Educational Objectives. Worldwide Incidence. Agenda. Gastric Adenocarcinoma: Risk Factors. Gastric Cancer Statistics

Transcription

1 Educational Objectives Evaluate the current evidence across multiple lines of therapy and appropriately sequence therapies for gastric and gastroesophageal (GEJ) cancers Mitigate toxicities associated with gastric cancer treatment regimens to improve patient outcomes Evaluate the safety and efficacy data for emerging therapies for gastric and GEJ cancers. Agenda Worldwide Incidence Introduction Overview Treatment in first-line setting Treatment in second-line setting Treatment in third-line setting Role of approved biologics. Emerging therapies Side effect management Questions and Answers Ajani et al. Nature Reviews Gastric Cancer Statistics Gastric Adenocarcinoma: Risk Factors National cancer institute: Surveillance, Epidemiology, and End Results program (SEER) Stat Fact Sheet: Stomach Cancer: Nutritional Low fat or protein consumption High consumption of salted, smoked, or preserved foods High nitrate consumption Low consumption of fruits, vegetables Medical Previous gastric surgery Helicobacter pylori infection (2x) Chronic atrophic gastritis Souza RF, et al. CA Cancer J Clin. 25;55: National Cancer Institute: Gastric Cancer Treatment PDQ. Environmental P Helicobacter pylori infection (2x) Poor food preparation (smoked) Lack of refrigeration Poor drinking water (eg, well water) Occupation (eg, rubber, coal workers) Cigarette smoking (1.6x) Hereditary Factors Germline CDH1 mutation Impaired function in Mistmatch repair genes (MLH1) Inactivating mutations in BRCA gene 1

2 STAGING: AJCC TNM Classification for Gastric Cancer STAGING: AJCC TNM Classification for Gastric Cancer NCCN Guidelines Version Gastric Cancer. J Natl Compr Canc Netw. 217 NCCN Guidelines Version Gastric Cancer. J Natl Compr Canc Netw. 217 Histological Classification Molecular Subtypes Diffuse Type Intestinal Type Ajani JA, Lee J, et al. Nature Reviews Disease Primers 3, 1736 (June 217) doi:1.138/nrdp Ajani JA, Lee J, et al. Nature Reviews Disease Primers 3, 1736 (June 217) doi:1.138/nrdp The Role of Chemotherapy in Advanced Gastric Cancer Multidisciplinary Care of Gastric and Locally Advanced GEJ Cancer Survival with best supportive care (BSC) alone ~ 3 months Chemotherapy affords survival in metastatic gastric cancer Benefit in weighted mean average survival ~ 6 months. Optimal chemotherapy for advanced gastric cancer: Is there a global consensus? Lordick, F., Lorenzen, S., Yamada, Y. et al. Gastric Cancer (214) 17: 213 2

3 Role of Surgery in Treatment of Gastric Cancer Refer to Medical Oncology For Advanced Disease Palliative Care No Surgical Candidate Yes Perioperative Chemotherapy Restaging Surgical Treatment of Locally Advanced Esophageal Cancer Definitive Chemoradiotherapy No Patient is medically fit and agrees to surgery Yes Neoadjuvant Chemoradiotherapy No Surgical Candidate Restaging Yes Yes Diagnostic Laparoscopy Peritoneal mets or Cytology positive No Refer to Medical Oncology For Advanced Disease Palliative Care Yes Evidence of metastatic disease No Surgical Resection Surgical Resection Phase III Trials Supporting Standard Practice in Advanced Gastric Cancer First- Line Chemotherapy TTP, Mos Study Treatment (n) RR, % (95% CI) Median OS, Mos PFS, Mos (95% CI) FAMTX (18) 21 (13-29) NA Webb et al [1] 45 (36-54) ECF (111) NA (P =.2) (P =.9) (P =.6) CF (224) 25 ( ) V325 DCF (221) 37 ( ) (P =.1) S-1 (15) NA SPIRITS Cisplatin + S-1 (149) NA 8.6 mo (95% CI: ) 9.2 mo (95% CI: ) 11. mo (IQR: ) 13. mo (IQR: ) NA NA 4. (IQR: ) 6. (IQR: ) (P <.1) 3.7 ( ) 5.6 ( ) NA NA Clinicaloptions.com/Oncology Webb A, et al. J Clin Oncol. 1997;15: Van Cutsem E, et al. J Clin Oncol. 26;24: Koizumi W, et al. Lancet Oncol. 28;9: REAL 2 : Study Design REAL-2 Results HR:.86 (.8-.99) Capecitabine is non-inferior to infused 5-FU More G3/4 neutropenia and hand foot syndrome Oxaliplatin is non-inferior to cisplatin HR:.92 ( ) Less G3/4 neutropenia, tromboembolism, alopecia More G3/4 diarrhea, G3/4 peripheral neuropathy. Cunningham et al. NEJM 28 3

4 ECF vs EOX Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma with Fluorouracil, Leucovorin Plus Either Oxaliplatin or Cisplatin Arm OS (m) 1 year survival p-value HR (95% CI) (95% CI) ECF ( ) EOX ( ).2.8 ( ) Improved efficacy of EOX compared to ECF for survival Cunningham et al. NEJM 28 Salah-Eddin Al-Batran; et al; JCO 28, 26, V-325 Study Design TAX 325 Study Results Kaplan-Meier estimates of (A) time to progression and (B) overall survival among chemotherapy-naïve advanced gastric cancer patients treated with docetaxel, cisplatin, and fluorouracil (DCF) or cisplatin and fluorouracil (CF; full analysis population). Eric Van Cutsem; Vladimir M. Moiseyenko; Sergei Tjulandin; Alejandro Majlis; Manuel Constenla; Corrado Boni; Adriano Rodrigues; Miguel Fodor; Yee Chao; Edouard Voznyi; Marie-Laure Risse; Jaffer A. Ajani; JCO 26, 24, DOI: 1.12/JCO Copyright 26 ECF vs FOLFIRI Treatment of Metastatic Disease (1 st Line) Time-to-treatment failure (TTF) according to treatment arm (Kaplan-Meier estimation). ECX arm: epirubicin, cisplatin, and capecitabine as the first-line treatment; FOLFIRI arm: irinotecan, leucovorin, fluorouracil bolus, and continuous infusion as the first-line treatment. HR, hazard ratio. OX EOX/ EOF Cape ECX/ EOX XP FLO FOLFIRI S-1/ Cis DCF ECF #Pts %RR 44% 45% 41% 34% 32% 54% 36% 45% TTP, months OS, months Rosine Guimbaud; Christophe Louvet; Pauline Ries; Marc Ychou; Emilie Maillard; Thierry André; Jean-Marc Gornet; Thomas Aparicio; Suzanne Nguyen; Ahmed Azzedine; Pierre-Luc Etienne; Eveline Boucher; Christine Rebischung; Pascal Hammel; Philippe Rougier; Laurent Bedenne; Olivier Bouché; JCO 214, 32, DOI: 1.12/JCO Cunningham NEJM 358:36;28, Kang Annals Oncol 2:666;29, Al-Batran JCO 26:1435;28, Dank Annals Oncol 19:45;28, Koizumi Lancet Oncol 9:215; 28, Van Cutsem JCO 24:4991;26, Webb JCO 15:61;1997 4

5 Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer: ToGA Primary endpoint: OS Patients with advanced gastric cancer screened for HER2 status (N = 383) Patients with HER2+ advanced gastric cancer (n = 81; 22% of successful screenings) Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-FU (n = 584) *Selected at investigator s discretion: 5-FU 8 mg/m 2 /day infusional on Days 1-5 q3w x 6; capecitabine 1 mg/m 2 BID on Days 1-14 q3w x 6. R 5-FU or Capecitabine* + Cisplatin 8 mg/m 2 q3w x 6 + Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose) (n = 294) 5-FU or Capecitabine* + Cisplatin 8 mg/m 2 q3w x 6 (n = 29) Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer (ToGA): OS 1. Median.9 Events OS HR 95% CI.8 FC + T FC Pts at Risk, n Mos Survival Probability P Value.46 Bang YJ, et al. Lancet. 21;376: Bang YJ, et al. Lancet. 21;376: Key Points First Line Treatment Chemotherapy with platinum compound (cisplatin, oxaliplatin) plus a fluoropyrimidine (fluorouracil [5-FU], capecitabine, or S-1) is the global standard Selective patients can benefit from triplet combinations but increased side effects must be considered. Overtoxic treaments like docetaxelcontaining triplet regimens cannot be recommended in older patients. Oxaliplatin and Irinotecan can substitute for cisplatin without compromising the efficacy of chemotherapy Trastuzumab in combination with chemotherapy is the recommended treatment for patients with HER2+ tumors 3+ by IHC or 2+IHC + FISH positive. Second Line Chemotherapy Second Line Chemo Gastric Cancer Phase III Trials Improved Survival Phase III REGARD Trial BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer Stratified by geographic region, weight loss (> vs < 1% over 3 mos), location of primary tumor (gastric vs GEJ) Patients with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine- containing combination therapy, ECOG PS -1 (N = 355) Ramucirumab 8 mg/kg IV q2w + BSC (n = 238) BSC + Placebo (n = 117) Treatment until PD, unacceptable toxicity, or death Docetaxel/Irinotecan vs BSC Docetaxel vs BSC Primary objective: OS Secondary endpoints: PFS, 12-wk PFS, ORR, DOR, QoL, safety Ford H Lancet Oncol 15:78; 214; Kang JH J Clin Oncol 3:1513; 212 Fuchs CS, et al. Lancet. 214 Jan 4;383(9911):

6 REGARD Trial of BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer: OS REGARD Trial of BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer: PFS Proportion Remaining Alive Ramucirumab Placebo Censored Ramucirumab Placebo Patients/events 238/ /99 Median, mos 5.2 ( ) ( ) 3.8 (95% CI) 6-mo OS, % mo OS, % HR:.776 (95% CI: ; P =.473) Proportion Without Progression Ramucirumab Placebo Censored Ramucirumab Placebo Patients/events 238/ /18 Median, mos 2.1 ( ) ( ) 1.3 (95% CI) 12-wk PFS, % 4 16 HR:.483 (95% CI: ; P <.1) Pts at Risk, n Ramucirumab Placebo Mos Mos Pts at Risk, n Ramucirumab Placebo Fuchs CS, et al. Lancet. 214 Jan 4;383(9911):31-9. Fuchs CS, et al. Lancet. 214 Jan 4;383(9911):31-9. RAINBOW Study RAINBOW: Overall Survival S C R E E N 1:1 R A N D O M I Z E Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 8 mg/m 2 day 1, 8 &15 of a 28-day cycle N = 33 Placebo day 1&15 + Paclitaxel 8 mg/m 2 day 1, 8 &15 N = 335 Treat until disease progression or intolerable toxicity Important inclusion criteria: Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma Progression after 1 st line platinum/fluoropyrimidine-based chemotherapy Stratification factors: Geographic region Measurable vs non-measurable disease Time to progression on 1st line therapy (< 6 mos vs. 6mos) Overall survival probability HR (95% CI) =.87 (.678,.962) Stratified log rank p-value =.169 RAM + PTX PBO + PTX Events 33 / / 26 Patients / Median(mos) (95% CI) 9.63 (8.48, 1.81) 7.36 (6.31, 8.38) 6-month OS 72% 57% 12-month OS 4% 3% Δ mos difference: 2.3 months Censored No. at risk RAM + PTX PBO + PTX RAM = ramucirumab; PTX = paclitaxel; PBO = placebo. *GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC Wilke H. Lancet Oncol. 214 Oct;15(11): Wilke H. Lancet Oncol. 214 Oct;15(11): The Role of Biologics HER-2 Inhibition Trial ToGa Bang et al. Lancet. 21;376: LOGIC Hecht et al J Clin Oncol. 216;34: JACOB Tabernero et al. Ann Oncol. 217;28(Supp 5):v29-v268. Line of Drugs Therapy 1 st Line Trastuzumab + Cis/5-FU vs Cis/5-FU 1 st Line Cape Ox+ Lapatinib vs CapeOx + P Patient Selection HER2 + IHC 2+ and FISH + or IHC 3 or FISH+ 1 st Line Pertuzumab + IHC 3+ vs IHC Trastuzumab + chemo 2+ and ISH vs Trastuzumab+chemo Survival 13.8 mos vs 11.1 mos HR (.74; 95% CI.6-.91) 12.2 mos vs 1.5 mos HR(.91 ( ) 17.5 mos vs 14.2 moshr.84; [CI].71-1.; Results FDA approval in 21 No improvement in PFS or OS NS TYTAN Satoh et al. J Clin Oncol. 214;32: Second Line Lapatinib + Paclitaxel vs Paclitaxel HER mos vs 8.4 mos P=.144 Did not improve OS significantly GATSBY Thuss-Patience et al. Lancet Oncol. 217;18: nd / 3 rd Line TDM-1 + Taxane vs Taxane alone HER2+ (IHC or ISH) 7 9 months for T-DM1 vs 8 6 mos for taxane ( [HR] 1 15 [95% CI ]; p= 86) No efficacy 6

7 EGFR Inhibition / EGFR Targeting Hepatocyte Growth Factor Targeted Agents Phase III: Negative Trials for EGFr REAL 3: ECX + / - Panitumumab (U.K.) Negative: Panitumumab had inferior outcomes EXPAND: Cape-Cis + / Cetuximab (E.U.) Negative: Cetuximab trended inferior COG: BSC vs Gefitinib (U.K.): Negative Trials conducted with no biomarker Selection of patients No biomarker identified in EG Cancer TRIAL RILOMET-1 RILOMET-2 MET Gastric Phase II NCT Drugs Rilotumumab + ECX vs ECX Rilotunumab + CX vs CX Ornatuzumab + FOLFOX vs FOLFOX Foretinib Patient Selection MET +/HER2- MET+/HER2- MET+/HER2- Unselected Results Closed due to toxicity Closed due to toxicity Inefective No improvement in PFS or OS Waddell T Lance Oncol 14: 481; 213 Lordick F et al Lancet 14:49; 213 Sutton JCO 3: 212 (suppl 34 abstr 6) Figure from Oncotarget, 217, Vol 8 (No 34), pp: Figure from Oncotarget, 217, Vol 8 (No 34), pp: VEGF/VEGFR Pathway Trial AVAGAST REGARD RAINBOW Line of Therapy 1 st Line 2nd Line 2nd Line Drugs XP + Bevacizumab vs XP+P Ramucirumab vs BSC Paclitaxel + Ram vs Paclitaxel Patient Selection No selection No selection No selection Survival 12.1 mos vs 1.1 mos HR.87; 95% CI,.73 to 1.3; P = mos vs 3.8 mos p= mos vs 7.4 mos Results NS hazard ratio.87; 95% CI,.73 to 1.3; P =.12 hazard ratio.87; 95% CI,.73 to 1.3; P =.12 Emerging Therapies Phase III NCT rd Line Apatinib vs Placebo No selection 195 days vs 14 days Improvement in PFS/OS Asian study Immunotherapy Approaches in GEJ Cancer Cancer Vaccines Immunotherapy Active Specific: Cancer Vaccines, MAGE-3, G17DT, FGFR peptide, DC vaccines Non-specific: Checkpoint inhibitors: anti CTLA-4, anti PD-1, Anti PDL-1 Passive Monoclonal antibodies: trastuzumab, ramucirumab, ACT, CTL, TIL, CART-T Aim to prime and expand tumor-specific T cells by delivering tumor antigens to drive effective T cell activation. 7

8 Cancer Vaccines Adoptive Cell Therapy Peptides derived from VEGFR 1 and 2 in combination with chemotherapy in patients with advanced gastric cancer resulted in partial response 55%. Masuzawa T et al. Int J Oncol. 212; 41 (4): Early phase studies of a DC vaccine combined with HER2 peptide in a small group of advance HER-2 positive patients and a pulsed DC MAGE3 peptide vaccine appeared to show modes effect. Further clinical development of DC-based vaccine approaches has been limited. In ACT, tumor-specific T cells are isolated from a patient, amplified and primed in vitro to tumor antigens or through genetic modification before being transfused into the patient. Cassian Yee Clin Cancer Res 213;19: by American Association for Cancer Research Immune Checkpoints CTLA-4 and PD-1/PD-L1 Immune Checkpoint Inhibitors MHC II TC R APC CD4 B7-1 B7-2 CTL-4 MHC II TCR APC CD4 B7-1 B7-2 CD28 PD-L1 PD-1 Coinhibition 1 - Prevent Costimulation Antigen specific presentation - 1 Antigen specific presentation Adapted from Immunobiology 8th edition, Garland Science 212) CTL-4 Directed Approaches PD-1 Directed Approaches Phase II Ralph et al II NCT Drug Tremelimumab (CTL-4 antibody) Ipilimumab (CTL-4 ab) vs best supportive care No of pts Line of Therapy 18 2 nd /3 rd line 114 Sequential after 1 st line Outcome ORR:5% TTP: 2.83 months MOS: 4.83 months PFS: 2.92 vs 4.89 (mos) OS: vs (mos) P value P=.36 P=.6433 Phase Ib KEYNOTE-12 I Segal et al. I/II Checkmate 32 Drug Pembrolizumab (PD-1 antibody) Durvalumab (MEDI4736, PD-L1 antibody) No of Patients 39 PD-L1 + Line of Therapy Any line Nivolumab (PD-1 antibody) 59 >2 lines I (Japan) Avelumab 2 2 nd /3 rd line Results ORR 22% mpfs: 1 9 (mos) mos: 11 4 (mos) 16 Any line ORR 25% ORR was 12% Median OS was 6.8 mo (95% CI, ) ORR 15% mpfs: 11.6 weeks 8

9 Phase 3 Study of NIvolumab (NIvo) In Previously Treated Advanced Gastrıc or Gastroesophageal Junctıon (G/GEJ) Cancer Phase 3 Study of NIvolumab (NIvo) In Previously Treated Advanced Gastrıc or Gastroesophageal Junctıon (G/GEJ) Cancer: ATTRACTION-2 Updated results and subset analysis by PD-L1 expression (ATTRACTION-2) The Lancet DOI: (1.116/S (17) ) The Lancet DOI: (1.116/S (17) ) Response by PDL-1 Expression KEYNOTE-59: Study Design Open-label, Multicohort Phase II Study Pts with recurrent or metastatic gastric or GEJ adenocarcinoma; ECOG PS /1; HER2/neu negative*; no prior PD-1/PD-L1 tx, systemic steroids, autoimmune disease, ascites, or CNS mets (N = 259) Cohort 1 2 prior lines of CT Cohort 2 No prior tx Cohort 3 No prior tx, PD-L1+ Pembrolizumab 2 mg Q3W Pembrolizumab 2 mg Q3W + Cisplatin 8 mg/m 2 Q3W + 5-FU 8 mg/m 2 Q3W or Capecitabine 1 mg/m 2 BID Q3W Pembrolizumab 2 mg Q3W Tx continued for 24 mos or until PD, intolerable toxicity, or withdrawal of consent; survival follow-up until study end, death, or withdrawal *HER2/neu positive allowed in cohort 1 if prior trastuzumab administered. Primary endpoints: ORR, safety; secondary endpoints: DoR, PFS, OS Exploratory biomarker endpoints: efficacy by MSI, GEP The Lancet DOI: (1.116/S (17) ) Fuchs CS, et al. ASCO 217. Abstract 43. KEYNOTE-59 (Cohort 1): Survival Response by PD-L1 Expression Response PD-L1 Positive (n=148) PD-L1 Negative (n=19) OS (%) All Pts OS (N = 259) Median OS, mos (95% CI) 5.6 ( ) 12-mo OS rate, % 23.4 PFS (%) PFS All Pts (N = 259) Median PFS, mos (95% CI) 2. (2.-2.1) % 95% CI % 95% CI ORR CR Mos Pts at risk, n Mos Pts at risk, n PR DCR Fuchs CS, et al. ASCO 217. Abstract 43. Reproduced with permission. 9

10 Checkmate 32 Gastric Cohort Best Reductions in Target Lesions Key Points Immunotherapy including immune checkpoint inhibition is a growing area of research in gastric and esophageal cancers. Certain tumor characteristics may predict favorable responses to these approaches. Checkpoint inhibitor with anti-pd-1 mab pembrolizumab and nivolumab has led to increased response rates in advanced heavily pre-treated patients Higher response rates in PDL-1 expression Combination approaches with chemotherapy, radiotherapy and targeted agents are likely to improve outcomes Clinical trials applying modern sequence technology that allows for identification of unique, tumor-specific neoantigen profiles are ongoing. Side Effect and Management 5-Fluorouracil/Capecitabine Toxicity Oxaliplatin Toxicity Toxicity similar to continuous infusion 5-Fluorouracil Common *Palmar-plantar erythrodysesthesia (Hand-foot syndrome) More common with capecitabine than 5- Fluorouracil Mucositis Diarrhea Photosensitivity Rare Nausea/vomiting Hyperbilirubinemia Cardiac toxicity Ocular toxicity *Grade 2 stop drug until resolved or grade 1. Consider dose reduction. Two types of neuropathy Acute neuropathy Cold sensitivity for first 5 to 7 days after each dose Chronic neuropathy Dose limiting cumulative peripheral neuropathy *Moderate emetogenic potential Myelosuppression Extravasation risk Delayed hypersensitivity 1

11 Prevention and Management of Platinum Induced Nausea and Vomiting Level 2: Patients receiving a moderately emetogenic agent or patients receiving midly emetogenic agent who have failed to respond to or are intolerant of at least two level 1 regimens: Aprepitant 125 mg PO before chemotherapy on day 1, then 8 mg PO daily on days 2 and 3, and Palonosetron.25 mg IV before chemotherapy, and Dexamethasone 1-12 mg IV/ PO before chemotherapy, then 8 mg PO daily on days 2-4 With or without Lorazepan 1 mg PO or IV before q4-6 hrs p.r.n., or Prochlorperazine 1 mg PO q4h-6 h p.r.n; or both Irinotecan Toxicity Diarrhea Early diarrhea < 24 hours after irinotecan Cholinergic type reaction Anticholinergics (Atropine) can be beneficial. Atropine.25-1 mg IV before Irinotecan Late diarrhea > 24 hours after irinotecan Prolonged diarrhea if not controlled. Aggressive loperamide can be beneficial Myelosuppression Moderate emetogenic potential Mucositis Ramucirumab Adverse Effects GI perforation permanently discontinue Thromboembolism ATE permanently discontinue VTE Continue with full dose anticoagulation with DVT or asymptomatic PE Permanently discontinue if symptomatic PE CHF permanently discontinue Delayed wound healing Hold 4-8 weeks prior to and 4-8 weeks after surgery ATE-arterial thromboembolism DVT deep venous thromboembolism VTE-venous thromboembolism PE pulmonary embolism CHF congestive heart failure Clinical Pharmacology Online. Accessed Nov 212 Gressett SM, et al. Ann Pharmacother. 29 Mar; 43 (3): Saif MW. J Support Oncol. 29; 7(6): Trastuzumab: Adverse Effects Infusion related reactions Occur during or within 24 hours 21-4% Can cause severe pulmonary toxicity ((can be delayed) Discontinue if life-threatening severe reactions Cardiotoxicity: LVEF decreased (4-22%) LVEF decreased and congestive heart failure Use caution in patients with heart failure, cardiomyopathy, ventricular dysfunction Recommended to undergo monitoring before and during therapy (MUGA or ECHO) May require holding trastuzumab and CHF treatment Clinical Pharmacology Online. Accessed November Side Effects vs Immune Related Adverse Events Side Effects: Immunotherapy Immune related adverse event (irae) Type of side effect Result of immune infiltration and inflammation May be diagnosed with a biopsy of the affected anatomic location May be a diagnosis of exclusion Responsive to corticosteroids Most common side effects of immunotherapy occur in 2-3% of patients Immune related adverse events are generally UNcommon iraes Incidence and Severity PD-L1 inhibitors PD-1 Inhibitors CTLA-4 Inhibitors CTLA-4 Inhibitors + PD- 1 Inhibitors Dermatological toxicities Rash Folicullar dermatitis Vitiligo Bullous pemphigoid Endocrine Toxicities Hypophysitis Hypothyroidism Hyperthyroidism Thyroiditis Adrenal Insufficiency Hepatic Toxicity Hepatitis Hepatomegaly Pneumonitis Acute interstitial pneumonia Diarrhea colitis 11

12 Management of Immune-related Adverse Events Excluding Skin and Endocrine Toxicities Conclusions Targeted therapies Biomarkers needed to identify patients Gene amplification> mutation in gastric cancer Trastuzumab: HER2+/amplified gastroesophageal/gastric cancers, only a minority are eligible for HER-2 targeting antibody therapy Newer HER2 agents Pertuzumab trial in the front line did not meet endpoint Ramucirumab + paclitaxel: translated into survival benefit Negative trials in unselected patients: EGFR agents + chemo Panitumumab, Cetuximab+ chemo detrimental VEGF-A Bevacizumab + chemo cmet trials in selected population highlight importance of biomarker use Boutros, C. et al. (216) Safety profiles of anti-ctla-4 and anti-pd-1 antibodies alone and in combination Nat. Rev. Clin. Oncol. doi:1.138/nrclinonc Conclusions (cont) Heterogeneity of GC has led to differentiating those tumors that depend on an immune regulatory mechanism: EBV driven tumors and the MSI subtypes. Distinct biology subtypes will allow for application of more targeted therapies. Developing effective immunotherapy will require further knowledge of the complex relationship between tumor and environment. Immunologic checkpoint blockade with anti CTLA-4 and PD- 1/PDL-1 have shown promising results. Further combination with immunotherapies might have synergistic effects. CME/MOC Credit Requesting MOC and CME If you are seeking MOC and CME credit, you do not need to complete the remainder of the paper form. Visit the website URL at the top of your evaluation form, or scan the QR code, then complete the online evaluation and pass the post-test for MOC credit. Please give your completed Activity Survey to on-site staff. Requesting only CME If you are seeking only CME credit, the remaining information on the paper form must be completed. Please use a dark pen. Return all forms to on-site CME staff. Thank you for joining us today! 12