Exploring CAR T Cells in GI Cancers at ASCO24

Dr. Shaalan Beg and Dr.Mohamed Salem discuss key abstracts that will be presented at the 2024 ASCO Annual Meeting, including hypoxia-response CAR T- cell therapy for solid tumors, GPC3-specific CAR T- cell therapy in hepatocellular carcinoma, and the promising efficacy of targeted therapies in GI cancers.  TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I am Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center. In today's episode, we'll be discussing some key abstracts in GI cancers that will be presented at the 2024 ASCO Annual Meeting. I'm delighted to welcome Dr. Mohammed Salem, a GI medical oncologist at the Levine Cancer Institute at Atrium Health, for this discussion. Our full disclosures are available in the transcript of this episode. Mohammed, it's great to have you back on the podcast. Dr. Mohamed Salem: Thank you, Dr. Beg. It's always a pleasure to be here. Thanks for having me.  Dr. Shaalan Beg: So we're seeing more and more exciting data emerge on the role of ctDNA in GI cancers. And that's a topic that we've covered fairly extensively on the podcast. This year, in Abstract 3513, investigators used a novel, highly sensitive HPV ctDNA assay to evaluate the clinical outcomes of HPV ctDNA status in people with localized anal cancer treated with chemoradiation. And we know that prior HPV infection is associated with 90% of anal cancers. Can you give us a summary of the study and why it's so important to the clinical care we're giving our patients today?  Dr. Mohamed Salem: Sure. So, as you already alluded to, in the current era of precision oncology or precision medicine in general, there is an effort to try to maximize treatment efficacy and minimize the side effects. We're trying to understand how to do that by developing more biomarkers. I think this was a very interesting study that was led by Dr. Morris of MD Anderson. As you mentioned, he tried to determine the correlation between that circulating tumor DNA at different timelines and also associated that with the relapse. Obviously, as we all know, HPV infection is linked to about over 90% of anal cancers, and anal cancer is increasingly common in the U.S.  The study design includes patients from stage 1, 2, and 3 anal cancer treated with curative intent concurrent chemo radiation and the plot sample to collect circulating DNA was taken at five weeks of treatment and then at various intervals, including 3months, 6  months, 9 months and 12 months, to detect the HPV circulating DNA. And the analysis was done to correlate detection of circulating DNA with a relapse.  So what they observed is after collecting the samples at the end of the treatment, which is 5 weeks, followed by 3 months, 6 months, 9 months, and 12 months following treatment using the correlation between the detection of circulating tumor DNA as well as the recurrence rate, they were able to identify that about 22% was seen at 5 weeks, 13% was seen at three months, then 10% was seen at 6 months, and 0% actually was seen at 12 months. In the final analysis, they concluded that detection of circulating DNA at 3 months was significantly associated with a relapse rate of those patients. And also, they looked at the baseline stage, T stage, end stage, age and other perhaps prognostic factors. But the clinical implication of that trial is this finding supports the potential of integrating now the circulating DNA analysis and routine post-treatment surveillance, which hopefully will help us identify those patients with high risk of relapse and whether they can be treated with adjuvant therapy  in context-free drug trial or even like more close surveillance. Obviously, this is a very novel study, so it needs validation. Also, we need to understand more about the platform used because with the immersion technology and how fast this field is moving, I think it's important to look at this platform or other platforms. I think as a concept it’s very interesting and hopefully will help us to identify patients with higher risk. So, I'm looking forward to hearing the full presentation. Dr. Shaalan Beg: Moving on to colorectal cancer, Abstract 3514 is a trial of hypoxia-responsive CEA CAR T-cell therapy for people with heavily pretreated solid tumors where this was administered intraperitoneally or intravenously. And you know, as a solid tumor oncologist or GI oncologist, we've been watching the hematologic space evolve so dramatically in the last five years with cellular therapies that it's exciting to see these CAR T-cell approaches being applied in solid tumors with some results. So can you talk about this study and whether you think it will influence clinical practice?  Dr. Mohamed Salem: Of course, I'm actually very excited to see this study because as you mentioned, CAR T-cell therapy has been utilized in hematological malignancies for the last several years and in fact it's becoming a center of care. As you know, it's very effective in certain tumors. Unfortunately, we did not see a similar result in solid tumors thus far. I know we are trying to make progress, but we are definitely not seeing the same efficacy in solid tumors. And also, of course, in CRC and many other tumors, we need more target options, so I was very excited to see this abstract. And I want to give a little bit of background why this abstract is important. Many solid tumors have a low oxygen level environment, hypoxia obviously, which can impact the effectiveness of CAR T therapy. So hypoxia can suppress the immune response, leading to poor performance of the immune cells like the T cell within the tumor. The investigators, to overcome that challenge, meaning hypoxia impacting the efficacy of the T cell, they were actually able to engineer a CAR T cell to be hypoxia responsive. And what does that mean? That the cells are designed to become more active in low oxygen conditions, which is more difficult in many of the solid tumors. The reason that's very interesting is because, one, it reduces exhaustion of the T cell, meaning like when you have the T cell active all the time, they get exhausted. So when you have the T cell in the resting state, until they reach the tumor environment and they get activated by the hypoxia status, now you reduce the expulsion of the T cell. But also that one overcomes the resistance. So once activated in the tumor hypoxic environment, this CAR T cell shows increased efficacy in targeting and killing the cancer cell.  Based on that concept, the investigators conducted a phase 1 dose escalation study in solid tumors. So this was a phase 1 open label group escalation study involving patients with tumor suppressed CEA and also had relapsed refractory second line treatment. The trial actually included 2 routes of administration, which I think was very interesting – IV versus intraperitoneal, IP, way of administration. And they enrolled about 40 patients between June of 2022 and January 2023. And 35 patients had colorectal cancer, 3 patients had gastric cancer, and 2 patients had non-small cell lung cancer. Overall, there was no surprising safety data. In terms of side effects, it was largely macrocystis, colitis. Unfortunately, they had 1 treatment that did not finish. But the interesting feature was the efficacy of that concept was demonstrated and in fact they were able to see more disease response and control at this rate with IP infusion, which I think is a very novel approach. I would look forward to trying and looking into this kind of delivery, especially in CRC and other tumors. Dr. Shaalan Beg: Because we've known that historically managing disease intraperitoneally has been challenging with cytotoxic chemotherapies and even surgical approaches that have been deployed can be fairly morbid as well. So looking at novel delivery mechanisms can help us understand, maybe be able to manage side effects of treatments in different ways and open doors for treatment in diseases that otherwise we couldn't manage. So definitely a very novel and exciting approach on this study.  Dr. Mohamed Salem: I agree. I think the idea of administering an IP route is a very interesting idea.   Well, Shaalan, there is another study in CRC, Abstract 3515. This is the first human study of ABBV-400, cMET–targeting antibody-drug conjugate in advanced solid tumors. Can you tell us about this promising data? Dr. Shaalan Beg: Yeah, so we've known that cMET is a very relevant biomarker across many cancers, particularly colorectal cancer, and it is overexpressed in a fairly large proportion of multiple diseases. But there hasn't been an effective regimen that has been found to be tolerable to target this specific biomarker. In this study, the investigators are evaluating an antibody drug conjugate, which takes the cMET targeting antibody telisotuzumab and conjugates it to a novel topoisomerase one inhibitor payload. And there's a phase one study that enrolled people across multiple different tumor types. This was presented at ASCO 2023. And this year, the investigators are coming in and giving the results of a colorectal cancer cohort within that study. Patients were enrolled in the dose escalation phase, and in the dose expansion phase, there were 122 colorectal cancer cases; so a fairly healthy size colorectal cancer population. And the median number of prior lines of therapy was 4, which is fairly consistent with what we would expect in our clinical population for people with colorectal cancer. So what they found in terms of efficacy is that the response rates, the confirmed overall response rates, were between 15 and 20%, depending on what dose of the medication the patients had received. They enrolled people regardless of cMET expression and then evaluated the response based on a higher or lower cMET expression. And those with higher cMET expression had an overall response rate of >30%, while those with lower cMET expression had a response rate of 10 to 15%. So they still had a response rate, which for fifth-line colorectal cancer is something to be aware of and it could be a marker of more significant clinical activity than other treatments that are out there.  And with the antibody drug conjugates, it's also important for us to keep an eye on the side effect profiles because a lot of these agents can have distinct side effect profiles that otherwise we wouldn't be familiar with. And in this study, 64% of participants had a grade 3 or above treatment emergent adverse events, and 41% had serious adverse events. So definitely something to think about. And most of these were hematologic toxicities, 30% had grade 3 or worse anemia. Neutropenia was seen, in grade three and above, was seen in 25%, leukopenia or grade three and above was seen in 12%, and thrombocytopenia again around 12%. And the non-hematologic toxicities were nausea, fatigue, vomiting and diarrhea. There was some interstitial lung disease, pneumonitis, which was seen in 7% of the total population, of which 2% had grade three or above. So definitely something to think about. From my perspective, I really am excited about this presentation because we're seeing evidence of clinical activity focused on cMET for refractory colorectal cancer compared to other agents that are out in the market. If this pans out in future studies, it could definitely change the way we deliver our treatments. Dr. Mohamed Salem: I totally agree that we actually need more therapy for those patients. And I'm not surprised that the myelosuppression, as you mentioned, was in fifth-line treatment. So this patient had large exposure to cytotoxic agents before.   So, looking at CAR T once more, there is a very interesting Abstract 4019, which is a study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR T, in patients with advanced hepatocellular carcinoma (HCC). What are your key takeaways from this study, Shaalan? Dr. Shaalan Beg: This is a first-in-human study. It enrolled people with advanced HCC who failed on one or more lines of prior therapy and they were given one single infusion of C-CAR031 after standard lymphodepletion and they enrolled 24 patients across 4 dose levels. If we look at the overall response rate, 50% of the 22 people who were eligible for response assessments had a partial response. This response rate varies based on the dose level itself and the investigators claim a 90% disease control rate. So definitely when we think about standard treatments for hepatocellular cancer after first line therapy, this is something which will catch a lot of people's attention. Again, with CAR T-cell therapy, we need to be aware of the risk of potential toxicities. There were no dose limiting toxicities and CRS or cytokine release syndrome was observed in 91% of patients, while a very small proportion, about less than 5%, had grade three CRS. Most of the side effects here were, again, lymphocytopenia, neutropenia, thrombocytopenia, and some transaminitis in 16% of patients. They did see tumor reduction in 90%, not only in the intrahepatic disease, but also in the extrahepatic disease. And again, these are people who had BCLC stage C disease. So this included people with hepatic and extrahepatic metastases. And in terms of prior lines of therapy, 96% of patients had either received immune checkpoint inhibitors and TKIs.  If we think about how some other immune therapy regimens are being developed in the GI cancer space, there is some indication that liver lesions may respond differently compared to extra hepatic disease. So in this case, they saw responses in both scenarios, which makes it very exciting, because even though we've seen many approvals of TKIs and immunotherapy, anti-androgenic therapy in hepatocellular cancer, the treatment of these patients is still extremely difficult because of their underlying hepatic dysfunction. And it'll be very interesting to see how this treatment unfolds.  Dr. Mohamed Salem: You summarized it very well, Shaalan. I echo your thoughts. What is also interesting about that study, it's actually targeted at the GPC strain, which is prevalent in HCC but not normal tissue, which goes back to your comment about the toxicity, and hopefully we can also manage treatment in the context of underlying liver disease.  Dr. Shaalan Beg: I guess it's fair to say that we're both very excited to see what's ahead in GI cancers at the Annual Meeting.   Mohamed, thanks as always for sharing your great insights with us on the ASCO Daily News Podcast.  Dr. Mohamed Salem: Thank you all for having me, and I'm looking forward to meeting you and all our colleagues in Chicago in a couple of weeks. Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcripts of this episode. I'll be back to cover late breaking abstracts and other key advances in GI oncology after the annual meeting, so please join me for more key insights from ASCO24 and on the ASCO Daily News Podcast. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today’s speakers:  Dr. Shaalan Beg  @ShaalanBeg  Dr. Mohamed Salem  @SalemGIOncDoc    Follow ASCO on social media:  @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Shaalan Beg:  Consulting or Advisory Role: Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen  Speakers’ Bureau: Sirtex  Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics  Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune    Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca  Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck