Dr. Manju George 0:00
Hello everyone. Welcome to DocTalks. I’m Dr. Manju George, the Scientific Director at PALTOWN. I organize these DocTalks, where we invite leading clinicians to talk to us about topics that are relevant to colorectal cancer patients and caregivers. And today, we have the pleasure having Dr. Anwaar Saeed with us. She’s an Associate Professor of Medical Oncology at the Kansas University Cancer Center and the Associate Director of the Early Phase Program. She’s going to tell us about the CAMILLA trial, but before that, let’s chat a little bit with her and ask her about her work. So Dr. Saeed, welcome.

Dr. Anwaar Saeed 0:43
Thank you Manju. Thanks a lot for the invitation. It’s really an honor and it’s my pleasure to be here today and talk about my research work and present the data on the CAMILLA trial, and also chat on future perspectives where we’re heading and any promising combinations or regimens in this field.

Dr. Manju George 1:03
I see on the website that you are an active member and lead investigator in the GI Oncology program and Early Phase Developmental Therapeutics Program, and I also see that you have a bunch of trials running. So could you tell us a little bit? – And so you had your medical degree at the Arabian Gulf University in Bahrain and then a clinical fellowship at the University of Kansas Medical Center. So do you want to tell us a little bit about your research activities and other trials that are going on at the Kansas University Medical Center?

Dr. Anwaar Saeed 1:34
Sure. So we are so invested in immune modulatory approaches. As we know, over the last few years, we have seen how checkpoint inhibitors, particularly the agents that target the PD1 and PD-L1 , have revolutionized the way we treat solid malignancies, as we’ve seen multiple approvals of those agents, either a single agent, or in combination with chemotherapy or other biologic therapies and multiple solid malignancies. And particularly I would say, over the last two to three years, we’ve seen those agents invading the GI or gastrointestinal cancer space, and particularly in hepatocellular carcinoma, upper GI cancer, like gastric and esophagus, as well as in colon cancer space as we are trying to identify a way of modulating those cold tumors to turn them into a hot tumor and make them respond to those immunotherapy agents. We’ve seen how those PD1 or PD-L1 inhibitors have already had approvals in the frontline setting and later line settings in patients with microsatellite instability high or mismatch repair deficient tumors. But when we look at the advanced stage colorectal cancer space, we’re looking at really not more than 5% – 10% of the whole population. So my interest and my investment in terms of research effort and activity really lies in finding a space for those agents in the majority of colorectal cancer, which represent the microsatellite stable space. So within this space I’m looking at combining those checkpoint inhibitors with novel agents. So the CAMILLA trials combining durvalumab with a multi VEGF tyrosine kinase inhibitor in this case, cabozantinib. And I also have other studies I’ll go into, looking at combining the checkpoint inhibitor or a PD1 inhibitor with cell cycle inhibitors. The one that I have interest in is called 9-ING-41. It’s an agent that is very interesting that combines very well with chemotherapy through chemosensitization effects, but has shown recently immune modulatory impact by modulating or upregulating, PD-L1 and LAG-3. As we know, LAG-3 is another checkpoint inhibitor just like PD-L1 and we know blocking it can unlock the immune system like how we block PD-L1. And so I’m really excited about that area of research, because I feel like combining agents like this with a PD1 inhibitor as well as chemo in the frontline space could really change the horizon for our patients. So I have that study, I got recently opened. It’s actually looking at the combination of chemo with PD1 and that agent in the pancreatic space but I have a vision of looking at a similar approach in patients with colorectal cancer in the frontline space. And then there are several other stuff, I’m also interested in the GI chemo prevention. And so me and my partner, his name is Dr. A.J. Mansell, are working on several chemo prevention ideas we have. I have an ongoing trial looking at omega-3 fatty acids as a chemo prevention option in patients with Lynch syndrome. We feel like we need a chemo prevention method, in those patients with Lynch syndrome who have 80% lifetime risk of developing colorectal cancer yet we don’t have any chemo prevention agents in this space beyond aspirin. I mean, there are some vaccine trials ongoing, but we don’t have any data yet from those. But we need something: diet modifications or a chemo prevention agent, so we’re looking at omega-3 fatty acids as a prescription drug using moderate doses. That trial is ongoing, and we’re hoping to present it at one of the upcoming conferences.

Dr. Manju George 6:00
Okay, thank you very much. That all sounds exciting and if you have a link of the trials, especially for CRC, that’d be kind of nice to see. And then I also saw the two posters, the one from GI ASCO earlier this year and the SITC. So if you can send me a PDF of those, that would also be something that would be very helpful. Okay, so we can get started on the CAMILLA trial then.

Dr. Anwaar Saeed 6:25
Sure. Thank you. I’m going to present our talk about highlights of immune modulatory approaches in patients with advanced microsatellite stable colorectal cancer with a spotlight on the CAMILLA trial and particularly cohort 2, as this trial is ongoing, has a multi-cohort focusing on testing this regimen of cabozantinib plus durvalumab in multiple disease cohorts, but we will focus today’s talk on the colorectal cancer cohort. As a background or rationale, looking at what we have tested so far in patients with colorectal cancer, before delving into the data from the CAMILLA trial, we know that cabozantinib in colorectal cancer as single agent leads to some, I would say, modest impact on disease control rate. There was a small phase 2 study that tested cabozantinib as monotherapy in patients with chemo refractory: patients who already tried and progressed on standard of care chemotherapy options– so we’re talking about the third-line and fourth-line setting. Usingcabozantinib as a single agent in this population led to a response rate of 3% so kind of modest responses here. And I would say reasonable disease control rate of 72.7% and they have a 12 week progression-free time of 34%. In comparison, when we look at how PD1 inhibitors perform in this population, in patients with microsatellite stable colorectal cancer. So looking at the trial that led to the approval of pembrolizumab in patients with MSI-High disease, in that trial they will count all patients, regardless of MSS. So we had a cohort in that trial that looked at pembrolizumab as a single agent in patients with microsatellite stable disease, as well as another cohort looking at it in the patients with microsatellite instability, or MSI-High. And as you see in the right hand side of the slide the trial has shown that pembrolizumab as a single agent, in patients with chemorefractory colorectal cancer, do not lead to any responses. So overall response rate of 0%, in patients with microsatellite stable disease, as opposed to really good responses, as you see here in the blue bars and the black bars, the MSI-High status. So clearly, immune checkpoint inhibitors as single agents do not really do anything, just do not work. As you see, progression-free survival here is two months. Similarly in cabozantinib. And then if we use this days tab, which is in contrast with historic results of standard of care agents that we currently have in the third-line setting, namely regorafenib and LONSURF. And I put them here just for us to compare– when we look at regorafenib as a single agent based on the CORRECT trial that led to the approval of this drug, overall response rate was 1%, the median progression-free survival was 1.9 months. Really similar to what we’ve seen with PD1 inhibitor in microsatellite stable disease. So a really minimal benefit to a placebo effect and a median overall survival of around six months. Similarly here, using LONSURF, as a single agent overall response rate is 1.6% so really not more than 2% here, median progression-free survival of two months, and then a median survival of seven months. So this is what we have, as a standard of care. And those single agent activity here with either cabozantinib or any checkpoint inhibitor, do not go beyond what we’ve seen as standard of care. So this is a background of what we have so far.

Dr. Manju George 10:37
Dr. Saeed, could you please go into a little bit more detail about how cabozantinib works?

Dr. Anwaar Saeed 10:44
Yes, cabozantinib, and I’m going to go on to the next slide, it will show you why we’re looking at cabozantinib, and why this drug. So what is the rationale of combining cabozantinib with checkpoint inhibitors, and before looking at the immunomodulatory effect of this drug, cabozantinib is a tyrosine kinase inhibitor, so it blocks the tyrosine kinases that are very important in phosphorylating very vital proteins that the cancer depends on for survival and proliferation or multiplication. There is a huge number of tyrosine kinase inhibitors out there, but those “dirty” tyrosine kinase inhibitors are the ones that block multiple tyrosine kinases, not just one. And the famous ones that led to multiple approvals, for example, cabozantinib, regorafenib, lenvatinib those all block the VEGF receptor-2 tyrosine kinase in addition to multiple other tyrosine kinases. Cabozantinib is one of them, it blocks the tyrosine kinase protein for VEGF receptor-2 and we know VEGF receptor-2 is a vital protein in our vascular endothelial system, and it helps with vascular proliferation and within the cancer tumor microenvironment we know that this vascular system is very vital for tumor replication and tumor growth, and any dysregulation in the vascular pathway is one way that the cancer uses to progress, metastasize and proliferate. Blocking the vascular system has shown, in for example, gastrointestinal malignancy, particularly in colorectal cancer, that it helps the chemotherapy work better. It improves the control rate and the median progression-free time, and it has shown to be a very good maintenance strategy, combining it with our standard of care chemo in this disease. And I’m referring by saying that, to Avastin, which is the standard of care drug that we utilize. The difference between Avastin and cabozantinib is Avastin is a monoclonal antibody that blocks the protein VEGF receptor-2, but just blocks the protein, not the tyrosine kinase, the enzyme that is linked to the protein. And so we call it a monoclonal antibody that blocks the protein receptor on the cell membrane, whereas cabozantinib is a VEGF receptor-2, blocks the same pathway, but it blocks the tyrosine kinase protein that is linked to that receptor. And it is not just blocking that VEGF receptor-2, it is a multikinase inhibitor. It blocks that protein, but also with it, blocks multiple other tyrosine kinases. So in this case, the profile of cabozantinib targets include “M-E-T” or “MET”, as well as “R-E-T” and multiple other tyrosine kinases like FLT and RET and KIT. We call it “dirty” tyrosine kinase because it blocks multiple kinases. It can lead to some certain side effects that I will highlight as we go through the slides. And as compared to the other multi-VEGF tyrosine kinase inhibitors, it has its unique targets because it is one of the only, I would say, approved multi-VEGF tyrosine kinase inhibitors that block both VEGF and MET at the same time. And we know that in gastrointestinal cancer malignancies, particularly colorectal cancer, the MET pathway plays a vital role, especially in patients who have RAS wild-type disease after progression on EGFR inhibitors like cetuximab or panitumumab. So that is what cabozantinib does as a drug.

Dr. Anwaar Saeed 15:04
But nowadays, because of all the immunotherapy approvals, there is a lot of research and trials that were done exploring, “how about looking at those biologic agents that block the tyrosine kinases and the vascular pathway and see if they could work well with immunotherapy? Do they have any immune modulatory impacts in a way that provide rationale to combining them with immune checkpoint inhibitors?”. And the reason for that is because when we modulate the vascular system in the tumor microenvironment, we know that the vascular system crosstalks with those checkpoint inhibitors, because this is what the cancer does to evade the immune system, modulating the vascular pathway, through the hypoxia pathway and such, it can upregulate certain checkpoints, like PD-L1. So for example, with this drug cabozantinib, it was tested a few years ago, back in 2014 in a colorectal cancer model, and testing it has shown that cabozantinib can reduce the immune suppressor cells in the circulation by suppressing T Regs and MDSCs, and those are suppressive T cells and it can boost the effector T cells like CD4 T cells and CD8 T cells. So, it has shown some immunomodulatory impact in colorectal cancer. And in a different model, in a prostate cancer in vivo model published in Nature back in 2017, combining cabozantinib with checkpoint blockade has led to significant suppression of MDSCs and significant boosting of the CD8 T Reg ratio. That was very significant in comparison to using either checkpoint blockade alone or using cabozantinib alone. This study clearly validates pre- clinically, that combining cabozantinib with immune checkpoint blockade leads to synergistic impact, and that provided the rationale to develop this trial. And not just this trial, because cabozantinib is being combined with immune checkpoint blockade and being tested in multiple other solid tumor types. But this is the first study that combined cabozantinib with immune checkpoint blockade in GI cancer malignancies, colon cancer and gastric and esophageal adenocarcinoma.

Dr. Anwaar Saeed 18:32
So this is the highlight of the schema for the CAMILLA trial, which is a phase 1/2 trial, combining cabozantinib with durvalumab in patients with advanced gastroesophageal cancer and other gastrointestinal malignancies. So, the highlight of what we’ve done for the Phase Ib part of the study: Part One of the study was a DLT evaluation or what we call dose limiting toxicity evaluation. We use the classic three plus three dose escalation, where we use the fixed dose of durvalumab, which is the standard dose for durvalumab, the PDL1 inhibitor. And this is a standard dose that we give once a month. So on the first day of every cycle–each cycle is four weeks. The first day of every cycle, the patient receives 1500 milligrams of durvalumab intravenously, in combination with cabozantinib, which is an oral agent. And in this phase, we escalated. We started with the lowest dose of cabozantinib, 20 milligrams daily, and then we went up to 40 milligrams daily in the next dose cohort. And then we went up to the maximum dose, which is 60 milligrams, so just three dose levels that we tested.

Dr. Anwaar Saeed 18:54
And then we opened the phase 2, or the expansion phase. So from phase 1, we’ve learned that going up from 20 to 60, we did not see any dose limiting toxicities per the protocol, per our protocol definitions of those limiting toxicities. However, most of the patients who went into the 60 milligram dose through the expansion phase needed dose reduction to 40 milligrams after cycle two, and most of this was related to accumulated fatigue and anorexia, or loss of taste and weight loss. Because of that, we regrouped and discussed in detail all the side effects that we’ve seen and the safety profile, and we agreed that the 40 milligram dose would be the happy medium, and we should use that as the recommended phase 2 dose. We did not see any fatal drug toxicities or adverse events throughout the study. For the phase 1 part, which included, as you see here, colorectal cancer as well as gastric and esophageal adenocarcinoma, I presented the first 20 patients’ data back in ASCO, 2020, just to show the preliminary results from the phase 1 at that time. We’ve seen really good, impressive results. Overall response rate was 25% among those first 20 patients, and a disease control rate of 85% and most of those patients, not most of them, I would say all of them have chemorefractory disease and they are micro satellite stable. So they progressed on the standard of care chemotherapy regimens in the front line, second line, and then they went on the trial. Those are the mature Phase 1b results that I presented at the SITC meeting. And as you see, those are the first 30 patients that went on the study. Part of them went on the dose escalation cohort, and then the second part was the dose expansion cohort. We have 17 patients among those with colorectal cancer, 10 patients with gastric and esophageal and 3 patients with hepatocellular carcinoma. As you see, we’ve seen a really good overall response rate 26.6% so around 27% disease control rate of 83% and a median progression free survival of 4.5 months, median survival of nine months, and the six month progression-free survival was 36.6%. And we looked at, as I highlighted earlier, because of the immune modulatory impact of cabozantinib, we expect some immune modulation and rationale for combining with durvalumab. We know from the upper GI literature and some other solid tumor literature as well, that PD-L1 expression, using the combined positivity score or CPS methodology, can predict or identify a subgroup of patients that might respond better to regimens that contain PD1 or PD-L1 inhibitors. So we ran a subgroup analysis, we obtained baseline biopsies, so before all of those patients went on the trial, we obtained a fresh tumor biopsy from all of them, and we tested those tumors for PD-L1 using the CPS method. And then we’ve seen that among the 30 patients were evaluable for response 12 of them have relatively high PD-L1 expression defined as CPS 5 and above. So among those 12 patients, we’ve seen better responses, which is in line with what what we’ve seen with using this methodology in patients with upper GI malignancies, when nivolumab and pembrolizumab was combined with chemotherapy in the frontline space and in that disease population. But so far, there’s no other studies that looked at PD-L1 CPS in patients with colorectal cancer who have advanced stage disease, or even early stage disease. This is the very first study that explored using this biomarker to identify a group of patients who might benefit the most from this combination, and we’ve seen that the overall response rate was better: 33%. Disease control rate is better: 91%,and the median progression-free survival was really better 6.1 months, and then the median survival was way better, not reached here, but I have up to date data that showed the median overall survival: 14 months. The six month PFS was 50% so those patients are able to stay on the study longer, and they are able to derive deeper responses than the rest of the patients.

Dr. Manju George 24:13
Dr Saeed, in the study, how many are colorectal cancer patients?

Dr. Anwaar Saeed 24:19
17.

Dr. Manju George 24:20
Okay.

Dr. Anwaar Saeed 24:21
So, among the 30 patients, we had 17 colorectal cancer, 10 gastric and esophageal and 3 HCC. And the colors here, if you look at the graphs, the green is the colorectal cancer patient, so most of those are colorectal. The red is the gastric and esophageal and the blue is the hepatocellular carcinoma or liver.

Dr. Manju George 24:44
Thank you.

Dr. Anwaar Saeed 24:44
Thank you. So this is just showing the couple more curves, highlighting the subgroups. As you see here, looking at progression- free survival, there’s a clear separation of the curve. Those patients really do better. Patients with PD-L1 CPS score 5 and above, there’s clear separation throughout from the get go and then, similarly, with the overall survival, clear separation of the curve. And this is why one way of identifying a clear biomarker, we know that PD-L1 CPS has its own pros and cons, and own challenges when it comes to testing it in the tumor micro environment, because of intratumoral and intertumoral heterogeneity, because if you obtain different biopsies from the same patients, you might get different results. But most of those patients have numbers ranging, if you find a CPS PD-L1, – CPS of 10 – from the primary tumor in the colon, is likely that you’re going to find eight or seven in the liver, or maybe higher in the liver. So despite the heterogeneity, it is one of the best markers out there that could identify the population that will benefit the most. And again, I have to say that this is a small sample size, and so we should not use this as a conclusion that this is a good marker, but this definitely sets the stage for us to test the marker in a larger patient population, in our larger study, and also in the ongoing study. So this just highlights what we have in the study so far before I review the results for the colorectal cancer cohort.

Dr. Anwaar Saeed 26:27
As you see, there’s four cohorts in the study, all of them are ongoing, except the colorectal, because we completed that enrollment of the colorectal cancer cohort. And I presented that data at the GI ASCO meeting. So 29 patients are expected to enroll in each one of those cohorts. We are almost done with enrolling to the gastric and esophageal cohort, and as I said, completed enrollment to the colorectal cohort and those two liver cancer cohorts are currently ongoing. We actually, on the cohort four of the liver cancer cohort here, we are testing the triplet. So in addition to cabozantinib and durvalumab, there is some data recently that have shown that combining durvalumab with another checkpoint inhibitor called tremelimumab, also from AstraZeneca, have shown really good responses in a small Phase 2 study in the 2nd line space. And then recently, this was validated based on the HIMALAYA trial, which is a large Phase 3 trial – FDA registration trial, in the front line space, and patients with advanced liver cancer. This combination, or doublet, showed positive results in this large frontline study. And based on that, we decided, well, if those two checkpoint inhibitors work very well, then we could probably just add this checkpoint to our doublet here in the CAMILLA study and test the triplet to see if we will be able to capitalize on what they’ve seen in the HIMALAYA study. So this is currently ongoing as part of cohort 4, and obviously, if we’ve seen good results with that triplet, my vision as far as next step is to possibly test the triplet in the other disease types, including colorectal cancer.

Dr. Anwaar Saeed 28:24
So with that, we can delve into the results of the colorectal cancer cohort, which tested again, the same regimen, in the MSS colorectal cancer population, mostly in the third-, fourth- and fifth- line setting. So, I already went through the background and discussed how combining checkpoint inhibitors with anti- angiogenic agents have antitumor activity in multiple cancer types. As an example, we could highlight renal cell carcinoma within the kidney cancer space, liver cancer and lung cancer in those spaces, combining agents that target the vascular pathway, or what we call antiangiogenic agents with immune checkpoint blockade led to benefit and led to approval of those drugs in those settings. Cabozantinib, as I highlighted earlier, is an anti-VEGF Receptor-2, MET and AXL multi-tyrosine kinase inhibitor. It has multiple studies in the pre clinical and the clinical space and various solid tumors that demonstrated favorable immune modulatory activity of this drug and clinical synergy when this drug combined with PD1 and PD-L1 inhibitors, like durvalumab, in this case. So this study is just following what was shown in other disease types, but testing it in the gastrointestinal cancer space, particularly colon cancer and gastric and esophageal cancer. Upon completion of this Phase 1b basket study that I just highlighted, evaluating cabozantinib and durva in those 30 patients and demonstrating favorable safety and efficacy, the trial was then expanded to a Phase 2, multi-cohort, multi-center study of 117 patients. It’s currently ongoing. We almost completed two cohorts, and two of our cohorts are still ongoing.

Dr. Anwaar Saeed 33:51
As far as the methods for this Phase 2, the patients who were enrolled in this Phase 2 received the recommended Phase 2 dose of cabozantinib, which is 40 milligrams daily, as I highlighted earlier, and they received a fixed dose of durvalumab, which is a standard dose for this drug, 1500 milligrams through IV infusion, once every four weeks. The enrolled patients should have a microsatellite stable disease or proficient mismatch repair phenotype. And this is the majority, around 90% of the advanced colorectal cancer population belong to this, or have this phenotype. They must have progressed on two or more lines of therapy. So we’re only testing this in the third, fourth and fifth-line setting. We have run a subgroup analysis on the RAS wild type tumors, and I will highlight them. We’ve been doing scans, or per the protocol, the scans were done every eight weeks, so every couple months the patients will have a scan to evaluate disease response. We allow disease beyond progression just one time, so if the patient shows any evidence for disease progression that meets our, what we call it: the RECIST criteria, the trial followed a modified RECIST criteria, meaning if thepatients have disease progression, we allow the patient to continue to study beyond progression one time and then repeat another scan in at least four weeks from the first scan that showed progression. If the follow-up scan shows disease progression, that means the progression is confirmed, and at that time, we can move the patient off the study and discuss other options. If the second scan shows response or improvement or stable findings from the first scan then we consider that this could possibly reflect something called pseudo progression in the setting of immunotherapy, and that patient would be allowed to continue the therapy.

Dr. Anwaar Saeed 34:13
So those are the baseline characteristics for the patients who went on the trial. So we had balanced, I would say female/male ratio around 50%, as far as the median age who went on the study? 57 years was the median age. But we have quite a good number of patients above the age of 60 who went on the study, 45%. As far as performance status, most of the patients have performance status of one. As far as sidedness, most of the patients had left-sided colorectal cancer, including rectum. So: 16 have rectal cancer; 25 patients have left-sided; and only 4 patients have right-sided colorectal cancer. The results, I would say, represent the left-sided, mostly, colorectal cancer space. As far as the RAS status, 41% or 12 patients who went on the study had wild type, and 17 patients had RAS mutant phenotype. As far as the HER2 amplifications, we had two patients on the study who had HER2 amplification and they went on the study after failing a HER2 targeted approach. Similarly with the RAS wild type, the study mandates that the patient fail the standard of care, EGFR blocker, whether cetuximab or panitumumab, before enrolling on the trial.

Dr. Anwaar Saeed 34:13
And as far as prior lines of therapy, as you see 100% of the patients who went on the study had at least two prior lines of therapy. 14 of them had two lines of therapy, meaning they received the regimen in the third-line. And then 15 of them, which is half of the patients who went on the trial, received the regimen in the fourth or fifth-line. As far as the prior therapies, we have four patients who went on the trial after failing LONSURF, and we did not have any patients who went on the trial with prior exposure to Regorafanib. Most of the patients who went on the trial had prior VEGF targeted agent, Bevacizumab, and around half of them had prior EGFR antibodies like cetuximab or panitumumab. And most of the patients have pretty good volume load of the disease. As you see, all of them, 100% of the patients went on the study had at least three sites of metastasis. Patients who have liver metastasis constitute 79% of the study population. So most of them have liver metastasis as well.

Dr. Anwaar Saeed 35:32
As far as the safety, as you see here, when looking at the significant grade three and above treatment-related adverse events, 31% of the patients, so 11 out of the 36 had grade three and above treatment-related adverse events. And as I alluded to earlier, we did not have any grade five, which are the fatal toxicities. So we do not have any patients who died because of toxicities related to the trial regimen, and those are either grade three or four, but mostly grade three. As far as the immune related adverse events, as this is an immunotherapy combination regimen, six patients had grade three and above immune related adverse events, and among those, three of them required at least four weeks of steroid therapy to calm down the immune therapy related toxicity. And as far as the dose modifications required, half of the patients who went off, around half of the patients who went on the study required a dose delay or hold in either durvalumab or cabozantinib. And as far as the number of patients who required permanent discontinuation of one of those drugs, it is, I would say, amazing that none of the patients had required permanent discontinuation of cabozantinib, but we have one patient who needed to have permanent discontinuation of durvalumab, and that is related to a recurrent immunotherapy related inflammation in the colon or colitis, after rechallenging. So, a patient developed immunotherapy related colitis, we treat it with steroid, then we rechallenge the patient with durvalumab again. And we’ve seen that that patient developed immunotherapy related adverse event again, so the colitis reoccurred. So in situations like this, we typically permanently discontinue the immunotherapy. We had one patient who have… those are the most common side effects that we’ve seen with the combination. Most commonly, as you see, and this is in line with with the side effects that for this type of combination, that what’s shown or what’s seen in other tumor types. The most common side effects, as you see here, are fatigue, nausea, diarrhea, anorexia, hand foot syndrome, liver enzyme changes – or we call it transaminitis, high blood pressure, hypertension, headache, thyroid issues, either hypothyroidism or hyperthyroidism. Skin Changes: mostly dry skin, inflammation and the mucosa membranes or oral mucositis, muscle cramp, commonly happens with cabozantininb and low cell counts, particularly thrombocytopenia, is common with cabozantinib as well, but not severe enough. So as you see, all of the patients that we’ve seen with thrombocytopenia had, I would say, grade one or two, proteinuria, weight loss. We’ve seen some patients with hair color changes and some other toxicities, as you see here.

Dr. Anwaar Saeed 38:47
So those are the efficacy results you see.

Dr. Anwaar Saeed 38:51
We have 29 patients who are evaluable for efficacy. Overall response rate was around 27.6% or 28% confirmed partial response. Those are the patients who had another scan after the first partial response that confirmed the same deep response that we’ve seen on the first scan, is 20.7%. The disease control rate is 86.2%, median progression-free survival is 3.8 months, and the median overall survival is 9.1 months, the six month progression- free survival is 34.5%. And as you may all know that we ran a subgroup analysis on patients who have RAS wild type, and because around half of the patients who went on a study had RAS wild type status we ran a subgroup analysis on this group, and as you see, in patients who have RAS wild type disease, the overall response is way better, 50%. The disease control rate is 83%, median progression-free survival is 6.3 months, their median overall survival is 21.8 months. So clearly, those patients, I would say, significantly benefit. There’s significantly improved progression-free survival and overall survival when compared to the overall population. If you look at the graphs, the green bars and the green arrows here, including the green lines in the spider plot, are all patients who have partial response. And when I run my analysis, I noticed that all of those green bars, green lines and arrows, belong to the RAS wild type. So those are the population that really benefit the most from the regimen. And so far, we don’t know why – we’re running an ongoing analysis – we obtained fresh tumor tissue before all of those patients went on the trial. So we’re running tumor environment assays to see if there are any new markers that correlate with better response beyond just the RAS wild type status, to identify why, maybe the RAS wild type has a different tumor microenvironment than the RAS mutant population, or maybe there is a pathway that’s upregulated after they fail the EGFR blocker, because all of those patients who have RAS wild type failed prior cetuximab or panitumumab before going on the study. So are we dealing with a situation where those patients progressed on cetuximab or panitumumab because they upregulated a different pathway than EGFR and we know from prior published literature that a common scenario in this situation is upregulation of MET, and we know cabozantinib is targeting the MET pathway. So it could be a scenario where cabozantinib came in the right space, MET was upregulated, and those patients benefited the most. Or, their tumor microenvironment is immune permissive, meaning the tumor suppressor cells are not that populated in the tumor microenvironment and throwing in durvalumab there led to way better survival advantage than the other group. So those are ongoing studies that I’m running and I’m hoping to definitely present at a later conference this year or early next year.

Dr. Manju George 38:51
Dr. Saeed, I had a question about the spider plot. The blue one which goes above, is that some kind of hyper- progression or something that you saw?

Dr. Anwaar Saeed 42:42
I would say the red ones, yes. So the red ones are primary refractory disease. They did not benefit. They did not have any stable scans. Most of the blue ones are the ones who have stable scan up to four to six months, so they have stable disease for four to six months. Some of them progress kind of slowly, but then they maintain overall…, if you look at this one, it’s an interesting line. There’s no flare, there’s slow progression, but then it stabilizes. And this is something we see with immunotherapy, even in other disease types that, if you allow patients to continue to be on progression, you might meet progression criteria at some point, but it’s only one. Like here, he had a rise, but then he maintained it.

Dr. Manju George 43:29
And I was wondering whether, in your wild-type RAS patients, do you think that EGFR inhibitors changed their sensitivity to PD-L1 inhibition and made them more sensitive? Is that something that you think might be going on?

Dr. Anwaar Saeed 43:44
Possibly. As we know, targeting the EGFR – so if we can extrapolate even from the HER2 literature, if you’re targeting HER2, especially nowadays with all of those HER2 agents trying to target HER2 and an immunotherapy agent, and we’re seeing tons of positive studies coming out showing that if you target HER2 with an immunotherapy agent, you get better responses. Even in the upper GI space, like in gastric and esophageal, for the first time in decades we’ve trumped the results of the TOGA trial. So trastuzumab and chemotherapy. We’ve been using this regimen as a standard of care for years up until now, when pembrolizumab was combined with Herceptin, we’ve seen that we can show better results than, Herceptin and chemo. So this talks to the EGFR pathway, because HER2 is part of the EGFR pathway. I think it’s already validated that if you target HER2 or EGFR pathway with an IO agent, you get better results. And it’s probably the case. Those patients received an EGFR blocker, their tumor microenvironment may be modulated, and then we threw the durvalumab there, and cabozantinib, so you targeted a different kinase on that same pathway. And you threw the durvalumab, so I think that’s probably what’s going on. But we cannot for sure tell what happened without the testing, but all of those are valid theories.

Dr. Manju George 45:13
Okay. The other question I had is that in our patient groups, people were interested in the LEAP trial, where they did lenva plus pembro, but that result is different from what you’re seeing, right? And why do you think there is a, I mean, it’s just a curious question, what is the difference? Is it the TKI targeting different things?

Dr. Anwaar Saeed 45:33
I think there’s multiple things that we could think of, because it’s hard to compare those, because we’re not doing head to head comparison here, right? And so the population of patients who went on that study might be different than this one. I do not know if they ran a RAS wild-type analysis. Maybe the patients who went on that study are mostly not RAS wild-type and mostly RAS mutant. That would definitely, if I repeat the study and block the RAS wild-type, you would imagine that my overall response rate would not be right. So I’m not sure what’s happening in that space and whether they, at least looked at their RAS wild-type population. Because we also know that if you do not mandate a fresh biopsy before the patient goes on the trial, you cannot just use the historic results to label that patient as RAS wild-type, because we know from newer studies that even in the RAS wild type could change. It’s an ongoing target, so the patients who develop resistance might be RAS mutant by the time they went on on the study so they cannot take their historic results to say lenvatinib doesn’t work. So just looking deeply into into those things, it may be that, even if they run a RAS wild-type analysis, it might be that those RAS wild-type patients turn into RAS mutant before they went on the study. And the reverse is true. Some of the RAS mutants could also lose their as the KRAS mutation, and have a RAS wild-type phenotype. So the fresh biopsies are also very important. And I know how challenging it is to obtain fresh biopsies, especially if it’s an industry study or very large phase 3 studies. So I think this is the benefit of this CAMILLA study, because it’s an investigator-initiated trial. I can control it. It’s being run at my institution. So mandating those fresh biopsies, though challenging, is feasible in those kind of proof of concept early phase trials, and I can definitely tell that those patients are RAS wild-type, because we did a fresh biopsy before they went on the study, and that’s what we’ve seen. So it may be that. And then also, I believe, cabozantinib has different tyrosine kinase profile. And if you look at comparing how cabozantinib performed, even in other disease types, really better than lenvatinib and regorafenib. So it is not just in colorectal cancer space. We’ve seen better results with cabozantinib across tumor types when looking at those agents in historic comparison. So it has something to do with that drug as well.

Dr. Manju George 48:13
Thank you so much. And then you were saying that in your study, you had a lot of patients who had liver mets, and that did not seem to affect it right? There’s this idea that liver mets are supposed to be globally immunosuppressive, but that is not the case for you, right?

Dr. Anwaar Saeed 48:28
Yes, I think, yes, definitely. I agree with the studies that showed how liver metastases can lead to immune resistant environment in the liver. And I totally agree with that. It doesn’t seem to impact a lot the results we’ve seen here, maybe because we’re talking about some molecular phenomena here, because when it comes to molecular phenomena, for example, with HER2 targeted therapy, we didn’t see that process, like those patients’ responded, regardless, right? So if you use the targeted agents in the right population, you see the results regardless of those studies. And I think that’s what’s probably happening. There might be, I mean, if you look at the RAS mutant in my population, they’re clearly not responding very well, right? So, yeah, something to do with the RAS wild-type.

Dr. Manju George 49:24
Yeah, it’s, it seems like, here is you’ve shown proof of real personalization of therapy, right? You’re looking at CPS, you’re looking at RAS status, and then you’re seeing that effect. So you can actually narrow down what is the specific population that is responsive to something like this.

Dr. Anwaar Saeed 49:42
Exactly. Yeah.

Dr. Manju George 49:44
This is very exciting.

Dr. Anwaar Saeed 49:45
Yes. The good part about being a clinician, researcher, and investigator, is that I’ve seen this hands-on in clinic. Because, as I was enrolling patients, I was like, “Oh, this patient has been one year, and this patient on the study, and then you see another patient who’s been beyond nine months. I was, “Okay, what’s common between them? There must be something”. And then you go look at their profile. Oh, they are RAS wild-type. And then you go back, and then you look at all of those who really responded and stayed on the study. All of them share one thing, RAS wild-type. So it’s exciting to test those agents in clinic. And see that. This is just the Kaplan Meier curves. And again, I’m really excited about this, and though it’s a small study size, but we can clearly show how those lines are separating. So the RAS wild-type really benefiting the RAS mutant is in the lower and the blue line is like when you lump everyone. So if you separate the RAS mutant by themselves and the RAS wild-type by themselves, there’s clear separation without any noise, even from the get go. So just to conclude, we have demonstrated that combining cabozantinib and durvalumab show promising efficacy and was fairly tolerated without any new safety signals in heavily treated microsatellite stable colorectal cancer patients. Wild-type RAS status was associated with improved overall response rate, progression-free survival and overall survival. So these encouraging results were a further evaluation of this regimen in a phase 3 randomized trial as salvage therapy in this population. And this is just a time to ill…, — we discussed the other VEGF tyrosine kinase inhibitors. So I created this table to contrast our data with or our results with what was published with the other VEGF tyrosine kinase inhibitors. And as you see, we can control the disease way better than all of the things tested. And most of those are, I included, mostly the US studies, as you see. So we’re talking about US population here with lenvatinib, regoranfinib and cabozantinib, we have the best disease control rate, we have way better overall response rate than the others, and then better progression-free survival. And obviously, if we just look at the RAS wild-type population, we have way better median survival than the other regimens. So I would like to, since we’re talking to our colorectal cancer population, and I had lots of questions from many patients, I would say, across the US, emailing me and through Twitter and other social media, asking about what’s next, we have RAS wild-type, where could we go? And all of those things. So I figured I should highlight the trial that will open soon. It’s a global study.

Dr. Anwaar Saeed 52:46
So Exelixis is taking this to a phase 3 trial. It’s called STELLAR-303, it’s a pivotal study, FDA registration trial that will combine the offspring of cabo, so XL092 is pretty much cabozantinib. This is the offspring of cabozantinib. So cabozantinib patent has come into to an end, so they have to go to a phase 3 trial. They have to use the offspring or their new drug. The difference between this drug and cabozantinib is that this was engineered to have a lower half life, and so the company is feeling like this will have a better side effect profile than cabozantinib without an impact on efficacy. So that engineering part to create this offspring did not touch the targets for cabozantinib. So it’s pretty much similar drug with maybe a better side effect profile. It will be combined with atezolizumab, which is similar to durvalumab, it is a PD-L1 inhibitor, a well known PD1 inhibitor as well. So the study will look at this combination regimen, XL092, plus atezolizumab in the microsatellite stable advanced colorectal cancer who have progressed on the standard of care therapy. So it will be a third-line study. So patients in the third-line and they have to have a RAS wild- type disease. So this is a phase 3 study that is tailored to the RAS wild-type space, or the RAS wild-type population. And I mean clearly, just based on the CAMILLA study results, it will have 600 patients enrolled across the globe. They will be randomized to either the combination regimen versus the control arm, which is regorafinib here. They chose regorafinib because in order to see that we are showing a benefit, we have to compare it with a VEGF tyrosine kinase inhibitor. That’s why LONSURF was not included. So this is pretty much the study, and it will be activated around the summer of this year, so we anticipate the first site to open. It is not in clinical trials.gov yet, but it should go within the next month with the first site opening.

Dr. Manju George 55:22
And is this going to be open at your place?

Dr. Anwaar Saeed 55:23
Yes.

Dr. Manju George 55:24
Okay, okay. And then, so people shouldn’t get on if they’re interested in this, they shouldn’t get prior regorafinib?

Dr. Anwaar Saeed 55:29
I would say yes, because it’s a third-line study. So they should fail the first- and the second-line chemo regimens. They should have a RAS wild-type status failing, and if they are RAS wild-type, they should fail prior EGFR targeted therapy like panitumumab or cetuximab, and then they get this regimen.

Dr. Manju George 55:49
Okay,

Dr. Anwaar Saeed 55:54
That’s hopefully, yeah, addresses all the questions.

Dr. Manju George 55:57
One other question I had was that with the LEAP trial, there was a lot of intestinal perforation with lenvatinib, and you didn’t have any, any of that with the cabo?

Dr. Anwaar Saeed 56:08
No, we did not have any colon perforations or intestinal perforations. In our gastric patients, though, and patients who have esophageal and gastric cancer, we had one case, one patient who had esophageal perforation, but that was a case – in that case, I presented that data at SITC, there was an immunotherapy-related inflammation in the wall of the esophagus, which might have triggered the perforation, but it’s really hard to say totally not related when he was also taking cabozantinib, but that was the only case that we’ve seen in our study patients.

Dr. Manju George 56:46
Okay and with this particular trial, are you expecting more sites to open in the US?

Dr. Anwaar Saeed 56:52
Oh, yeah, they will have, I’m not sure exactly how many sites, but it will be open through the US. There will be multiple sites in the US, multiple sites in Europe and Eastern Asia.

Dr. Manju George 57:06
Okay. Okay, there is a question that has come in: Regarding the rationale behind choosing an anti PD-L1 rather than an anti PD1 in CRC, MSS patients do you think there is room for radiotherapy in this subset of patients as a means of immune priming?

Dr. Anwaar Saeed 57:30
Well, that’s a nice question. We don’t really know if radiation therapy provides immune priming. There are ongoing studies and similar in several solid tumor types that use the radiation therapy as a way to do immune priming. It would be hard to test it in a stage IV setting though, in a large study like this, especially if we don’t have validation for that concept, because the concept is being studied in order to validate it. So without validation, it would be hard to incorporate it in a study like this. But one thing also to think of when we think about radiation therapy as modulator of immune response, especially in a stage IV setting, I think it’s really hard to adopt this, or especially nowadays with all of those immune modulators there. Why use a classic kind of anti-tumor burning with radiation when we have novel agents that could be taken as an oral pill or something to combine, especially if we are seeking systemic immune modulatory impact rather than regional immune modulatory impact. So that’s my opinion.

Dr. Manju George 58:49
I think that people were very interested in the abscopal effect, like you radiate one site and you see something happening in other places. But so far, I don’t think there are any studies which show that is true, right?

Dr. Anwaar Saeed 59:00
Totally agree. This is exactly my answer. When they raised this question about the abscopal effect, show me one clinical study. We’ve seen case reports and case series – do we have a clinical study showing that there is a true absopal effect, or we’re just talking about it, you know? So, so far, we don’t have any studies that validated, that’s carbon effects, okay,

Dr. Manju George 59:26
Okay. Any other questions? Yeah, and thank you for spending all this time with us and answering all the questions. This was a great presentation. Good luck with all your coming studies, I’m sure that we will be looking forward to what is coming out from your lab and your work.

Dr. Anwaar Saeed 59:46
Thanks a lot. Thanks a lot, Manju, and this is my pleasure anytime, I’m happy to address any questions down the road that will come up, or come back and present stuff. I’m so happy and thanks again for the invitation.

Dr. Manju George 1:00:00
Yeah, thank you very much. And thank you all for participating. If you have any questions, feel free to email me, and I’m sure that I can email them to Dr. Saeed, or she’s on Twitter, and she’s very active. So thank you very much.

Dr. Anwaar Saeed 1:00:13
My pleasure, bye bye.