My name is Dr. David Ilson, Professor of Medicine at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center in New York, New York.

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1 Welcome to this CME/CE-certified activity entitled, Integrating the Latest Advances Into Clinical Experience: Data and Expert Insights From the 2016 Meeting on Gastrointestinal Cancers in San Francisco. This educational activity is jointly provided by the Postgraduate Institute for Medicine and AXIS Medical Education and is supported by educational grants from Novartis Pharmaceuticals, Taiho Oncology, Inc., and Lilly. My name is Dr. David Ilson, Professor of Medicine at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center in New York, New York. My disclosures include consulting fees from Amgen and Eli Lilly. Our discussion today will include the most exciting and compelling data in gastric cancer from the 2016 gastrointestinal cancers meeting, and insights on how these clinical advances may be practice changing. So let's begin! The first study I'd like to highlight is by Dr. Kang from Korea. This was a randomized, multicenter, phase 3 trial of trastuzumab emtansine (T-DM1) versus a taxane in patients with previously treated HER2-positive metastatic gastric or gastroesophageal (GE) junction cancer. The interest in T-DM1 comes from breast cancer. We already know that in HER2- positive gastric cancer, first-line use of trastuzumab improves all outcomes. This study looked at second-line treatment in HER2-positive disease, comparing standard use of a taxane either paclitaxel or docetaxel with the new agent T-DM1. The first phase of the study was to establish a dose of T-DM1 to administer, and this dose was established as 2.4 mg/kg. Then the study proceeded to the phase 3 portion, in which patients were randomized 2:1 to receive T-DM1 versus standard taxane, either paclitaxel or docetaxel. The primary endpoint was overall survival. Patients more commonly received docetaxel versus paclitaxel on the control arm, and the median duration of overall follow-up was comparable. On the next slide, we can see, unfortunately, that there was no evidence of any improved survival for the specifically HER2-targeted drug, T-DM1, compared to use of a taxane, so the primary endpoint of the trial was not met.

2 Conclusions from this study include that the use of a HER2-targeted agent, T-DM1, did not show any efficacy advantage over standard taxane therapy alone in the second-line treatment of HER2-positive gastric or GE junction cancers. T-DM1 was well tolerated. These results are disappointing, given the promising results for T-DM1 in the second-line treatment of breast cancer. The next study I'd like to discuss is Abstract 2, presented by Dr. Peter Enzinger. This was a multicenter, double-blind, placebo-controlled trial comparing first-line chemotherapy treatment with FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) versus FOLFOX plus the VEGF (vascular endothelial growth) targeted agent, ziv-aflibercept, in patients with previously untreated esophagogastric adenocarcinoma. Patients were randomized 2:1 to receive standard FOLFOX or to receive FOLFOX plus the addition of ziv-aflibercept. The primary endpoint in this trial, which was treatment in the first line, was to improve 6-month progression-free survival. Unfortunately, the administration of ziv-aflibercept did not improve the primary endpoint; there was no difference in percentage of patients progression-free at 6 months, and this was comparable for the placebo arm versus the ziv-aflibercept arm. One-year overall survival was also not significantly affected. Response rates also appeared to be similar for the 2 treatment arms. But, again, progression-free survival was not significantly changed with the addition of ziv-aflibercept to chemotherapy compared to chemotherapy alone. So conclusions from this study are that the addition of a VEGF-targeted agent, zivaflibercept, did not appear to improve outcome in the first-line treatment of GE adenocarcinoma using FOLFOX. Therapy was generally well tolerated, although there were more episodes of hypertension, not surprisingly, in the patients treated with zivaflibercept. There was a potential indication of a benefit in patients who experienced grade 3 hypertension; however. this biomarker has not stood the test of time in other trials of VEGF-targeted agents. So this negative result adds to other negative results of trials of first-line VEGF-targeted agents in GE cancer, including the trial of bevacizumab in first-line therapy, which did not improve outcome. We now, however, await the results of the global RAINFALL trial, which is looking at the first-line use of the VEGFR-2 (VEGF receptor 2) targeted agent, ramucirumab, added to first-line chemotherapy. But, unfortunately, this is again a negative result and is in line with the negative data also seen for bevacizumab.

3 The next abstract I'd like to talk about is by Dr. Le. This looked at an expansion cohort of patients treated with nivolumab monotherapy in patients with advanced or metastatic gastric or GE junction cancer. Patients received the anti programmed cell death protein 1 (PD-1) agent, nivolumab, at a dose of 3 mg/kg every 2 weeks. Many of these patients were heavily pretreated, and essentially this study was looking for a signal of activity looking at objective response rate. If we look at the outcome and I should mention that in this trial there was no biomarker selection for patients patients did not have to have overexpression of a biomarker such as programmed cell death protein ligand 1 (PD-L1); all patients were allowed entry regardless of their PD-L1 status. Of the 59 patients treated, a modest response rate of 14% was seen, including some partial and complete responses, and stable disease in another 20% of patients. The authors also looked retrospectively at PD-L1 expression. It did appear that in the patients who had higher expression of PD-L1, there was a numerically higher response rate compared to low PD-L1 expressers, but the numbers on this trial are very small. And I should emphasize that even in the PD-L1 negative patients, there still was some signal of activity with a response rate of 12%. So I think there is an indication of some benefit for this agent, and this will need to be studied in larger sets, and to establish whether a biomarker such as PD-L1 should be used to select patients. But, again, the fact that responses were seen in PD-L1 negative patients indicates that this biomarker may not be mandatory. Conclusions from this study include that nivolumab was well tolerated, and that a response rate was seen a modest one but a signal of activity, and that most of these patients had extensive prior therapy. The next abstract looks at another immunotherapy agent, pembrolizumab. These are data from the expansion cohort of patients treated with pembrolizumab who had either esophageal adenocarcinoma or squamous cancer. Patients again were mostly heavily pretreated and received pembrolizumab 10 mg/kg once every 2 weeks. Again, this was an expansion cohort looking for a signal of activity, and the primary endpoint was to look at response. An encouraging response rate of 30% was observed; again, this is a very small number of patients. Most of the patients treated in this trial had squamous cancers, and only 5 patients had adenocarcinoma, but responses were seen in both subgroups.

4 This is the waterfall plot showing that approximately 50% of patients had some measurable antitumor activity; again, the number of adenocarcinomas was quite small, but there is a signal of activity here both in squamous cancers and adenocarcinoma. Now, unlike the nivolumab study that I just presented, biomarker selection was required in this study, with patients having to have at least a 1% positivity rate for PD-L1 expression in either the tumor or the stroma. So these were biomarker-selected patients, and again a modest signal of activity was seen. So the authors concluded that an encouraging signal of activity, a 30% response rate, was seen. But, again, remember that these are quite small numbers and most of the patients had squamous cancers, and approximately half of patients had some measurable degree of antitumor activity. The drug was well tolerated. So I think now we await results of larger expansion trials in this disease to see whether there is, indeed, a signal of activity, but I suspect that both this drug and nivolumab will move forward in further trials. Then the last abstract I'd like to discuss is by Dr. Le. This was a trial also looking at PD-1 blockade, but specifically targeting patients with mismatch-repair-deficient gastrointestinal cancers other than colorectal cancer; so these were microsatellite instability (MSI)-selected gastrointestinal non-colorectal cancers. The authors have previously published their results in MSI-high colon cancers, indicating a significant signal of activity. Now they present data from the expansion cohort looking at noncolorectal cancers that were also MSI high. And, again, this study represents treatment of MSI-high non-colorectal cancers with pembrolizumab. Here we see a rather significant response rate of nearly 50%, and another perhaps 20% to 30% who had stable disease, with an overall disease control rate of 76%; however, a response rate of 50% in a population of patients with refractory gastrointestinal cancers is quite remarkable. Conclusions from this study include that mismatch repair deficiency can be easily determined using commercially available tests. This can be by immunohistochemistry staining for the mismatch repair proteins, or looking specifically for microsatellite instability testing. It appears that these data support their previously reported observations that MSI-high disease appears to be highly responsive to checkpoint blockade with anti PD-1 therapy, and this was seen across tumor types. Patients treated in this trial had cholangiocarcinoma,

5 stomach cancers, duodenal cancers, pancreas cancers, ampullary cancers, and bile duct cancers, so it appears that MSI-high status may be a strong biomarker for response to anti PD-1 therapy. This is not surprising because MSI-high tumors have a high mutation burden, and tumors that have a high mutation burden probably present more antigens to the immune system and stimulate a better immune response. High mutation load also appears to correlate with response to immunotherapies in other cancers, such as melanoma and lung cancer. So I think MSI testing in the era of immunotherapy is going to become more ubiquitous; we're going to start testing refractory solid tumors for MSI-high status because these may be patients who are good candidates for late-line use of immunotherapy. The activity and often durable nature of these responses indicate that immunotherapy may be a promising new therapy for patients with MSI-high disease. However, MSI is, unfortunately in many cancers, relatively rare. In metastatic colon cancer, MSI-high disease only accounts for approximately 5% of tumors. In gastric cancer, it may be anywhere between 15% and 20% of patients with hypermutations and MSI-high disease, and in other cancers the rate of MSI status may vary. But I think it's a clear signal that these agents appear to be active in MSI-high tumors, and that further research is needed. Given this striking activity seen in late-line therapy, I suspect that use of these agents may move up to earlier-line treatment, and potentially even adjuvant treatment in MSIhigh tumors. So I think, in conclusion, this was a very exciting meeting. I focused on discussion of new targeted agents and immunotherapy drugs. I think we've learned from the gastrointestinal symposium that again we have a negative trial of first-line VEGFtargeted agent in GE adenocarcinoma with the addition of ziv-aflibercept not improving outcome compared to chemotherapy alone. We also have negative results for the second-line use of a HER2-targeted agent, T-DM1, which appeared to be no better than taxane-based chemotherapy alone in the second-line treatment of HER2-positive esophagogastric cancer. We saw very promising results for anti PD-1 therapy, including positive results for pembrolizumab in patients who were biomarker-selected for treatment, including a significant signal of activity in squamous cancer of the esophagus, and significant activity in MSI-high non-colorectal gastrointestinal cancers. For nivolumab, which did not use a biomarker selection, we saw modest activity in GE junction and esophageal adenocarcinomas, with a suggestion of a higher response in patients who had higher expression of PD-L1.

6 In the future, we will need to better refine selection of patients for immunotherapy trials and establish clearly whether biomarkers are needed, and what the optimal biomarkers are. At this point, candidates for biomarkers include PD-L1 expression and MSI-high status. Again, it's a very exciting time with new developments of new agents and a lot of promise for the future. Thank you very much.

7 References Doi T, Piha-Paul SA, Jalal SI, et al. Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK- 3475). J Clin Oncol. 2016;34(suppl 4S): abstract 7. Enzinger PC, McCleary NJ, Zheng H, et al. Multicenter double-blind randomized phase II: FOLFOX + ziv-aflibercept/placebo for patients (pts) with chemo-naive metastatic esophagogastric adenocarcinoma (MEGA). J Clin Oncol. 2016;34(suppl 4S): abstract 4. Kang YK, Shah MA, Ohtsu A, et al. A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (LA/MGC/GEJC). J Clin Oncol. 2016;34(suppl 4S): abstract 5. Le DT, Bendell JC, Calvo E, et al. Safety and activity of nivolumab monotherapy in advanced and metastatic (A/M) gastric or gastroesophageal junction cancer (GC/GEC): results from the CheckMate-032 study. J Clin Oncol. 2016;34(suppl 4S): abstract 6. Le DT, Uram JN, Wang H, et al. PD-1 blockade in mismatch repair deficient noncolorectal gastrointestinal cancers. J Clin Oncol. 2016;34(suppl 4S): abstract 195.