George Yacoub, MD, assistant professor of Hematology & Oncology at Wake Forest School of Medicine, discusses "Novel Therapies and Current Clinical Trials in HPB Oncology."
GEORGE YACOUB: So I will talk about novel therapies and ongoing clinical trials in pancreatic and biliary oncology. I'm not going to go over the liver cancers because I already covered that this morning. Ironically, actually there are some promising results in pancreatic cancer. So a few things that I will share with you that look pretty promising-- so much different than the HCC talk. These are the current therapies that we have now. Just briefly, and you can read them. In the adjuvant setting, we have gemcitabine and 5 fluorouracil. In the metastatic setting, we have gemcitabine, gemcitabine plus erlotinib, FOLFIRINOX, and then gemcitabine plus nab-paclitaxel or Abraxane. And as Dr. [INAUDIBLE] mentioned this morning, there's actually a new drug that just got approved yesterday. So it was formerly known as MM-398, which is a nanoliposomal encapsulation of irinotecan. It allows the irinotecan to stay longer in the circulation, so more of it would be uptaken into the cancer cells. So the Phase III Napoli study randomized patients with previously-treated pancreatic cancer-- so patients that have been previously on gemcitabine and progressed-- into three arms. One would receive single agent MM-398. The second arm will get single-agent 5-FU leucovorin only. The third arm would get the combination. The single-agent arm actually did not do well, so we're now looking at the data from the other two arms-- either the single-agent 5-FU or the combination with MM-398. So median survival was 8.9 months with a combination, versus 5.1 months with 5-FU leucovorin only. And this was statistically significant. And actually, this is pretty impressive, because this is second-line results. I mean, this is not first-line, so this is almost nine months in the second-line setting. So in pancreatic cancer, this is pretty good. Median progression-free survival also almost doubled from 1.5 months to 3.1 months. And as I said, this was just FDA approved yesterday. That's its name. I'm not sure how it's pronounced, but it's probably Onivyde. So this is another option that would be added to our regimens. I'll show you some other promising results-- earlier results though-- and a few of them have not actually even been published. They just got presented in this year's ASCO. So first, nimotuzumab, which is an anti-EGFR monoclonal antibody. So it's similar to cetuximab or panitumimab. So it works by blocking the EGFR receptor. In a randomized phase II in patients with untreated locally advanced or metastatic pancreatic cancer, patients were randomized to receive either Gem plus Nimo or Gem plus placebo. Primary endpoint was overall survival. Secondary endpoint was PFS, safety, response rates, quality of life. In terms of one-year overall survival, almost doubled from 19.5% to 34% with the combination, one-year PFS more than doubled, and both were statistically significant. However, the median survival showed the trend in favor of the combination Gem and nimotuzumab, but this was not statistically significant. So was the median PFS. In a subsequent analysis of people that were 62 years of age or older, this did actually reach the statistical significance. The drug was safe and well tolerated with no grade 3 or 4 toxicities. The interesting thing, though, is this was conducted prior to knowing what we know now about the role of KRAS in resistance to anti-EGFR therapy. So in colon cancer, we later learned that people that have KRAS mutation don't respond to anti-EGFR therapy. In this study, that was not known when the patients were randomized. So it included patients that were KRAS-mutant that would not respond, and patients that were KRAS wild type. So they're looking at this in a phase III study-- same concept-- Gem plus nimotuzumab, versus Gem plus placebo. But they're only enrolling patients who are KRAS wild type. So the concept appears promising, and we'll see how the Phase III study pans out. Next study, it's a different concept. IMM-101 is a mycobacterium, which works as a systemic immunomodulator. It was studied in patients with advanced pancreatic cancer in a phase II trial in the first-line setting. So patients were randomized to receive IMM-101 plus gemcitabine, verses gemcitabine as a single agent. Median survival-- this included patients with locally advanced metastatic disease. So in the whole group, the median survival was in favor of the combination, Gem plus IMM-101, as well as the median PFS. When they looked at patients with metastatic disease, then even the median survival was more pronounced-- 7.5 months versus for 4.4 months, and the PFS was almost doubled from 2.3 months to 4.4 months. IMM-101 was also well tolerated. This agent is pretty early in development, also was presented at the last ASCO. So the presence of inflammatory monocytes in the tumor microenvironment is associated with poor outcome in pancreatic cancer. So what this does is it inhibits the chemokine receptor on the inflammatory monocytes, so decreases the amount of inflammatory monocytes in the tumor microenvironment. This is a phase Ib study. Patients were randomized to FOLFIRINOX versus FOLFIRINOX plus this agent. This is a borderline resectable or locally advanced study. The results are not mature yet, but these are some of the results that have been released so far. In the experimental arm, they had 35 patients. Six are still in treatment, six dropped out for various reasons. The other 23 patients that were available for evaluation-- 12 had a partial response and 11 had stable disease. Curative resections were achieved in four out of the five borderline resectable and two out of the 18 locally advanced. So, of course, we're looking forward to more updated results and to see how this will pan out later. A third concept is immunotherapy. So initially the GVAX Pancreas vaccine was developed. It's a GM colony-stimulating factor, secreting allogeneic pancreatic tumor cells. So it induces immunogenicity to the cancer antigens. So one of the important cancer antigens on pancreatic cancer cells is mesothelin. So it's usually administered with Cytoxan, which inhibits the regulatory T cells. In this study, they are looking at it in combination with CRS-207. This is live-attenuated Listeria, that also expresses the same antigen, mesothelin. So the idea is, maybe combining both would allow for more synergy and maybe more immunogenicity against mesothelin, which may kind of stimulate the immune system more to attack the mesothelin on the patient's pancreatic tumor. So this is second line or beyond, so patients were previously treated. Were randomized to receive either two doses of GVAX plus Cytoxan, followed by four doses of CRS-207 or six doses of Cytoxan and GVAX. Patients who were stable were offered additional courses. Primary endpoint was overall survival. Secondary endpoint was safety and clinical response. As I said, this is second line or beyond, so most patients have received therapy before. But 51% of the patients have received actually two or more systemic therapies in the metastatic setting. These are the survival curves. This curve actually is for patients that at least received one dose-- so patients that received one, up to six doses or more. As you can see, there is a survival benefit in favor of the combination. This one is patients that have received three doses at least. So as you can see here, in both groups patients will start with receiving the Cytoxan and GVAX. And then after that, the experimental arm will receive CRS-207, four doses. The control arm will receive four more doses of the same, Cytoxan and GVAX. So they basically excluded patients that received only two doses of therapy, which means they did not get any of the experimental drug, which is this the CRS-207. So the benefit in survival is even more pronounced after excluding patients that only received two treatments. So overall survival in the whole population was 6.1 months versus 3.9. In the group that received at least three treatments, the overall survival was 9.7 months versus 4.6 months. This is actually pretty impressive. This, in some patients was a second line, in other patients was even a third line, so this is pretty impressive for pancreatic cancer. Side effects were pretty minimal-- mainly immunological side effects-- fevers, lymphopenia, fatigue. Some patients also had increased LFTs. It's being looked at in another randomized phase II. They're combining now GVAX plus CRS-207, with or without nivolumab. We know that nivolumab is coming out with positive results in many cancers, so now they're looking at that in combination with immunotherapy. These are some of the important ongoing phase III studies in the advanced setting. So the first study is looking at Gem versus FOLFOX in the first line setting in pancreatic cancer. They're also looking at a biomarker. It's the human equilibrative nucleoside transporter 1. What this does, it facilitates the uptake of nucleosides through the plasma membrane and through the mitochondrial membrane. So in some retrospective analysis of the ESPAC adjuvant studies, they saw that this biomarker, low levels of it, would be associated with inferior survival in gemcitabine-treated patients. So here they are looking at FOLFOX versus gemcitabine in both patients that have high levels of this compound and also in patients that have low levels of this compound. The other first line study-- it's actually not in the advanced setting. It's borderline resectable or locally advanced setting, using chemotherapy plus or minus a HyperAcute Pancreas, which is another vaccine. Second line studies after progression with first line chemotherapy. So we have a study with capecitabine plus ruxolitinib, which is a Jakafi drug that we use in myelofibrosis, versus capecitabine plus placebo. And then we have another second line-- glufosfamide, a new chemotherapeutic agent, verses 5-FU in the second line setting. These are the most important phase III studies that are currently ongoing. These are some earlier studies that are looking at different pathways, some agents targeting the Notch pathway, the Hedgehog pathway, histone de-acetylation, DNA hypermethylation. In the adjuvant setting, there are two concepts we are trying to look at. First is what's the best chemotherapy regimen to use in the adjuvant setting, and then what is the role of new adjuvant therapy. So these two studies both are phase III currently ongoing, looking at the new adjuvant component and also using a different adjuvant regimen. So here, patients get three months or six cycles of FOLFIRINOX, followed by surgery, followed by six cycles of FOLFIRINOX after surgery, versus the standard of care, which is six cycles of adjuvant gemcitabine. In this study they get eight weeks of chemotherapy. But the regimen that's being used here is GemOx-- gemcitabine and oxaliplatin-- followed by surgery, followed by six cycles of gemcitabine, versus the control arm, which is the standard of care surgery followed by adjuvant gemcitabine. So we're trying to see, with patients that get these more recent regimens of more chemotherapy would do better, and what is the role of new adjuvent therapy. These are strictly adjuvant studies-- so comparing the standard of care gemcitabine in the adjuvant setting to FOLFOXIRI, which is like FOLFIRINOX but with some dose modifications. This is the modified FOLFIRINOX version versus gemcitabine in the adjuvant setting. And this is Gem plus the nab-paclitaxel or Abraxane, versus the standard of care, which is Gem. These are the studies we have here at Wake Forest. We have two studies with CPI-613, which is a compound that affects altered mitochondrial enzymes. So in patients with good performance status, it's done in combination with FOLFIRINOX. In patients with poor performance status, it's studied as a single agent. We also have the Gem plus or minus Abraxane study that I showed you in the adjuvant setting. We have the Jakafi plus capecitabine study in the second line setting after progression on first line chemotherapy. We also have a study in borderline resectable or locally advanced disease, where patients get chemotherapy plus or minus the hyperacute vaccine. Next I'll briefly go over biliary tumors quickly. Of course, very, very limited data because these are very uncommon tumors with limited studies, very limited phase III data. The standard of care in the metastatic setting is gemcitabine plus cisplatin. We sometimes use 5-FU/oxaliplatin in the second line setting, not based on data, but based on earlier phase II studies or extrapolation from other GI tumors. Some studies looked at EGFR. So here, looking at cetuximab, which is an EGFR monoclonal antibody, the phase II BINGO study randomized patients to receive either GemOx versus GemOx plus cetuximab. They showed no added benefit from cetuximab. Same problem as in the nimotuzumab study that I showed earlier. This was prior to the KRAS era, so patients were not excluded based on having a KRAS mutation. Still looking at anti-EGFR therapy here, with a sister drug, panitumumab, with one study looking at Gem/Cis plus or minus panitumumab, the other one looking at GemOx plus or minus panitumumab. The good thing here is they're excluding patients with KRAS mutations, so they're only enrolling patients with KRAS wild type. Still looking at EGFR, but now a different pathway-- instead of using monoclonal antibody, using a tyrosine kinase inhibitor. Phase III study with erlotnib-- gem/ox plus or minus erlotnib-- included patients with colangiocarcinomas, gallbladder cancers or ampullary cancers. It was a negative study, actually no overall survival or progression-free survival benefit. However, in an unplanned subset analysis, they excluded patients with gallbladder and ampullary cancers and only looked at patients with colangiocarcinoma. And the PFS appeared to be in favor of the combination arm. The phase II study with GemOx plus BEV, non-randomized phase II, PFS was 7.6 months, overall survival was 14.2 months. These are the ongoing phase III studies in the adjuvant setting. As you can see here, the control arm is actually observation, because there is no standard of care in the adjuvant setting after colangiocarcinoma. Of course, we still do offer adjuvant chemotherapy or adjuvant chemo plus chemoradiation in selected patients, but there's no standard of care because of the limitation of data. So most of the adjuvant studies are using observation as the control arm. One is looking at adjuvant capecitabine, the other is looking at adjuvant GemOx the other is looking at adjuvant Gem/Cis. In the advanced setting, we have a study looking at GemOx versus XELOX in the first line setting. And have a study looking at FOLFOX versus observation in the second line setting, after progression on Gem/Cis. We only have one study here at Wake with the CPI-613, again, in patients with advanced bile duct cancer. Thank you. [APPLAUSE]
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