My disclosures include consulting fees for Amgen, Boston Biomedical, and Genentech.

Transcription

1 Welcome to this CME/CE-certified activity entitled, Integrating the Latest Advances Into Clinical Practice: 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. J. Randolph Hecht; I'm a Professor of Clinical Medicine and Carol and Saul Rosenzweig Chair for Cancer Therapies Development, as well as Director of the UCLA GI Oncology Program at the UCLA School of Medicine in Los Angeles, California. My disclosures include consulting fees for Amgen, Boston Biomedical, and Genentech. Our discussion today will include the most exciting and compelling data in colorectal cancer from the 2016 gastrointestinal cancers meeting, as well as insights on how these clinical advances may be practice changing. So let's begin! The study I'd like to highlight is the STEAM trial, which was presented by Johanna Bendell. This trial, "Overall Response Rate in STEAM" was a randomized, open-label, phase 2 trial with 3 different arms. This was based on data from Dr. Falcone and his Italian group looking at combining all three active agents all 3 active cytotoxic agents in colorectal cancer: 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI). This group has looked at this treatment over a number of years either alone or in combination with biological agents and showed that this combination has led to improved survival. Now more recently, he combined this with the standard biological agent, bevacizumab the TRIBE trial. So this was FOLFOXIRI plus bevacizumab, and it was compared in that trial to FOLFIRI (5-FU, leucovorin, irinotecan) plus bevacizumab, and there was an improvement seen in outcomes. So the STEAM trial was looking at FOLFOXFIRI actually given two different ways, which I'll discuss in a minute, versus a regimen that would be more standard in the United States, which is FOLFOX (5-FU, leucovorin, oxaliplatin) plus bevacizumab. Now, you know, I'd say there's been a lot of controversy as to whether these patients can tolerate, you know, the combination of all 3 cytotoxics, or whether it's better to just do doublets rather than a triplet. The other question has been since patients who fail first-line

2 therapy usually get second-line therapy, why would throwing everything in the entire kitchen sink at the beginning work? And I think there's some interesting data that's come out of the previous trials that a higher percentage of people fall off between first line and second line than we realize, and that only about two-thirds of patients who get first-line therapy get second-line therapy. So that's a potential reason why giving everything upfront may be, you know, beneficial. So what Dr. Bendell looked at was what she called concurrent FOLFOXFIRI/bevacizumab, and that would be considered to be the standard of, you know, very similar to what Dr. Falcone had said. The other arm that she looked at was what really is alternating FOLFOX and FOLFIRI, which she called sequential FOLFOXFIRI/bevacizumab. And finally, the control arm remember this was a randomized phase 2 trial was FOLFOX plus bevacizumab. The patients were treated for a total of 4 months; this was an induction phase, which is what we normally would do with these drugs, particularly with an oxaliplatin-containing regimen. And then patients went to a maintenance phase where they could receive either 5-FU plus leucovorin plus bevacizumab or capecitabine plus bevacizumab. If disease progressed, then they went to second-line therapy, which was generally a fluoropyrimidine-based chemotherapy according to investigator's choice. The endpoints that were looked at in this trial were investigator-assessed response rate in the first-line therapy, as well as PFS1, which is basically from the time that the patient started therapy until first disease progression, which is usually on maintenance therapy. So, the arms were fairly well balanced between the 3 arms. It's a relatively small trial only about 300 patients so much smaller than a lot of the large, randomized trials that people, you know, are used to looking at like or some of the other large recent trials. But, what they showed was that there was an increased response rate in either of the FOLFOXFIRI arms between 60% and 62% versus slightly under 50% with the FOLFOX/bevacizumab arm. The question, of course, that comes up with this is how important is response rate. And there probably are times where this may be important particularly as you're trying to get someone to surgery or someone has very rapidly growing disease but, in general, response rate is only so useful as an endpoint. Now the other thing that Dr. Bendell showed was that there was an improvement in PFS1, which is what we would normally do, progression-free survival. So median progression-free survival in the FOLFOXFIRI arms was 11.4 months versus 9.3 months in the FOLFOX plus bevacizumab arm. This was a hazard ratio of about 0.7.

3 So, you know, the question is really what to make of this large randomized phase 2 trial. Well one is that in the American study, the combination of all 3 drugs was relatively well tolerated, which is what had been seen in the Italian trials. Two, it also showed that the response rate not surprisingly was higher compared to what we consider a more standard regimen of FOLFOX plus bevacizumab. The other thing that it showed, at least right now, was that the alternating FOLFOX and FOLFIRI looked similar to the FOLFOXFIRI but, you know, I don't think there were enough patients to recommend this. Now, the downside, of course, is not surprisingly, there were even though it was well tolerated there were more grade 3 events on this. And so I think, at least right now, I think this is very interesting, but I can't say that this is something that I necessarily would want to do. So, with this combination, I think that the most likely scenario that I could foresee someone using this would be, once again, in someone who really needs a response because they have a large burden of disease, and you're, though, a relatively good performance status, and you're concerned about the patient falling off the cliff. Occasionally we will use this, particularly in young patients who are candidates for liver resection, but there's a large bulky disease, and shrinking the tumor down would be helpful. There were some data from the TRIBE trial, the Italian trial; the numbers were small that in patients with BRAF mutant colon cancer, which is up to 10% and those patients tend to do very poorly that in those patients the combination of all 3 drugs seemed to do better, although the numbers were small, and we'd love to see what happens in the patients with BRAF-mutation positive disease in the STEAM trial. So, let's leave that and go to the other trial a large, randomized trial that was presented recently; the MAVERICC trial. The background for MAVERICC is that a number of groups including Heinz-Josef Lenz, who is the first author on this had been looking at biomarkers not just for targeted therapies but also for cytotoxic agents. This really goes back for several decades, and particularly what they've looked at has been thymidylate synthase, for fluoropyrimidines, which has never really panned out. The other biomarker that's been looked at not just in colorectal cancer but also in gastric, as well as other cancers has been ERCC, which may predict for a response or lack of response to platinum-based agents. So this trial, which was a phase 2 trial, was looking at modified FOLFOX6 plus bevacizumab and patients were randomized 1:1 versus FOLFIRI plus bevacizumab. Now the thing that was interesting was that patient's tumor was analyzed specifically for

4 ERCC-1. And this was a relatively large trial, but they used ERCC-1 as a stratification criteria. There were almost 400 patients in the trial. In effect, this was a trial where the patients were not assigned as per ERCC-1, but instead were stratified. The other thing that's interesting about this trial is that it's really one of the largest if not the largest trial that directly compared, in first-line metastatic colorectal cancer, an oxaliplatin-containing regimen versus FOLFIRI. The other caveat, of course, both arms (this being a modern trial) received bevacizumab. So the endpoints that they had looked at were progression-free survival by treatment group. There were two endpoints I think that were particularly interesting. One is that when you looked at patients who had high and they have a specific biomarker that Dr. Lenz has been working on for at least 15 years, and it's changed over time but they used their own prespecified biomarker for ERCC-1 and when you look at that, it didn't really matter whether the patient received an oxaliplatin-containing regimen or irinotecan. So, there were some small differences, none of which were statistically significant. The other thing that was interesting particularly with this trial was that this was the largest single trial comparing oxaliplatin to irinotecan. A number of centers around the country use irinotecan frontline. In the United States, the majority of patients who have not received oxaliplatin in the adjuvant setting get an oxaliplatin-based regimen upfront; while in Europe, it's actually closer to 50/50. But in this trial even though it was really not necessarily designed for this there appeared to be a longer progression-free survival, and this was not statistically significant and perhaps even overall survival with patients who received FOLFIRI/bevacizumab versus modified FOLFOX6 plus bevacizumab. So, now let's next go to rectal cancer. Rectal cancer is different than colon cancer in a number of different ways. In the metastatic setting, we tend to treat them the same. Under the microscope, they look very similar. However, the treatment, particularly of early rectal cancer, is different because the surgery is more difficult; the surgery is potentially mutilating in patients who end up having abdominoperineal resection. And, because the local recurrence rate is higher, we tend to use radiation. Now, over the past several decades, there really has been a significant improvement in the surgery for rectal cancer. The widespread adoption of total mesorectal excision has significantly reduced the risk for local recurrence, which is one of the things that's feared. Locally recurrent rectal cancer can sometimes be salvaged, but it really is a terrible problem, and when you can't salvage, it can be a terrible and painful way to die. Now, based on British and European data, total mesorectal excision has become the standard, and local recurrence rates are actually fairly low, usually in the 5% or so range.

5 Unfortunately, in the United States, I have to be honest that not every patient ends up getting total mesorectal excision. Now also, for the past several decades, radiation has been a part of the treatment of rectal cancer. And initially it was given postoperatively based on the German Sauer trial that most patients who get radiation actually get it preoperatively, which has a number of potential advantages. There seems to be less toxicity, there's an increased chance of sphincter sparing due to downstaging, and patients did at least as well if not slightly better. So, in Europe, they've been giving radiation in a different fashion than we do in the United States, particularly in Scandinavia. In the United States, we tend to give a long course, which is usually about 5 to 6 weeks of radiation, 50.4 Gy over 28 fractions. However, in Scandinavia, there was a tendency to give 5 large fractions right before surgery. That's convenient, it's less expensive, but it doesn't allow for downstaging. So, what I'm going to present now is the Polish trial, which Bujko presented. This was a randomized trial; patients who had fixed, according to physical exam, clinical T3 or T4 rectal cancer. It was a randomized phase 3 trial. The other thing that was part of this is that the patients also received oxaliplatin. So, the so-called control group received (since oxaliplatin was not standard) a 5-FU bolus; they also received oxaliplatin without 5-FU, which would not be considered standard, together with an American or mostly western European way of giving radiation over 28 fractions. This was then followed by 5-FU and oxaliplatin prior to surgery. What they called the control arm was this short course, 5 high doses (5 5 Gy) of radiation upfront followed by FOLFOX. Now, there were differences in how much chemotherapy patients got, but I think the most important thing about this is that patients tended to do well no matter what you did. Most patients had an R0 resection, meaning that there was no microscopic disease left behind. Most people were able to go to surgery. A few people had metastatic disease at the time of surgery. Now, they also observed patients, even though this is a relatively small trial. But, you know, patients who were on the 5 5 arm actually had slightly better overall survival, but there were differences in the amount of chemotherapy that they ended up getting. I think what you can say from this is that the American way of doing it and the western European way of doing it is expensive, takes a long time with radiation, delays surgery, and can delay chemotherapy to a certain extent that is not necessarily better. And there is a trial called RAPIDO that's a large, multinational, multicenter trial that's being done that will use a more head-to-head comparison as to whether we can get away with fewer radiation treatments and end up with at least as good outcome.

6 Now the other rectal trial that was presented was an update of the ACCORD 12 trial from the PRODIGE group or French group. This has been presented before. And just to briefly go over, patients had T3 to T4 Nx rectal tumors; a large trial, almost about 600 patients. They were randomized to 2 groups that were not necessarily apples to apples. One group got standard capecitabine plus standard 45 Gy radiation; the other had a higher dose of radiation together with capecitabine plus oxaliplatin. This presentation was a follow-up for this. I think the important thing is that we already know the local control rate was very similar between the arms, and this is one of the reasons why people don't give oxaliplatin upfront. So despite the fact that there was a higher radiation given in the so-called experimental arm, there really weren't large differences. This is more longer-term followup, with 5-year follow-up. Disease-free survival was very similar, but not statistically significantly different, and there was an approximate 4% to 5% difference in disease-free survival. So, the authors concluded that oxaliplatin led to more toxicity without any significant benefit. And I'm going to just talk for a few minutes about the question regarding oxaliplatin and rectal cancer. So, in stage III colon cancer, on the basis of the C07 and the MOSAIC trial, postoperative therapy with generally FOLFOX or perhaps CapeOx has become the standard, though the benefit of adding oxaliplatin to a fluoropyrimidine in disease-free survival is relatively small in the published studies that it's really only approximately about 5% but, of course, adds significant toxicity. There's also been some retrospective data that patients who are elderly (over the age of 70) may not benefit. So now there have been at least four large trials the ACCORD trial, the NSABP R-04 trial, a large German trial, as well as a smaller Chinese trial that have reported differences in disease-free survival. What they're showing is that there's really a relatively small improvement in disease-free survival, approximately 5%. Because people may die of other things, none of them have shown an improvement in overall survival. So, I would say that even though this is the standard and is in the NCCN Guidelines the benefit of oxaliplatin in rectal cancer is relatively small. To finish up about rectal cancer, I think that we will also probably see perhaps some changes in the way that we give radiation therapy. So, next I would actually like to briefly talk about two abstracts that were presented. Both of them are really sort of jumping off points to talk about things that are really very exciting and very interesting in colorectal cancer. The first one was an abstract by Heeke, of Georgetown, who in collaboration with Caris a company that does multi-gene analysis of tumors. They looked at differences between older patients and younger patients. And really what I wanted to talk about was and this has been in the news recently (there's a

7 paper that will be coming out soon in Cancer that ended up getting a certain amount of press) we think of colorectal cancer as an older person's disease, and the vast majority of the patients who get this are over the age of 50. Now, over the past decade or more, the incidence of colorectal cancer has gone down. I would like to think that it's due to screening with colonoscopy; some of it may be changes in diet or exercise. But the incidence definitely is going down. There is one subgroup, however, where the incidence is actually rising, which is unusual about any of the major malignancies. And those are younger patients particularly under the age of 40. Now when we think of patients who are younger, we specifically think of people with inherited predispositions such as Lynch syndrome; these patients tend to have right-sided cancers and often have a family history. Familial polyposis is an even smaller group of patients. But what we're seeing now is particularly in academic centers like here at UCLA a large number of patients with distal cancers, rectosigmoid, who have no family history, who do not have Lynch syndrome, who do not have abnormalities in DNA mismatch repair. It's really unclear why this is happening; whether it's environmental, or whether there are genes that we just have not been able to test for. Now, in this abstract, especially considering there were multiple looks at many different genes, there were relatively small differences between older and younger patients. However, I think this is a field where we're going to be seeing a lot more research in the next couple of years. And I think it's really incumbent on primary care physicians to realize that when a patient has symptoms particularly change in bowel habits or rectal bleeding that that's not ascribed to hemorrhoids. That people who are under 40 can have colorectal cancer, as well. The next group of abstracts I d like to talk about all have to do with a novel thymidinebased nucleoside analog called TAS-102 that was recently approved for salvage colon cancer. None of these are groundbreaking trials, but they help fill in a little bit of the information about the drug, which many of us are now learning how to use. The first is from Dr. Mayer, who was the first author on the registrational trial. This is just an update of the survival data, and sometimes this changes between when a trial is published and the final data are presented and show that there is really, once again, some modest benefit with about a 2-month improvement in overall survival that did not change as they followed patients further on. The next 2 abstracts have to do with looking at different subgroups. The first by Dr. Ohtsu, who is a well-known Japanese researcher, looked at the same RECOURSE trial, which is the registrational trial, and looked at geographical differences in how patients did. Now, this is important because there are differences in how people do with similar drugs, with fluoropyrimidines, particularly in the setting of toxicity, where patients in Asia seem to have less toxicity than people in Western Europe and then people in the United States. And, perhaps to a certain extent, not just the

8 toxicity, but with efficacy as was seen with S-1. So they looked at different groups, whether it was Japan, the European Union, or the United States, and at least from an efficacy standpoint there seemed to be no significant differences and when they looked at toxicity, there also did not seem to be any significant differences. So I think this is actually, of all the abstracts, perhaps the most important, showing that this is not just an Asian only drug. The next subgroup analysis was done by the ubiquitous Eric Van Cutsem, who also is one of the senior authors on the RECOURSE trial, and what he and his colleagues showed was that not surprisingly there was some more toxicity as we see with all our agents in older patients, particularly the older-old, but on the other hand that efficacy was seen when compared to placebo. Finally, another abstract from Masuishi from Japan looked not at the same data that we ve been talking about from the RECOURSE trial, but at a retrospective group of patients who were either treated with TAS-102 or regorafenib, which is the other oral agent that has been approved in this setting, on the basis of very similar data versus placebo also with modest activity, and what they showed in this nonrandomized trial with all the caveats that go along with that, was that efficacy seemed to be fairly similar, but the toxicities were different, which is what had been seen from the registrational trials for both of these. Due to the nonrandomized, retrospective nature of this, I think this is an interesting data set; however, really the only way to tell whether one drug is superior to another will be in the setting of a randomized trial. And finally, I'd like to just talk about two trials in progress that were presented at the meeting. Both of them are based on using a PD-1 (programmed cell death protein 1) antibody in colorectal cancer. Last year at ASCO, Dung Le presented really phenomenal results in patients who have abnormal DNA mismatch repair. Now, many of these patients had inherited predispositions or Lynch syndrome. But, up to 15% of all colorectal cancer patients have abnormal DNA mismatch repair, and about 3% of patients with metastatic disease have this. Now, in general, colorectal cancer has not really been invited to the immunotherapy party, unfortunately. And what we've seen is multiple negative cohorts worth really no benefit. So this is very different from lung cancer or melanoma or even to a certain extent gastric cancer. However, in this small group of patients, there was a 90% disease control rate and about a 65% chance of long-term benefit. So, what these 2 trials are one for previously treated, another one actually in untreated patients; for this very small subgroup that, in this case, the drug is pembrolizumab but an anti PD-1 may actually be as effective as chemotherapy and may lead to long-term benefit. The final question is what do we do with the other 97% of people? And there are a large number of trials some of which we're doing, for example, with oncolytic viruses but other agents trying to get an immune response to patients who have what's called

9 microsatellite stable or no loss of DNA mismatch repair, the vast majority of patients with colorectal cancer. So, this was an interesting meeting. I think the studies that were presented are provocative and to a certain extent particularly the FOLFOX versus FOLFIRI may change some people's practice. Most of this, hopefully, will be setting up for studies in the future. Thank you very much.

10 References Bendell JC, Tan BR, Reeves JA, et al. Overall response rate (ORR) in STEAM, a randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRIbevacizumab (BEV) vs FOLFOX-BEV for the first-line (1L) treatment (tx) of patients (pts) with metastatic colorectal cancer (mcrc). J Clin Oncol. 2016;34(suppl 4S): abstract 492. Bujko K. Neoadjuvant chemoradiation for fixed ct3 or ct4 rectal cancer: results of a Polish II multicentre phase III study. J Clin Oncol. 2016;34(suppl 4S): abstract 489. Diaz LA, Le DT, Yoshino T, et al. KEYNOTE-177: first-line, open-label, randomized, phase III study of pembrolizumab (MK-3475) versus investigator-choice chemotherapy for mismatch repair deficient or microsatellite instability-high metastatic colorectal carcinoma. J Clin Oncol. 2016;34(suppl 4S): abstract TPS789. Francois E, Gourgou-Bourgade S, Azria D, et al. ACCORD12/0405-Prodige 2 phase III trial neoadjuvant treatment in rectal cancer: results after 5 years of follow-up. J Clin Oncol. 2016;34(suppl 4S): abstract 490. Heeke AC, Xio J, Reddy SK, et al. Molecular characterization of colorectal tumors in young patients compared with older patients and impact on outcome. J Clin Oncol. 2016;34(suppl 4S): abstract 505. Le DT, Yoshino R, Jager D, et al. KEYNOTE-164: phase II study of pembrolizumab (MK-3475) for patients with previously treated, microsatellite instability-high advanced colorectal carcinoma. J Clin Oncol. 2016;34(suppl 4S): abstract TPS787. Lenz HJ, Lee FC, Yau L, et al. MAVERICC, a phase 2 study of mfolfox6- bevacizumab (BV) vs FOLFIRI-BV with biomarker stratification as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mcrc). J Clin Oncol. 2016;34(suppl 4S): abstract 493. Masuishi T, Taniguchi H, Hamauchi S, et al. A retrospective comparison between regorafenib and TAS-102 for refractory metastatic colorectal cancer. J Clin Oncol. 2016;34(suppl 4S): abstract 723. Mayer RJ, Ohtsu A, Yoshino T, et al. TAS-102 versus placebo plus best supportive care in patients with metastatic colorectal cancer refractory to standard therapies: final survival results of the phase III RECOURSE trial. J Clin Oncol. 2016;34(suppl 4S): abstract 634.

11 Ohtsu A, Yoshino T, Wahba MM, et al. Phase III RECOURSE trial of TAS-102 versus placebo with best supportive care in patients with metastatic colorectal cancer: geographic subgroups. J Clin Oncol. 2016;34(suppl 4S): abstract 646. Van Cutsem E, Benedetti FM, Mizuguchi H, et al. TAS-102 versus placebo (PBO) in patients (pts) 65 years (y) with metastatic colorectal cancer (mcrc): an age-based analysis of the recourse trial. J Clin Oncol. 2016:34(suppl 4S): abstract 638.