10,30-13,15 III Sessione I risultati clinici Moderatori: Michele Maio - Valter Torri
11,45-12,00 Stomaco Giordano Beretta
III Sessione I risultati clinici Stomaco Giordano D. Beretta Humanitas Gavazzeni Bergamo
Gastric cancer Despite slight decline in mortality 4th most commonly diagnosed cancer globally 2th most common cause of cancer-related death in men Global incidence rates in 2007 Almost 1.000.000 cases Nearly 800.000 deaths Advanced/metastatic gastric cancer has poor prognosis 1 year survival rates <5-15% Tassi di incidenza e mortalità standardizzati x 100000 ab In Italia il carcinoma gastrico rappresenta la quarta causa di morte per tumore: 14.000 nuove diagnosi stimate nel 20105 10.000 decessi nel 2012 AIOM-AIURTUM 2015
III Millennio: Studi Aggiunta di Docetaxel: Fase III benefico nel carcinoma OS (0,6 gastrico mesi) ma Tox avanzato > TCF Studio Regime Pts (N.) RR (%) PFS (mesi) OS (mesi) p (OS) Dank, 2005 TAX-325, Van Cutsem, 2006 Kang, 2006 SPIRITS, Narahara 2007 CF IRI + 5FU/AF CF DCF FP XP S1 S1 + CDDP 163 170 224 221 137 139 25,8 31,8 25 37 29 21 4,2 5,0 3,7 5,6 5,0 5,6 150 31 4,0 Terapia 148 54 Standard: 4,6 8,7 9,0 8,6 9,2 9,3 10,5 11,0 13,0 NS 0,02 NS 0,0366 JCOG 9912, Boku 5FU ci 234 9 2,9 10,8 0,055 2007 IRI + 236 38 4,8 12,3 0,034 Fuse ASCO CDDP+Fluoropirimidina+/-Antraciclina 2009 S1 234 28 4,2 o 11,4 Docetaxel Abs 4514 REAL-2, Cunningham 2008 FLAGS, Ajani et al, JCO 2010 ECF EOF ECX EOX CDDP + F CDDP + S1 Capecitabina non inferiore S-1 attivo solo nelle popolazioni orientali OS EOX vs ECF: HR 0.80 (p 0.02) Tox < EOF-EOX 263 245 250 41 RR 30-50% 42 46 PFS 4-7 mesi 6,2 6,5 6,7 244 48 7,0 526OS 8-11 31,9 mesi 5,5 527 29,1 4,8 9,9 9,3 9,9 11,2 7,9 8,6 NS NS
ToGA TRIAL Bang et al; Lancet 2010
HR for death comparing 2 nd line chemotherapy with BSC HR for death comparing 2 nd line irinotecan with BSC HR for death comparing 2 nd line docetaxel with BSC Kim Hs, Ann Oncol 2013
The REGARD Trial Fuchs et Al, Lancet Oncology 2014
The RAINBOW Trial Wilke et Al, Lancet Oncology 2014
Trial Treatment OS (mo) HR Delta (mo) AIO 2010 Kang et al 2012 Cougar-2 2013 REGARD 2013 RAINBOW 2014 Quin 2014 INTEGRATE 2015 Irinotecan BSC Irinotecan/ Docetaxel BSC Docetaxel BSC Ramucirumab BSC Ramucirumab + Paclitaxel Paclitaxel Apatinib BSC Regorafenib BSC 4.0 2.4 5.3 3.8 5.2 3.6 5.2 3.8 9.6 7.3 6.5 4.6 5.8 4.5 0.48 + 1.6 0.65 + 1.5 0.67 + 1.6 0.77 + 1.4 0.80 + 2.3 0.71 +2.1 0.74 + 1.3
How Many Gastric Tumours? Gastric Cancer Epidemiology and Heterogeneity Not a Single Disease Significant global heterogeneity Toward a molecular classification Proximal non diffuse, diffuse, distal G-INT vs G-DIF Implications for drug development Immunoterapia in Oncologia: attualità e prospettive Milano 11 dicembre 2015 Oncologia Medica
8% 22% 20% 50% NATURE 2014 Immunoterapia in Oncologia: attualità e prospettive Milano 11 dicembre 2015 Oncologia Medica
How Many Gastric Tumours? Tumors positive for Epstein Barr virus: they display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of PD-L1 and PD-L2. Microsatellite unstable tumors: they show elevated mutations of genes encoding targetable oncogenic signaling proteins. Tumors with chromosomal instability: they show marked aneuploidy and focal amplification of receptor tyrosine kinases. Genomically stable tumors: they are enriched for the diffuse his-tological variant and mutations of RHOA
Innate and Adaptive Immune Cells in Gastric Cancer Immunotherapy Dendritic Cell (DC) Based Vaccines
Innate and Adaptive Immune Cells in Gastric Cancer Immunotherapy Vaccines from Tumor Associated Antigens Gastrina HLA-24 e HLA-2 Therapies Using Natural Killer (NK) Cells Cytotoxic T Lymphocytes (CTLs) Tumor Infiltrating Lymphocytes (TILs) Chimeric Antigen Receptor- (CAR-) Expressing T Cells
Combined cellular immunotherapy and chemotherapy improves clinical outcome in patients with gastric carcinoma cellular immunotherapy (CIT) with ex vivo-activated and expanded immunocytes could improve patient immune status to enhance the therapeutic outcome in patients with GC Cytokine-induced killer (CIK) cells are a heterogeneous population of immunocytes that include CD3þCD56þ cells, which partly share the same killing mechanism as NK cells CIK cells can regulate the immune status in vivo and directly kill tumor cells both in vitro and in vivo Cui J, Cytotherapy 2015
Checkpoint Inhibition in Gastric Cancer Therapy As with other solid organ tumors there has been an increasing interest in immunotherapeutic treatment approaches in AGC, primarily focused on the use of immune checkpoint inhibitors Checkpoint pathways are used by the adaptive Melanoma immune system to maintain selftolerance, modulate immune response and attenuate Renal autoimmune cell tissue cancer damage during the body s normal responses to infection Cancer cells use these pathways to avoid immune Lung recognition cancer and destruction, and targeting this process to induce immunemediated Colon cytotoxic cancer effects is MSI one of the most rapidly evolving fields in modern oncology Programmed death 1 receptor (PD-1) and cytotoxic T-lymphocyte (CTL)-associated antigen 4 (CTLA-4) are inhibitory molecules that downregulate immune response through their ligand-receptor interaction. any tumor can respond to the immune checkpoint inhibition strategy
Correlation between programmed death-1 gene polymorphism (PD- 1.5C/T) and gastric cancer. frequencies of PD-1.5CT genotypes were higher in GC patients compared with control individuals (OR = 1.77; P = 0.026). (Savabkar et al., 2013). Possible association between binding site polymorphisms in the B7- H1 gene and the risk of gastric adenocarcinoma. Some genotypes had a strong correlation with the clinico-pathological features of gastric cancer including grade, depth of tumor infiltration, and stage (P < 0.001) (Wang et al., 2013). Association of cytotoxic T lymphocyte-associated antigen-4 gene haplotype with the susceptibility to gastric cancer. By the haplotype analysis, logistic regression showed that the frequency of haplotype A (GAT) and D (AGT)in the case group is significantly different compared to control group(or = 2.00, P < 0.001; OR = 1.62, P = 0.043, respectively). This may imply that the genetic variations within CTLA-4 gene maybe a critical risk factor to the susceptibility of gastric cancer (Houet al., 2010). Role played by PD-1 expression in progression of gastric cancer. PD-1 expression on CD4+ and CD8+ T cells from gastric cancer tissues was higher than that from normal controls. This has been linked to disease progression. immune evasion mechanism as a method of contribution to gastric carcinogenesis (Saitoet al., 2013).
overexpression of B7-H1/PD-L1 and B7-H4 in gastric cancers may correlate with poor clinico-pathological characteristics and shorter patient survival time (Luet al., 2011). expression of B7-H1 was associated with lymph node metastasis and poorer clinico-pathological stage and prognosis of gastric cancer patients. The expression levels of this determinant in patients with lymph node metastasis and an advanced clinico-pathological stage were distinctly higher (P < 0.05). The patients with enhanced expression of B7-H1 experienced a lower overall survival rate and a worse prognosis (P < 0.05) (Hou et al., 2014). Expression of B7-H1 and PD-1 was found to be increased in gastric carcinoma, but absent in normal gastric tissue. B7-H1 expression in gastric carcinoma was inversely correlated with TILs infiltration. B7-H1 expression in tumor tissue was significantly correlated with some poor clinico-pathological parameters including depth of invasion, lymphnode metastasis and distant metastasis (Liu et al., 2008). No PD-L1 detectable in normal gastric tissues and very weak expression in gastric adenomas, but it could be detected in 42.2% of gastric carcinoma tissues. There was no correlation between PD-L1 expression and age, sex, tumor location or the degree of tumor differentiation in the gastric carcinomas. PD-L1 was significantly correlated to tumor size, invasion, lymph nodemetastasis and survival of patients (Wu et al., 2006).
Immune checkpoint inhibitors in EGC Durvalumab Atezolizumab Presented By Geoffrey Ku at 2015 ASCO Annual Meeting
Pembrolizumab is a humanized IgG4 kappa monoclonal antibody that directly blocks the interaction between the programmed death 1 (PD-1) receptor and its 2 ligands, PD-L1 and PD-L21
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency Le DT NEJM 2015
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency Le DT NEJM 2015
KEYNOTE-012: Gastric Cancer Cohort only PD-L1 positive tumors were eligible Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Because the immune-related response may not be fully captured by conventional response criteria, it would be interesting to assess the response with immune-related response criteria to further confirm the activity of pembrolizumab. Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Maximum Percentage Change From Baseline in Tumor Sizea (RECIST v1.1, Central Review) Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Pembrolizumab in PD-L1+ Adv Gastric Cancer (KEYNOTE-012) Trend toward association of higher PD-L1 expression with improved ORR, PFS, and OS Muro et al found a significant association between PD-L1 expression level and objective response rate (ORR; one-sided P=0.10). Median overall survival (OS) was not reached, but the 6-month OS rate was surprisingly high (69%). Muro K, et al. ASCO GI 2015. Abstract 03. 22. ClinicalTrials.gov. NCT02335411.
Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting Immunoterapia in Oncologia: attualità e prospettive Milano 11 dicembre 2015 Oncologia Medica
Association Between Efficacy and <br />PD-L1 Expression Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting
Correlation of Gene Expression Signatures and Clinical Outcomes in Patients With Advanced Gastric Cancer Treated With Pembrolizumab (MK-3475) Ongoing translational studies have allowed identification of biomarkers beyond tumor PD- L1 expression as potential enrichment biomarkers across a broad range of tumor types This hypothesis-confirming study tested 4 multigene immune-related gene expression signatures that were previously established in patients with melanoma who were treated with pembrolizumab These predefined signatures were then independently tested in patients with recurrent or metastatic gastric cancer treated with pembrolizumab in the KEYNOTE-012 study Shankaran V et al. Presented at ASCO 2015 abs 3026
Correlation of Gene Expression Signatures and Clinical Outcomes in Patients With Advanced Gastric Cancer Treated With Pembrolizumab (MK-3475) Total RNA was isolated from 2- to 5- μm-thick formalin-fixed paraffinembedded (FFPE) sections fixed on positively charged slides using a RecoverAll FFPE isolation kit (Ambion) Gene expression profiling was conducted on a 680-gene custom code set on the NanoString platform per manufacturer s instructions; it included all the genes from the predefined signatures Normalized gene expression values from the NanoString assay were calculated by taking a log transformation of quantile normalized data, normalizing over the set of genes being examined on the NanoString panel. A scalar signature score was obtained by taking the arithmetic average of the normalized member genes Subjects who had RNA expression profiling and survival data were included in this analysis Shankaran V et al. Presented at ASCO 2015 abs 3026
Correlation of Gene Expression Signatures and Clinical Outcomes in Patients With Advanced Gastric Cancer Treated With Pembrolizumab (MK-3475) Association of immunerelated gene expression signatures wit best overall response (complete response [CR] + partial response [PR]) and progression-free survival (PFS) was evaluated using logistic or Cox regression with signature scores as a continuous variable. Both best overall response and PFS were assessed by the investigator Shankaran V et al. Presented at ASCO 2015 abs 3026
Correlation of Gene Expression Signatures and Clinical Outcomes in Patients With Advanced Gastric Cancer Treated With Pembrolizumab (MK-3475) Of the 39 patients enrolled, 33 had RNA expression profiling data used for this analysis Objective response rate in this subgroup was 30% Significant association between gene signatures and best overall response and PFS At the Youden index derived cutoff, the interferon gamma (IFN-γ) signature maintain high negative predictive value (NPV) while still providing meaningful enrichment of response rates Positive predictive value (PPV), 45%; NPV, 92%; and prevalence, 61% An increase in IFN-γ signature was associated with longer PFS Shankaran V et al. Presented at ASCO 2015 abs 3026
Correlation of Gene Expression Signatures and Clinical Outcomes in Patients With Advanced Gastric Cancer Treated With Pembrolizumab (MK-3475) These immune-related gene expression signatures, including genes of T-cell function, antigen presentation machinery, and IFN-γ signaling, are strong predictors of clinical benefit from anti PD-1 treatment for gastric cancer, even among a group of patients already considered to be PD-L1+ Using these gene signature scores may allow for enrichment of responders while maintaining a high NPV The results of this analysis were similar to those of additional analyses using the immune-related gene expression signatures to evaluate candidate predictive biomarkers for response to pembrolizumab treatment for other cancers NanoString and the use of gene expression information may provide an additional tool to determine the patients most likely to respond to pembrolizumab Shankaran V et al. Presented at ASCO 2015 abs 3026
Immunoterapia in Oncologia: attualità e prospettive Milano 11 dicembre 2015 Oncologia Medica