical trials on surgical and adjuvant treatment of gastric cancer, publishing more than 200 articles, which include 4 publications in the The New England Journal of Medicine. Dr Sasako is committed to globally spreading Japanese concepts of oncological surgery and also Eastern clinical studies to international surgeons. He continues to establish standard treatment of gastric cancer not only in Japan but also in Europe and the USA. Springer Healthcare IME 5

6 Kei Muro Aichi Cancer Center Hospital, Japan Dr Muro graduated from the Faculty of Medicine, Tokyo in 1990 and completed his training of internal medicine at the Iwaki Kyoritsu Hospital in He then went on to complete his residency of Gastrointestinal Oncology Division at the National Cancer Center Hospital East in 1997 where he was also a Staff Doctor. In 2006, he became Chief of the Department of Clinical Oncology at Aichi Cancer Center Hospital, and adjunct Professor at Nagoya City University Graduate School of Medical Sciences a year later. In 2013, Dr Muro became adjunct Professor at Tokyo University Graduate School of Medical Science and also Director of the Outpatient Treatment Center at the Aichi Cancer Center. Since 2015, Dr Muro has been Clinical Professor at the Nagoya City University Graduate School of Medical Sciences. Yung-Jue Bang Seoul National University Hospital, South Korea Professor Bang, Professor of Medical Oncology, is the President of Biomedical Research Institute and Director of the Clinical Trials Center of Seoul National University Hospital. He has been working for Seoul National University College of Medicine and Hospital since He has served many positions including Director of the Cancer Research Institute, Chairman of Department of Internal Medicine, and Chairman of the Korean Cancer Association. Professor Bang has co-authored more than 400 papers in SCI-indexed journals including The New England Journal of Medicine and The Lancet. He is primarily interested in phase I trials and gastric cancer trials. He is the Principal Investigator of a number of international gastric cancer trials including ToGA, CLASSIC, SHINE, GOLD, and JAVELIN Gastric 300. Springer Healthcare IME 6

7 The surgical treatment pathway Mitsuru Sasako Hyogo College of Medicine, Japan Click here to view a clip from Mitsuru Sasako s presentation Professor Mitsuru Sasako used two case studies to guide the audience through the surgical pathway of patients with operable advanced gastric cancer. The case details, along with the audience votes on various treatment options and the evidence supporting these options, are described below. Also keep an eye out for the Q&A between the symposium Chair Dr Ian Chau (The Royal Marsden Hospital, London, UK) and the panellists, shown in orange boxes. Case 1 In a 53-year-old male presenting with anaemia and occasional dysphagia, an oesophagogastroduodenoscopy revealed the presence of a large tumour extending 5 cm above and the same distance below the gastrooesophageal junction (GEJ). The tumour was classified as Siewert type 2 and a positron emission tomography (PET) scan showed several perigastric lymph node metastases, as well as a mediastinal node metastasis. Chau: Is it normal practice to conduct a PET scan in patients with junctional adenocarcinoma in your institution? Sasako: Yes, PET scans are done routinely in my hospital. Bang: In most cases, we would not do a PET scan. Muro: We sometimes do PET scans for individuals with advanced disease. Sasako asked the audience which treatment option they would choose for this patient, and nearly half (46.2%) opted for chemotherapy followed by surgery, with direct surgery followed by adjuvant chemotherapy the second most popular option (19.8%). Commenting on the audience choices, Sasako said that direct surgery would be a reasonable option for this patient as he lacked distant metastases, especially if the thoracic surgeon was accustomed to performing lymph node dissections. But he pointed out that there is evidence supporting the addition of chemotherapy, and proceeded to outline it. The MAGIC trial showed that both progression-free survival (PFS) and overall survival (OS) were significantly longer for the 250 gastro-oesophageal cancer patients randomly assigned to receive chemotherapy (epirubicin, cisplatin and infused fluorouracil) before and after surgery than for their 253 counterparts who underwent surgery alone (respective hazard ratios [HRs] of 0.66 and 0.75) 1. As shown by subgroup analysis, the approach was especially effective in patients with junctional tumours, with an HR of death below Although the number of patients in the subgroup was small, Sasako said that patients with GEJ tumours can be good candidates for this approach. He also discussed the CROSS trial 2, in which 178 patients with oesophageal or GEJ cancer were randomly allocated to receive preoperative chemoradiotherapy plus surgery, while 188 were assigned to surgery alone. The addition of chemoradiotherapy significantly prolonged OS, with a 5-year rate of 47% versus 34% for surgery alone (HR=0.66). Springer Healthcare IME 7

8 5-y OS CRT-S:47% vs S : 34%: HR: ( ) Figure 1: Results of the CROSS trial comparing surgery either with or without neoadjuvant chemoradiotherapy; 5-year overall survival in the a) total study cohort and b) stratified by tumour histology (van Hagen P et al. N Engl J Med 2012; 366: ) Subgroup analysis demonstrated that histology was a crucial factor, such that patients with squamous cell carcinoma derived a greater OS benefit from the addition of chemoradiotherapy than those with adenocarcinoma. Also critical was the clinical N stage, with chemoradiotherapy plus surgery favoured more strongly among individuals harbouring tumours classed as stage 0 than those with N1 tumours. Patient s course Sasako s patient received two courses of S-1 plus cisplatin chemotherapy, and although the tumour shrunk, it was still Chau: I notice you used S-1 and cisplatin as neoadjuvant treatment for this patient is that standard of care in Japan? What about in Korea? Sasako : Yes, at the moment it is in Japan. Bang: In Korea, we generally use doublet, but for patients with borderline resectable disease, we would consider a triplet regimen of cisplatin or oxaliplatin, docetaxel and capecitabine.... Cont. Chau : How many cycles would you normally give in such a situation? Muro: Generally we use three cycles. fairly large. The upper mediastinal lymph node metastasis reduced in size from 25 mm to 10 mm, and a pathological assessment of the resected specimen classified it as ypt3, ypn1 (with 2 of 81 nodes affected). At this point, two-thirds (66.4%) of the attendees said they would proceed with chemotherapy, whereas the remaining third (33.6%) opted for chemoradiotherapy. The presenter said that the appropriate option is chemotherapy, explaining that postoperative chemoradiation has lost its role, not only in East Asia but also globally, since the phase III CRITICS trial showed no OS difference between the 393 gastric cancer patients who received adjuvant chemotherapy and the 395 given adjuvant chemoradiotherapy 3. D2 surgery does not need further local control by adding irradiation to chemotherapy. Springer Healthcare IME 8

9 Chau: In Japan and Korea, are patients with junctional adenocarcinoma given preoperative chemoradiotherapy routinely? Sasako : Not really in Japan. Bang: In Korea, we use chemotherapy alone for patients with gastric adenocarcinoma, whereas for those with squamous disease, we use chemoradiotherapy. Patient s course The patient under discussion received neoadjuvant chemotherapy with cisplatin plus S-1, followed by twofield dissection and intrathoracic oesophagogastric anastomosis, and postoperative chemotherapy with single-agent S-1 for a year. He is alive and recurrencefree 87 months after surgery. Chau: I note that you used the S-1 and cisplatin doublet as the neoadjuvant regimen, but postoperatively you give S-1 alone do you think there is no need to continue the platinum? Sasako: In our experience, it is difficult to give doublet treatment postoperatively to Japanese patients unlike for Western patients, perhaps due to a difference in fragility between populations, therefore, we revert to single-agent S-1 in the adjuvant setting. Bang: We would have continued the platinum during the adjuvant phase as well, especially for individuals with stage 3 disease. Case 2 A symptom-free male aged 64 years was suspected of having gastric cancer due to elevated tumour markers during a health check; the suspicion was confirmed after an oesophagogastroduodenoscopy showed a large tumour in the gastric body with greater curvature involvement. He underwent computed tomography (CT), which revealed several bulky nodes, and staging laparoscopy, which showed no peritoneal metastasis. Sasako asked the audience to choose between chemotherapy and chemoradiotherapy, both followed by surgery, and the majority (76.8%) chose the first option, which he said was reasonable given the limited role of neoadjuvant chemoradiotherapy in gastric cancer. After undergoing chemotherapy, which helped reduce the size of the tumour, the next step for the patient was surgery. The question put to the attendees was whether the procedure should include total gastrectomy (yes, 60.6%), splenectomy (information not available) and para-aortic node dissection (yes, 58.2%). Sasako said that total gastrectomy was the correct option as we do not often see clinical complete responses to neoadjuvant chemotherapy in gastric cancer, and then discussed the evidence supporting splenectomy and para-aortic node dissection. The JCOG 0110 trial compared splenectomy with spleen preservation in patients with gastric adenocarcinoma located in the upper third of the stomach without involving the greater curvature, and found no significant difference in OS between the groups 4. Furthermore, the trial showed that spleen preservation was non-inferior to splenectomy in this patient population. However, for individuals with tumours invading the greater curvature, splenectomy could be the better option, said Sasako. He cited the study by Kosuga et al which showed that primary tumours involving the greater curvature were significantly more likely to metastasise to the splenic hilar nodes than tumours located elsewhere; however, the 5-year OS rate was 100% for patients who underwent splenectomy to remove the nodes 5. With regard to para-aortic node dissection, prophylactic dissections are no longer carried out since the JCOG 9501 study showed comparable OS rates for patients who underwent D2 surgery alone and those who had para-aortic node dissection in addition 6, the presenter said. However, therapeutic dissection remains a challenge. Springer Healthcare IME 9

10 Research suggests that for patients with borderline resectable gastric cancer, neoadjuvant chemotherapy followed by D2 surgery plus para-aortic node dissection can have excellent results. The JCOG 0405 trial enrolled 51 patients with bulky nodes and/or para-aortic node metastases; participants received S-1 plus cisplatin followed by D2 surgery and para-aortic node dissection with curative intent 7. The 5-year OS rate for the entire cohort was 52.8%, and was 57.0% for those with only para-aortic node involvement. References 1. Cunningham D et al. N Engl J Med 2006; 355: van Hagen P et al. N Engl J Med 2012; 366: Verheij M et al. J Clin Oncol 2016; 34 (suppl; abstr 4000) 4. Sano T et al. Ann Surg 2017; 265: Kosuga T et al. Gastric Cancer 2011; 14: Sasako M et al. N Eng J Med. 2008; 359: Tsuburaya A et al. Br J Surg 2014; 101: Therefore, given the much lower complete response rate with neoadjuvant chemotherapy in gastric cancer than in breast cancer, para-aortic node dissection should be added to D2 in borderline resectable cases. Patient s course The patient underwent total gastrectomy with splenectomy as the tumour had invaded the greater curvature. Furthermore, the transverse colon was partially resected, and cholecystectomy and para-aortic node dissection was performed. Pathological analysis of the specimen showed no residual cancer cells in the stomach, colon or any lymph node. And many lymph nodes contained fibrosis, necrotic tissue and foamy cells, demonstrating the remarkable effect of chemotherapy, Sasako told the audience. If all patients showed such results, we would stop doing extensive surgery, but this is an exceptional case. Springer Healthcare IME 10

11 Optimising patient care in metastatic gastric cancer Kei Muro Aichi Cancer Center Hospital, Japan Click here to view a clip from Kei Muro s presentation Dr Kei Muro focussed on the available therapeutic options for patients with metastatic gastric cancer, referring to two patient cases to highlight the key points. Case 1 A 69-year-old man with no prior medical history presented with slight dysphagia, and after undergoing oesophagogastroduodenoscopy was diagnosed with Siewert type 2 GEJ cancer. The disease had metastasised to the liver and the para-aortic lymph nodes, and immunohistochemistry (IHC) showed that the tumour was HER2-positive. Treatment with six cycles of capecitabine, cisplatin and trastuzumab resulted in a partial response, after which the regimen was continued for another four cycles until disease progression. Chau: I note that you gave the patient 10 cycles of capecitabine, cisplatin and trastuzumab. Is it normal practice to continue chemotherapy until disease progression? Muro: Generally, we initially give six cycles of the triplet, followed by capecitabine and trastuzumab as maintenance. Cont. Bang: We would give six cycles of doublet chemotherapy plus trastuzumab, followed by trastuzumab alone as maintenance, although in some cases we would continue the capecitabine as well. On being asked to decide the next step for this patient, the majority (61.2%) chose treatment with a taxane (weekly paclitaxel) and ramucirumab, with 29.9% opting for a taxane (weekly paclitaxel or docetaxel) plus trastuzumab. Muro was intrigued that 30% of attendees would continue trastuzumab, as there is no evidence to support the use of anti-her2 therapy beyond progression despite being evaluated in multiple trials. For instance, the phase III TyTAN trial 1, which investigated the addition of lapatinib to paclitaxel in patients with HER2-positive advanced gastric cancer, found that OS was comparable between the dual regimen and paclitaxel alone groups. And in the phase III GATSBY trial 2, median OS did not differ significantly between the HER2-positive patients with advanced gastric or GEJ adenocarcinoma randomly assigned to receive trastuzumab emtansine (DM1) and those given a taxane. Chau: What about in South Korea?... The presenter added that an analysis of 46 patients treated at their hospital showed that although PFS is significantly longer for patients who do versus those who do not Springer Healthcare IME 11

12 receive trastuzumab beyond progression, OS remains comparable 3. He also pointed out that research has shown loss of HER2 expression following first-line anti-her2 treatment. In a study by Janjigian et al, 35% of 23 patients who progressed on trastuzumab were found to have lost HER2 positivity 4. Even in our institution, we found that three of four patients who received HER2 therapy for primary gastric cancer in 2015 tested negative for HER2 when a rebiopsy was performed post-treatment [unpublished data], Muro told the audience. Therefore, it is surprising that clinicians would still consider trastuzumab as a second-line option in this patient population, he said, adding that the popularity of ramucirumab is less surprising given recent results. In the phase III RAINBOW trial 5, previously-treated patients with advanced gastric or GEJ adenocarcinoma had a significant 19% lower risk of death with the addition of ramucirumab than placebo to paclitaxel. The anti-angiogenic agent has also shown promise in HER2-positive patients, as shown by a biomarker analysis of the REGARD trial 6, and also for those previously treated with trastuzumab 7. However, Muro urged caution in interpreting these results as both analyses had a limited sample size. Nonetheless, in the most recent Japanese guidelines for the treatment of metastatic gastric cancer, the combination of paclitaxel and ramucirumab is recommended as the most preferred second-line regimen 8. The presenter also drew attention to the change in prescribing practice at his institution since ramucirumab was approved prior to the approval, 80% of patients received taxanes, but since then, 63% have been treated with ramucirumab plus paclitaxel [unpublished data]. He pointed out that this dramatic change has only been possible because the angiogenesis inhibitor is reimbursed in Japan, which, unfortunately, is not the case in other countries. Patient s course The patient received weekly paclitaxel plus ramucirumab, to which he had a partial response, but 28 weeks after initiating treatment, his disease progressed. Figure 2: Overall survival results of the RAINBOW trial (Wilke H, et al: Lancet Oncol 2014; 15: ) Springer Healthcare IME 12

13 Sasako: How many biopsy specimens are sufficient to confirm HER2 status? Muro: Usually two or three samples are plenty. Case 2 Muro asked the symposium attendees how they would treat a 70-year-old man diagnosed with stomach cancer located in the middle of the gastric body after presenting with anorexia. Ultrasound imaging showed the presence of pleural effusion and large ascites, a physical examination established the performance status as 2 and immunohistochemistry showed that the tumour was negative for HER2. Chau: When a patient has ascites, are you concerned about giving an oral fluoropyrimidine? Muro: In this case, oral intake was limited but not impossible, but yes, we would not give oral fluoropyrimidine if oral intake was unstable. Bang: I would choose FOLFOX for this particular patient as I think that an oral agent could be a problem. Sasako: I think either 5-FU monotherapy or FOLFOX would be valid options as oral intake is not stable. The audience response was mixed, with 29.9% opting for S-1 or capecitabine together with oxaliplatin and 24.7% each choosing FOLFOX or cisplatin alongside either 5-fluorouracil (FU), S-1 or capecitabine. Patient s course We gave the patient the modified FOLFOX6 regimen, said Muro, which resulted in a dramatic shrinkage of ascites, a reduction that continued over 7 months of treatment. Expanding on the therapeutic options for patients with ascites, Muro said that the FLTAX regimen (5-FU, l-leucovorin and paclitaxel) has shown promise in peritoneal disseminated gastric cancer patients with massive ascites or inadequate oral intake. The regimen was found to be feasible as first-line therapy in a Japanese multicentre study 9, and a phase II/III trial (JCOG 1108/ WJOG 7312G) comparing 5-FU plus leucovorin either with or without paclitaxel is ongoing 10, although recruitment is slow, the presenter said. He also discussed the PHOENIX-Gastric Cancer trial a phase III study evaluating intra-peritoneal paclitaxel plus S-1 and intravenous paclitaxel (n=114) versus S-1 plus cisplatin (n=50) in gastric cancer patients with disease that had metastasised to the peritoneum or ovary, but no other location 11. The treatment arms were unbalanced with respect to the amount of ascites, such that more patients in the intra-peritoneal paclitaxel arm had small or moderate ascites whereas the majority in the control arm had no ascites. Median OS did not differ significantly between groups in the primary analysis, at a median of 17.7 and 15.2 months for the experimental and control arms, respectively, and a hazard ratio of But in a sensitivity analysis adjusting for baseline ascites, treatment with intra-peritoneal paclitaxel significantly reduced the risk of death by 41%. The findings were similar in the per-protocol population, with a significant 36% lower risk of mortality in the experimental arm. Although the sample size was small, noted Muro, the data are very good. Audience member: What is your opinion on the addition of epirubicin in gastric cancer patients? Muro: We absolutely do not use epirubicin in Japan. I think it is not needed. Chau: Our current take on this is that epirubicin is a component that we do use in some cases, but do not regard as essential. Springer Healthcare IME 13

14 References 1 Satoh T et al. J Clin Oncol 2014; 32: Kang YK et al. J Clin Oncol 2016; 34 (suppl 4S; abstr 5) 3 Narita Y et al. Oncol Lett 2016; accepted for publication 4 Janjigian YY et al. J Clin Oncol 2015; 33 (suppl 3; abstr 63) 5 Wilke H et al. Lancet Oncol 2014; 15: Fuchs CS et al. J Clin Oncol 2015; 33 (suppl; abstr 4029) 7 European public assessment report (EPAR) for Cyramza. medicines/human/medicines/002829/human_med_ jsp&mid=wc0b01ac058001d124 Accessed 10 January Japanese Gastric Cancer Association. Gastric Cancer 2017; 20: Iwasa S et al. Jpn J Clin Oncol 2012; 42: Japan Clinical Oncology Group clinical trials. en/trials/index.html Accessed 10 January Ishigami H et al. J Clin Oncol 2016; 34 (suppl; abstr 4014) Springer Healthcare IME 14

15 Future directions in metastatic gastric cancer Yung-Jue Bang Seoul National University Hospital, Korea Click here to view a clip from Yung- Jue Bang s presentation In the final talk of the symposium, Professor Yung-Jue Bang provided an overview of the agents and combinations being evaluated in the metastatic gastric cancer setting. He explained that the current options for systemic treatment are cytotoxic chemotherapy or targeted agents, such as trastuzumab and ramucirumab, but what about the future? Bang believes there are three options: we can develop better agents or combinations for validated targets or agents against novel molecular targets or we can explore immune checkpoint blockade. All three approaches have been explored, he said, with varying degrees of success. New approaches to target HER2 Here we have two options either to develop a different anti-her2 antibody or to generate an antibody drug conjugate, the speaker pointed out. Pertuzumab is an example of the former approach; unlike trastuzumab, it interferes with HER2 dimerisation, thereby disrupting multiple HER signalling pathways 1. In combination with trastuzumab and chemotherapy, pertuzumab has shown efficacy in HER2-positive metastatic breast cancer 2, and is being explored in patients with HER2-positive advanced gastric cancer. The findings of the JACOB study, comparing trastuzumab plus cisplatin alongside pertuzumab or placebo, are expected in Trastuzumab DM1 is a monoclonal antibody cytotoxic drug conjugate that has demonstrated efficacy in the second-line treatment of HER2-positive advanced breast cancer 3. But in patients with advanced gastric cancer, the conjugate failed to improve survival over chemotherapy, as shown by the phase II/III GATSBY 4 trial, also discussed by Dr Muro. Mutually exclusive amplification Figure 3: Gene amplifications in gastric cancer (Deng N et al. Gut 2012; 61: ) Springer Healthcare IME 15

16 Identifying and validating novel molecular targets Recent research has identified amplifications of five different genes FGFR2, KRAS, EGFR, ERBB2 and MET in between 4 9% of patients with gastric cancer 5, suggesting that over a third of gastric cancer patients could potentially be treated with receptor tyrosine kinase/ras-directed agents. However, the results of clinical trials investigating such approaches have mainly been negative. For instance, the phase III trials 6,7 of rilotumumab which binds to HGF and blocks it from binding to its receptor c-met, thereby inhibiting c-met activation and onartuzumab which targets c-met directly were terminated early despite promising early-phase results. The FGFR inhibitor AZD4547 also failed to significantly prolong PFS relative to treatment with paclitaxel, despite being well tolerated by patients enrolled on the SHINE trial 8. The main reason for failure was the marked intratumour heterogeneity of FGFR2 amplification, said Bang. One novel targeted approach that has shown success is the antibody against isoform 2 of claudin-18 (CLDN18.2), which is a major structural component of tight junctions. In the FAST trial 9, patients with advanced gastric or GEJ adenocarcinoma positive for CLDN18.2 expression (defined as an IHC score of 2 or higher in at least 40% of tumour cells) were randomly assigned to receive first-line epirubicin, oxaliplatin and capecitabine (EOX) with or without the anti-cldn18.2 antibody IMAB362. The addition of IMAB362 significantly improved PFS and OS, with median times of 7.9 versus 4.8 months and 13.2 versus 8.4 months, respectively. Targeting DNA repair agents has been less successful, however, said Bang. OS improved with the addition of the PARP inhibitor olaparib rather than placebo to paclitaxel in patients with advanced gastric cancer who had progressed on first-line therapy, but the improvement was not statistically significant 10. Immune checkpoint inhibition The response to immune checkpoint inhibitors such as those targeting CTLA-4 or PD-1/PD-L1 has been somewhat mixed in gastric cancer patients, observed Bang. The phase II CA study 11, in which gastric or GEJ cancer patients who had at least stable disease after firstline chemotherapy were randomly assigned to receive maintenance ipilimumab or best supportive care, was negative, with no significant improvements in PFS or OS with the CTLA-4 blocker. However, some ipilimumabtreated patients had a durable response, which suggests that treatment with immune checkpoint inhibitors can be effective in some patients. PD-1 blockade with the monoclonal antibody pembrolizumab also evokes a response in some patients. In the phase Ib KEYNOTE-012 trial 12, some degree of tumour shrinkage was observed in just over half the participants, and while not all patients derived benefit from pembrolizumab treatment, durable response was seen in those who did. The key is to select individuals most likely to benefit, remarked the presenter, with tumoural PD-L1 expression the most reliable marker at present. Case study Bang shared a further patient case for the audience to discuss. A 51-year old man presented in the emergency room with haematemesis and melena, and a gastroscopy showed the presence of an ulcero-infiltrative mass in the gastric body. After undergoing a CT scan which indicated peritoneal seeding among other features the patient underwent a palliative total gastrectomy, and was referred to the presenter s institution. Chau: Professor Sasako, what are your thoughts on palliative gastrectomy in patients with peritoneal disease? Sasako: Palliative gastrectomy was considered an option prior to the results of the REGATTA trial, which showed no benefit of the surgical procedure. I prefer to use radiation to stop bleeding from the gastric tumour, so radiation followed by chemotherapy. In further work-up, pathological analysis classed the Springer Healthcare IME 16

17 tumour as T4aN3aM1, IHC showed the absence of HER2 amplification, and postoperative CT showed no measurable lesion. Which regimen would you recommend, asked Bang. The most popular choice was the combination of capecitabine and oxaliplatin (XELOX), followed by FOLFOX, where each was chosen by 32.8% and 20.7% of symposium participants, respectively. The patient received nine cycles of XELOX, and after remaining relatively well for 7 months, was found to have multiple peritoneal seeding nodules with multifocal bowel invasion and small amount of ascites. Of the second-line therapeutic options presented to the audience, the large majority (61.7%) chose paclitaxel plus ramucirumab, with 18.5% opting for weekly paclitaxel and 7.4% for FOLFIRI. Bang said that paclitaxel plus ramucirumab would be the right choice should there be no financial restraints, but the anti-angiogenic agent is not reimbursed in Korea. They decided to carry out an extensive biomarker analysis, including IHC and next-generation sequencing (as part of the GIANT study), and detected loss of PTEN expression and a PI3KA mutation. Such dysregulation of the PI3K-AKT pathway is a hallmark of various human diseases and can be targeted by small molecule inhibitors of PI3K and AKT, explained Bang. Therefore, the patient was treated with five cycles of paclitaxel and an AKT inhibitor in a clinical trial, but after an initial response, he progressed. At this point in the treatment pathway, the majority (57.7%) of the attendees said they would enrol the patient onto a clinical trial of a PD-1 or PD-L1 antibody, with around 12% each choosing ramucirumab monotherapy, irinotecan or FOLFIRI. The presenter explained that the results of an additional biomarker analysis revealed that the patient harboured a tumour that was negative for PD-L1 expression, which begs the question: Would you still consider a clinical trial of a PD-1 or PD-L1 antibody in this patient? Chau : Would you consider enrolling a patient in a clinical trial of a PD-1 or PD-L1 inhibitor even if the patient is negative for the biomarker (tumoural PD-L1 expression)? Bang: Yes, I would. Muro: I agree, because PD-L1 is not a confirmative biomarker. Responses have been observed even in patients with PD-L1 negative tumours. Chau: Professor Bang, what are your views on the personalised medicine approach? Bang: Personalised medicine is the future, but we are not there yet. We need more evidence, and better strategies, before we can incorporate precision medicine in gastric cancer. References 1 Juntilla TT et al. Cancer Cell 2009; 15: Swain SM et al. N Engl J Med 2015; 372: Verma S et al. N Engl J Med 2012; 367: Kang YK et al. J Clin Oncol 2016; 34 (suppl 4S; abstr 5) 5 Deng N et al. Gut 2012; 61: ClinicalTrials.gov. NCT Accessed 10 January ClinicalTrials.gov. NCT Accessed 10 January Bang YJ et al. J Clin Oncol 2015; 33 (suppl; abstr 4014) 9 Al-Batran SE et al. J Clin Oncol 2016; 34 (suppl; abstr LBA4001) 10 Bang YJ et al. Ann Oncol 2016; 27 (suppl 6; abstr LBA25) 11 Moehler MH et al. J Clin Oncol 2016; 34 (suppl; abstr 4011) 12 Muro K et al. Lancet Oncol 2016; 17: A larger proportion of the audience said they would consider it than not. Springer Healthcare IME 17

18 This programme is made possible thanks to independent educational sponsorship from Eli Lilly and Company