Gastrointestinal Malignancies Research Advancements: [Slides] Insights from Farshid Dayyani, MD

Dr. Farshid Dayyani discusses the Gastrointestinal Malignancies Research Advancements


Gastrointestinal Malignancies Research Advancements: Insights from Farshid Dayyani, MD

By Farshid Dayyani, MD, PhD

Thank you so much for inviting me to this meeting. I was asked to give an overview of research in GI malignancies, and I made 200 slides. Then I realized we have 25 minutes. I practiced this morning.  I can't do it in 18 minutes, so it will be a very concise, here's my disclosures. What I will try to do is I think I'll show you very recent data, let's say the past year or so, where I think the practice might change based on the data or trials where I think will contribute in to change practice very soon when we read out on the on the data in GI cancers, it will be, boom boom. But I think it will be informative. Let's start with G Junction. The first thing we had GI ASCO (for gastrointestinal malignancies) was the confirmation of the CheckMate 649 trial, where the 3 year follow up of the addition of Nivolumab to chemo backbone, FOLFOX showed a sustained benefit in terms of overall survival. But in all comers, but also in patients specifically with a CPS score of 5 or more overall survival, as you can see here, and that was also maintained with a progression-free cell survival. About 1 in 6 patients remained progression-free at 2 years with the addition of Nivolumab. What's new? What's new is the competitor studies, so to speak, with the other PD-1 inhibitor Pembrolizumab. That was very recently presented as part of the ESMO virtual plenary, the check KEYNOTE-859 trial. The chemo backbone was a somewhat different, it was a global study and the IV backbone was infusion over 5 days with Cisplatin or CAPOX  challenging in patients in Orange County who are younger, from underserved communities who have a higher rate of cignet cell, poorly differentiated and have difficulty taking oral. When it comes to using the backbone chemo here is here's for you, one way to try to overcome the issues, you either have to give your patients 5 days of infusional, 5 if you with a Cisplatin, or if they can't take POS, then they can't go on a trial. So I think these are things to think about if you want to really do drug development. So either way this trial was presented primary endpoint overall survival chemo with or without Pembrolizumab and strikingly in, in my view, even if you're not supposed to do trial to trial comparison, strikingly similar result as we see confirming the benefit of addition of checkpoint inhibitor, anti-PD-1 inhibition in gastroesophageal adenocarcinomas in the first line setting in intent to treat OS and PFS very similar hazard ratios to CheckMate 649 duration of response, 8 months response rate also in increased this is not published to my knowledge in manuscript form and we don't have the PDL one CPS subsets yet. But still positive trial for OS. So you have now more options. So what about targets biologics in the first line setting. If you think, for example, patients with a CPS score of zero who might not be derived for significant benefit of addition of checkpoint inhibitors here we had at GI ASCO (for GI malignancies) the SPOTLIGHT trial. Patients with CLDN18.2 strongly positive tumors were randomized to FOLFOX with ORT without Azo uxb. So CLDN18.2 tight junction protein that can get exposed in solid tumors especially in gastroesophageal tumors and other GI cancers. Zolbetuximab is a monoclonal antibody against CLDN18.2 SPOTLIGHT trial. Straightforward randomization patients were pre-selected based on CLDN18.2 over expression 75% or higher of the tumor cells, strong expression they were randomized to now a much more modern mollified, FOLFOX6 regimen backbone with or without Zolbetuximab. Primary endpoint was primary primary progression-free survival, which was clearly met as you can see, clear early separation, 50% progression-free at 12 months. Key secondary endpoint was overall survival, and that was also met. This is one of the I think other significant improvements in gastrointestinal cancers (gastric cancer) for CLDN18.2. Obviously we need to wait for a companion diagnostic to become routine and the drug to get approved. What you, what I didn't include here because that was just presented yesterday, or two days ago, is the GLOW trial. GLOW trial is a companion to that with a CAPOX backbone rather than FOLFOX. We're very similar, that also showed the significant benefits. So no matter if you use a oral Fluorouracil Oxaliplatin, or FOLFOX backbone, I think that's one option, especially if you think about patients who are CPS 0.


So what's next for gastroesophageal cancers (gastric cancer)? I think I wanna highlight, two interesting targets that might change practice soon. One of them you might have heard about be Bevacizumab is a IgG1 monoclonal antibody against the FGFR2b receptor, right? If you're treating GI cancer as heil cancers (gastric cancer), you're used to a lot of TKIs for FGFR2 translocation and fusions, this is for protein overexpression for the FGFR2b protein it's an IHC assay. The phase 3 trial was based on this phase 2 randomized trial the FIGHT that was presented by Dr. Weinberg from UCLA in 2 20 21 we're about 80 patients were randomized, one to one to FOLFOX or without BEMA, and what we saw is PFS primary endpoint was met, was improved with the addition of BEMA and overalls valve was also improved. But what I want to show here we learned from that trial that target expression matters. The higher the targets expression, meaning FGFR2b expression, they higher the relative benefit from the addition of the monoclonal antibody. So that has led to the FoRtitude trials, there's 2 randomized phase 3 trials in first line setting based on FGFR2b overexpression. So you have to pre-screen your patients and only with high expressors will be eligible. There's two trials, one of them is with FOLFOX plus minus BEMA, and the other one is FOLFOX NIVO plus minus BEMA. At UCI, we decided to participate only in one, so we minimize competition. It's called UCI 21-193. So you have a new patient with metastatic gastroesophageal adenocarcinoma, consider this trial for them. The good thing is the trial allows for one cycle of FOLFOX, with or without NIVO. While the patient is in screening, so if they're symptomatic, and certainly try to cool them off while you're standing out the tissue and see whether they're eligible for FGFR2b overexpression.


The other trial that I'm excited about is a monoclonal antibody about against DKK1, Dickkopf-1 is a modulator of the wind signaling pathway, very important pathway in GI cancers. Colorectal cancers, but also gastroesophageal carcinomas. Here again, the preliminary data was the run-in trial. Of the DisTinGuished trial with DK N zero one, that's the monoclonal antibody that blocks DKK1 combined with an anti-PD-1 antibody Tislelizumab withCAPOX in advanced disease. So we participated in that one, and as you see on the waterfall plot a very encouraging everybody, almost everybody had some sort of tumor shrinkage independent of. PD-L1 expression level. So that's what with the green and blue bars here. So that has led to what we call UCI 20-63, the DisTinGuished trial where patients are with untreated metastatic gastroesophageal adenocarcinoma are eligible to go on this trial. The good thing about this one is, so we have both the FoRtitude and DisTinGuish open. And the way we triage the patient is again, in this trial you can also give a cycle of FOLFOX. And while you're waiting for biomarker, if their FGFR2b overexpressed, they go on FoRtitude. If they're negative, they can go on DisTinGuish. The good thing about DisTinGuish is it stratifies based on DKK1 expression, but doesn't select for it. So really you can maximize trial accrual by I think appropriate trial selection that you open for your patients. I want to highlight something that's homegrown, it's an investigative trial at UCI is the STOPGAP trial that our great Dr. Maggie Senthil, our chief of surgical oncology is spearheading with myself. It's a phase 2 trial of systemic chemotherapy followed by intraperitoneal chemotherapy and IPEC CRS in patients with gastric cancer, peritoneal carcinomatosis, again, when it comes to overcoming barriers to care, trying to bring in inequity. Here at UCI for example, we have 60% Asian and Latinx population patients in our gastric cancer population 80% of diffuse type gastric cancers are in these minorities. And they typically have a very characteristic distribution pattern with early peritoneal dissemination, poor prognosis. If you look at chemo only data 9 months or less. So the concept here was that, full systemic control of the disease for the first 3 to 4 months. And that goes beyond FOLFOX, maybe a checkpoint inhibitor. If the patient is symptomatic, it can give them flat and we cite to reduce them, and then we do a diagnostic laparoscopy. And if the PCI peritoneal carcinomatosis index is coming down, it's in the 10, 15 range, then we will place an IP port, and give them 3 months of IP chemo with the Nab-Paclitaxel and IV 5 if you, which I adopted based on the PHOENIX-GC trial, the Japanese trials, and afterwards, if there's a PCI score is reasonable, let's say 11 or less, they go to HYPIX CRS and we render these stage 4 patients disease free. We are about 10 patients in, and our first patient enrolled is now 13 months out in ET. So this is a, the good thing about this trial is I wrote it in a way where you can submit patients at any time. They can have up to 4 months of systemic treatment before they're screened for eligibility. So anytime the first two, 3 months, if you have a patient with peritoneal carcinomatosis consider enrollment. 

What about colorectal cancers (gastric cancer)? I think clearly a third line option, the SUNLIGHT trial presented at GI ASCO (for gastrointestinal malignancies) a few weeks ago where TAS-102 was combined with Bevacizumab based on very convincing phase 2 data published in Lancet Oncology a couple of years ago. And just very briefly see early separation of overall survival benefit with the addition of Bevacizumab to TAS-102, these are strictly third line patients, versus TAS-102 alone, and a I think a robust OS curve as well that you see with the addition. I think that might be a new standard of care. If you don't have a clinical trial, you have to look for neutropenia, nausea, cytopenias that we already knew from the phase 2 trial might be expected adverse events (vomiting blood, difficulty swallowing, helicobacter pylori). What we did at UCI, we were trying to see whether beyond VEGF inhibition, if you target some of the operative pathways meaning cMET and AXL through a TKI in this case, Cabozantinib, that's another investigating shared trial we present at GI ASCO (for GI malignancies) whether we get some activity and whether it's even possible to combine TAS-102 with Cabozantinib. So we enrolled in 6 months, 15 patients. We did not have any MTDs, and we could show that TAS-102 at the standard dose, 30 milligram per square days, 1 through 5 and eight through 12, combined with the standard CARBO dose of 40 for combinations is tolerable, no MTDs. These are much more heavily pretreated patients than the SUNLIGHT study. So that's another option that you might think even beyond progression on Bev, whether you might have still some additional activity with this combination. 


Switching gears quickly to hepatobiliary cancers, just as a reminder we have now a new second standard of care in first line unresectable HCC with child p a or preserved liver function with the addition of TM and anti-CDL-1 antibody, CTLA-4 antibody, to Durvalumab, anti-PDL-1 in unresectable disease based on the HIMALAYA trial, very brief, the design patients, this is very randomized to the STRIDE regiment Treme times single dose plus DURVA for up to 2 years or Serafenib the trial met the primary endpoint. I think one of the things that is intriguing is the 3 year survival rate of about 30% in the STRIDE regimen compared to Serafenib. So that was that led to the approval of that regimen in the first line setting. What about earlier lines of treatment? Now we've have, we've completed systemic trials, randomized systemic trials for intermediate disease neoadjuvant, but two important adjuvant trial completed. One of them reported per press release. That's the one I'm showing you here, the IMbrave 050 used the IMbrave 150 ATEZO BEV regimen, that has been our standard of care to date until recently ATEZO BEV for 1 year as adjuvant for HCC, that's high risk, and the high risk criteria are shown below. These patients were randomized, one to one to ATEZO BEV for a year, or active surveillance. And what we've heard is this press release the trial met its primary endpoint, which is recurrence-free survival. So we are looking very much forward to seeing the full set of data. Hopefully at the one of the upcoming meetings to look at the magnitude, benefit the toxicities and secondary endpoints to make an informed decision of whether to offer patients with high risk disease in the adjuvant setting systemic therapy. At UCI, we have another investing issue at trial that has been ongoing. We are Dr. Abi-Jaoudeh, our chief of Interventional Radiology, and I, we are investigators on that study. Where we took the concept of synergy between a checkpoint inhibitor and an anti-VEGF for multi tyrosine kinase inhibitor in HCC and tried to synergize with local regional treatment. I know there is a proliferation of this study, but this study is called UCI 19-49. That means the concept I discussed with XLs is as a supporter in thousand in year 2018. So what we will do is unresectable, non-metastatic liver confined HCC undergoes induction with one dose of Ipi-Nivo, CTLA and PD-1 blockade. And then we will tase the primary tumor to try to kill as much as possible. And then we maintain the patients up to 2 years of Nivolumab with Cabozantinib. That's a combo that I think has better data in RCC than HCC, but certainly it has activity in that disease as well. Just here as an example, that's one of our patients with cryptogenic HCC, she's a retired nurse who presented to us in September of 2021 with this huge tumor that you see on the right side. AFP curve shown below. So we induced her and you can already see by May, by about 6 months, significant necrosis, calcification. We took her to surgery, so this tumor that should have never gone to surgery, went to surgery, 80% necrosis, that's the path report and her most recent MRI from last month, NED. I also show you some MRD assays, tumor informed MRD assays;, she remained in remission and is traveling right now. 


For pancreatic cancers, for the first time, we have a randomized phase 3 trial in firstly metastatic pancreatic adenocarcinoma where the comparator was not Gemcitabine. So this was the NAPOLI 3 trials where the NLI Reflux regimen Oxsali-5 few, with Liposomal Irinotecan was compared to the standard regimen Gemcitabine Nab-Paclitaxel. That was also presented by Dr. Weinberg at GI ASCO (for gastrointestinal malignancies) this year. Patients were randomized one to one to NAF Vir Nab-Paclitaxel with overall survival as primary endpoint, study was positive. Primary endpoint was met 11.1 months versus 9.2 months. Again, hazard ratio 0.83, and you also see improvement in progression-free survival in the intended to treat population. The toxicities are somewhat different. You'll have more diarrhea, nausea, as you would expect with a triplet regimen with the Lyposomal Irinotecan, but more neuropathy and cytopenias with GEM/Nab-Paclitaxel. So that could be regarded as one of these first standard of care options in the first line setting. If you don't have a trial. 

Switching gears,  HCC t o Cholangiocarcinomas again, as a refresher, the TOPAZ-1 trial was presented where GemCis with or without Durvalumab were evaluated in unresectable patients. And this was presented at ESMO, I think last year for the first time and now published as well. The OS PFS improved with the addition of Durvalumab, independent of PD-L1 expression. Numerically higher response rate as well about 26-27%. So I think that's one standard option. And then the other trial that we all were eagerly participating and in the crude in a really a record time by my former colleague Dr. Shroff at the University of Arizona SWOG 1815 trial where treatment intensification by adding Nab-Paclitaxel to GEM/CIS was evaluated. I took these slides out because of time issues, the phase 2 trial in JAMA Oncology was a very convincing, 80% disease control rate, 40% plus response rate, and this was reaching 20 months in this poor risk population. So we were very eager to see, and that was presented at GI ASCO (for gastrointestinal malignancies) this year, unfortunately, negative study, no improvement in overall survival, no improvement in progression-free survival. There were some secondary analysis that were, I think, thought provoking if you have intraoperative cholangio or non-metastatic disease, there seemed to be a benefit to the triplet over the doublet therapy, gallbladder cancer seemed to have some. I think there's still a hypothesis generating to see how you can move the field forward in HCC in terms of target therapies, I took the slide out for Tivantinib  and other EFGR-1 through 4 highly seritive inhibitor was approved recently for a FGFR2 rearranged cholangiocarcinoma.


I'm gonna summarize here, I think for first line gastro esophageal adenocarcinomas, anti-PD-1 is now validated plus chemo backbone. Question based on CPS score. What we don't see is a detriment. So if you look at anti-EGFR therapy and RAs mutated colorectal carcinomas, and you give the biologic, you actually see a detriment in outcome. What we don't see is, what we don't appear to see is detrimental outcome. If you give the checkpoint inhibitors, the hazard ratio might be 0.9, 0.95. But that takes me to the second bullet point. If and when anti-Cldn1 monoclonal antibodies are approved Cetuximab based on the trial I showed you, that might be an option for patients with CPS 0 who are CLDN18.2 positive. In third line, purely third Lamin metastatic colorectal carcinoma. If you don't have a clinical trial, the addition of BEV to TAS-102 improves OS PFS. You have to look for cytopenia, maybe even use prophylactic growth factors, first line unresectable HCC Child-Pugh A, liver, because that was part of the eligibility criteria for all these trials. In addition to Atez Bev, now we have Treme+Durva, a anti-VEGF free regimen in first line setting that's approved advanced cholangiocarcinoma. Gem/Cis is possibly the new standard of care until something better comes along based on TOPAZ-1, GCN, or GAP as we used to call it. Treatment anticipation does not seem to improve outcomes, but will have some higher toxicities. Metastatic pancreatic adenocarcinoma Nalirifox improved OS/PFS over GEM/Nab-Paclitaxel. That's all we have in terms of randomized phase 3, there's other trials ongoing, including at UCI, with second generation immune therapies and obviously trials are ongoing to address further needs. Just to keep it brief here, I'm happy to answer any questions and if you want to look for trials, UCI oncology flowcharts. I'll stop here and thank you for your attention. 


What is exciting in the landscape for Gastrointestinal Malignancies in clinical trials?

There are several exciting developments in the landscape of clinical trials for gastrointestinal malignancies. Here are a few:

  1. Targeted therapies: The development of targeted therapies that specifically attack cancer cells is a promising area of research. For example, clinical trials are exploring the use of drugs that target specific proteins or genetic mutations in cancer cells, such as HER2 inhibitors for gastric cancer and BRAF inhibitors for colorectal cancer.

  2. Immunotherapy: Immunotherapy, which harnesses the power of the immune system to fight cancer, has shown exciting results in gastrointestinal malignancies. Clinical trials are exploring the use of checkpoint inhibitors, CAR-T cell therapy, and other immunotherapy approaches for various types of gastrointestinal cancers.

  3. Combination therapies: Combination therapies that combine different treatment modalities, such as chemotherapy and radiation therapy or immunotherapy and targeted therapy, are being investigated in clinical trials. These approaches may offer improved outcomes compared to single therapies alone.

  4. Liquid biopsies: Liquid biopsies, which involve the analysis of circulating tumor DNA (ctDNA) or other biomarkers in blood samples (Eg blood tests), are an emerging area of research in gastrointestinal malignancies. Clinical trials are exploring the use of liquid biopsies for early detection, monitoring treatment response, and predicting treatment resistance.

  5. Precision medicine: The use of precision medicine, which involves tailoring treatment based on a patient's individual genetic and molecular characteristics, is an exciting area of research in gastrointestinal malignancies. Clinical trials are investigating the effectiveness of personalized treatment approaches for various types of gastrointestinal cancers.

Overall, there are many exciting developments in the landscape of clinical trials for gastrointestinal malignancies. These advances offer hope for improved outcomes and a brighter future for patients with these types of cancers.


10 Key Takeaways about Gastrointestinal Malignancies

  1. Gastrointestinal malignancies are cancers that develop in the digestive system, including the esophagus, stomach, liver, pancreas, small intestine, colon, and rectum.

  2. These cancers are often difficult to detect in their early stages, which can lead to a poorer prognosis (if not found in the digestive sysetem).

  3. Risk factors for gastrointestinal malignancies include a family history of cancer, a diet high in processed and red meats, smoking, heavy alcohol consumption, and certain medical conditions such as inflammatory bowel disease.

  4. Treatment for gastrointestinal malignancies typically involves a combination of surgery, chemotherapy, and radiation therapy.

  5. Advances in diagnostic imaging and biomarker testing have improved the accuracy of diagnosis and allowed for more personalized treatment approaches.

  6. Immunotherapy, which harnesses the power of the immune system to fight cancer, is a promising new treatment option for some types of gastrointestinal malignancies.

  7. Multidisciplinary care teams, including gastroenterologists, oncologists, surgeons, and radiation oncologists, are crucial in providing comprehensive care for patients with gastrointestinal malignancies.

  8. Screening and surveillance programs can help detect gastrointestinal malignancies early in high-risk populations, such as those with a family history of cancer or certain medical conditions.

  9. Lifestyle modifications, such as maintaining a healthy weight, eating a balanced diet, and exercising regularly, can help reduce the risk of developing gastrointestinal malignancies.

  10. Ongoing research is essential in developing new and improved treatments for gastrointestinal malignancies and improving outcomes for patients with these types of cancer.

Farshid Dayyani, MD, PhD - About The Author, Credentials, and Affiliations

Farshid Dayyani, MD, PhD, is a highly accomplished physician and researcher who holds both an MD and a PhD degree from the University of California, Irvine (UCI). Through cutting-edge research in gastric cancer and clinical practice, he has spent his whole career trying to improve medical knowledge and care for patients.

Dr. Dayyani's research is mostly about coming up with new ways to treat cancer, especially blood cancers like leukemia and lymphoma. He has written a lot of articles that have been published in top medical journals, and he has been asked to talk about his work at conferences all over the world.

Dr. Dayyani is a well-known researcher, but he is also an experienced doctor who has cared for thousands of patients with skill over the course of his career. He is known for his caring way of taking care of patients and his dedication to using the latest medical technologies and techniques to help his patients get better.

Dr. Dayyani's many accomplishments have earned him a reputation as a leading figure in the field of oncology, both nationally and internationally. He has won many awards and honors for his work in medical research and caring for patients, and he is still a driving force in the search for new and better ways to treat cancer.