Good day, everyone. Welcome to Affimed's AFM24 update call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. As a reminder, today's conference is being recorded. I would now like to introduce your host for today's call, Alexander Fudukidis, Head of Investor Relations at Affimed. Please go ahead.
Thank you, Kevin, and thank you all for joining us today for today's call to discuss the findings from the poster presentation of our AFM24 monotherapy study in non-small cell lung cancer that was presented earlier today by Dr. Anthony El-Khoueiry, Associate Director of Clinical Research at USC Norris Comprehensive Cancer Center and Principal Investigator of the AFM24 studies. Before we begin, I'd like to remind everyone that we issued a press release earlier today and have since added the presentation that we will be using on this call, both of which can be found on the investor relations section of our website. On the call today, we have members of our management team, including Dr. Adi Hoess, our Chief Executive Officer, Dr. Andreas Harstrick, our Chief Medical Officer, Dr. Arndt Schottelius, our Chief Scientific Officer, and Dr. Wolfgang Fischer, our Chief Operating Officer.
Dr. Anthony El-Khoueiry is able to join us on the call, so you will be hearing from him. We also have our Chief Financial Officer, Angus Smith, on the call. The team will be available for Q&A after the prepared remarks. Before we start, I'd like to remind you all that today's presentation contains projections and forward-looking statements regarding future events. These statements represent our beliefs and assumptions only as of the date of this call. Except as required by law, we assume no obligation to update these forward-looking statements publicly or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future.
These forward-looking statements are subject to risks and uncertainties, and actual results, may differ materially from those expressed or implied in the statements due to various factors, including, but not limited to, those identified under the section Risk Factors in our filings with the SEC, and those identified under the section entitled Forward-Looking Statements in the press release that we issued earlier today. With that, I'll turn the call over to Adi. Adi?
Yeah. Thank you, Alex, warm welcome to everybody joining us for this call this afternoon. We're excited to be presenting the first data from our AFM24 monotherapy expansion cohorts today, including the data that was presented in our poster at ASCO this morning. Before we go into the data, let me highlight some of the important findings from the AFM24 program to date, which is here on slide four. As you know, the AFM24 program encompasses three clinical studies. AFM24-101 is the monotherapy study. The data we presented today demonstrate the signs of clinical activity in heavily pre-treated patients, most notably in EGFR mutant non-small cell lung cancer and a well-managed safety profile. The second study, AFM24-102, is investigating the combination of AFM24 with the PD-L1 inhibitor, atezolizumab.
Data presented at last year's ASCO showed initial evidence of the synergy between AFM24 and atezolizumab, with a particularly impressive response in the gastric cancer patients who had progressed following multiple lines of treatment, including a PD-1 checkpoint inhibitor. Our third study, AFM24-103, is investigating the combination of AFM24 with SNK01 autologous NK cell. This study has demonstrated the feasibility of administering AFM24 together with NK cells, the safety of this approach, and signs of clinical benefits for patients. Enrollment in this study has been challenging, and we believe an allogeneic NK cell may be better suited for combination of AFM24. Based on these important findings, our focus for AFM24 program going forward will be on the combination study with atezolizumab. Again, the study is called AFM24-102. We expect to have our next data on this study in the second half of this year.
Leveraging the signs of clinical activity that we observed in the monotherapy study, we'll be adding an additional cohort to investigate now EGFR mutant non-small cell lung cancer to this study. Andreas Harstrick will provide more information on the rationale for the combination approach later in the call. To remain focused, we'll be wrapping up the AFM24-101 and the AFM24-103 studies as a result of these findings. With that, I'll hand the call over to Andreas Harstrick to review the background on AFM24.
Yeah. Thank you, Adi, and also a warm welcome from my side to everybody on the phone. As you see on slide six, and I think it's important, just to have a little reminder about the nature and the biology of AFM24, and how it differs from conventionally available EGFR inhibitors, both TKIs and conventional signal blocking antibodies like Erbitux or panitumumab. What you see on this slide is on the left side, a graphic representation of the mechanism of action of conventional EGFR targeting agents. The common feature of these agents is that they are disrupting the signaling cascade, which transports signals, either growth or survival signals, from the cell membrane, where the EGFR receptor is activated by ligands, through a number of different intermediate steps down to the nucleus. There are several challenges and limitations to this approach.
First and foremost, we have learned that many tumor cells, even though they do express EGFR, are not dependent on the signaling cascade. Even if you potently inhibit the signaling cascade, these cancer cells find ways to survive, usually by using alternative mechanisms. Furthermore, resistance can occur in any of the downstream steps, and makes EGFR signaling independent from ligand activation. Thirdly, since many normal tissues express or use EGFR signaling pathway for survival, profound inhibition of this pathway has been associated with significant clinical toxicity, especially skin toxicity and mucosal toxicity. If we move on slide seven, here you see the difference between the conventional EGFR targeting agents and the novel molecule AFM24. As you will recognize, the whole signaling cascade is no longer on this slide, and this is completely irrelevant for the mode of action of AFM24.
For AFM24, the EGFR, the extracellular domain of the EGFR receptor, only serves as a docking station. AFM24 forms a bridge between the tumor cells that needs to be destroyed, and members of the innate immune system, mainly the NK cells, but also, and probably equally important, the macrophages. If we can move on slide seven. Here you see the consequences of this mode of action, and this is the well-known immunicity cycle. It all starts on the left side, where the initial interaction is between NK cells and the tumor cells. Here, AFM24 plays an important role to activate this part of the immune system. The NK cells will then start to destroy tumor cells, and thereby liberating novel tumor-associated antigens that are processed by macrophages and dendritic cells. Another important feature of the mechanism of action of AFM24.
This liberation and presentation of tumor antigens triggers the activation and the clonal expansion of tumor-reactive T cells, shown as the green little cells on this slide, which is the logical rationale for a combination of drugs like AFM24, that activate the innate immune system, and thereby provide a kickstart. Agents that impact the adaptive immune system, like PD-1 and PD-L1 inhibitors, making the newly generated T cells much more active. On the next slide, also to just recapitalize, you see the programs that we initiated with AFM24. The AFM24-101 monotherapy study, where we evaluated, initially, the pharmacokinetic and pharmacodynamic potential of AFM24, and defined the recommended phase II dose.
As you know, we have now taken the recommended phase II dose into the expansion cohorts for EGFR mutated non-small cell lung cancer, which will be the main topic of today's discussion, but also to colorectal cancer and renal cell carcinoma, where we will provide initial data. The AFM24-102 combination, the combination with atezolizumab, is currently enrolling into the expansion cohort, EGFR wild-type non-small cell lung cancer, gastric cancer, and then an exploratory cohort that can include patients with hepatocellular carcinoma, biliary tract cancer, and pancreatic carcinoma. Adi Hoess mentioned, the AFM24-103 study, the combination with autologous natural killer cells. We initially started this program as a broad program to evaluate early signs of activity, which would allow us to focus on the most promising cohorts to be continued, and this will be one of the topics of our concluding remarks later in this call.
With this, it's my pleasure to hand over to Anthony El-Khoueiry, who has been extremely helpful, extremely active in all of our trials, and he will report the data, both across all indications, as well as go more into detail in the non-small cell lung cancer EGFR mutations cohort.
Anthony, thank you for joining us here.
Thank you very much. I'm Anthony El-Khoueiry. I'm a medical oncologist at the USC Norris Comprehensive Cancer Center in Los Angeles. My area of specialty is early drug development. I direct our phase I program for solid tumors. I also focus in the space of gastrointestinal cancers. I'm excited to share with you some data, as was stated earlier, about the activity and safety of AFM24. On slide 11, you see the different dose level cohorts that we explored during the dose escalation portion of the study, starting at 14 milligrams all the way up to 720 milligrams. What's very important is that because AFM24 has a well-managed safety profile, we did not have a maximum tolerated dose.
We selected 480 milligrams as our phase II dose, based on an aggregate of data, including pharmacokinetics, receptor occupancy, and activity. At this dose level, we certainly show sufficient saturation of CD16 on the NK cells and signs of activity as well. 720 milligrams was safe as well. As I said, we did not reach an MTD. What we learned during the dose escalation is that the drug was having on-target effects as designed. We saw consistent elevation of cytokines in the blood of patients in the periphery, including TNF-alpha and interferon gamma, which are signs of activation of the adaptive immune system, of both actually, but also the adaptive immune system.
we saw that the natural killer cells in the blood, in the periphery, were actually being activated as well at doses starting at 160 and higher. Next slide, please. On slide 12, in summary, we saw favorable safety during dose escalation. The most common side effect during dose escalation was infusion-related reactions, which were mostly of low grade one and two, and they were easily manageable by giving the drug in a titrated fashion and pre-medicating the patient. When we went into the expansion cohorts, including colorectal, renal cell carcinoma, and non-small cell lung cancer, we did not see any changes in the safety profile. It remained the same. Of note, that even AFM24 is modulating the immune system, it is not causing cytokine release syndrome type events.
Even though it's targeting EGFR or using it as a docking station, it's not causing the classic severe EGFR toxicity in the skin and the mucosa. We saw minor rashes that were easily manageable. There was one event of grade five pneumonitis, a patient who passed away with pneumonitis, unfortunately, but this is a patient who also had progression of their disease and multiple other comorbidities. The investigators on the dose escalation call mostly felt that this was unrelated to the study therapy, but because a relation could not be ruled out completely, it is mentioned here. Immune-mediated events, which plague checkpoint inhibitors, were not seen with AFM24. Again, overall, a favorable safety profile that's allowed us to dose escalate, as I showed earlier. Next slide, please. Now, let's go into activity.
On the left, you see a waterfall plot with all the various colors, this is from the expansion cohorts on the study. In yellow, is non-small cell lung cancer, red is renal cell carcinoma, and green is colorectal cancer. You clearly see that we see tumor shrinkage or reduction in target lesions in all the tumor types. Of particular interest here are the yellow bars, representing the partial responses in patients with non-small cell cancer, non-small cell lung cancer. We also saw prolonged stability and some tumor reduction in patients with colorectal as well as renal cell carcinoma.
Naturally, based on this early data, we felt that the non-small cell lung cancer patients, which all had EGFR mutations, appeared to benefit the most, which will be the focus of the rest of my slides from here on. I already mentioned, as is summarized in the box on the right, that we saw tumor reduction and prolonged stability in colorectal and renal cell carcinoma. Of note, a renal cell carcinoma patient had further reduction down to 28%, so just 2% short of a partial response, and that's not included in the bar graph on the left currently. Next slide. We are now on slide 14. The swimmer's plot on the left highlights the durability of both the responses and the stability of disease.
You can see that we have durable stability or response in various tumor types, but particularly the yellow lines representing non-small cell lung cancer. The activity is summarized on the right with non-small cell lung cancer. Two partial responses are confirmed, five stable diseases lasting three point five months or longer, so two scans. Renal cell carcinoma, three out of six valuable patients with stable disease, and I mentioned the one with 28% reduction in target lesions. Lastly, with colorectal, two patients with stability of disease and one having completed 10 cycles, which is equivalent of 10 months of therapy. Next slide. Let's focus a bit more now on the EGFR mutant cohort of non-small cell lung cancer patients. To set the stage for why we are excited about this activity, this is an area of unmet need.
Patients with EGFR-mutated non-small cell lung cancer, in first line, are usually treated with osimertinib, which is a third-generation tyrosine kinase inhibitor that targets the mutation in the EGFR receptor. After progression on osimertinib, that is certainly not an established standard with favorable activity. In clinical care, what we do is give patients chemotherapy in second line or chemotherapy combined with atezolizumab, sometimes with the addition of bevacizumab, and none of these are actually, again, approved. They are listed as possible therapies in NCCN guidelines, but not as preferred or recommended therapies, and generally not reimbursed in the EU either. Certainly, second line and beyond, the clinical trials and novel therapies are the favored options for patients with EGFR mutation and non-small cell lung cancer. Next slide.
We recruited a total of 15 patients with non-small cell lung cancer and EGFR mutation. Their characteristics are summarized in the table on the left. I'll draw your attention to the fact that, as expected, 80% of them had adenocarcinoma, which is where the majority of these EGFR mutations occur. They had a median of two prior lines of therapy, but up to 12 prior lines, and you can see that they were exposed to a variety of EGFR tyrosine kinase inhibitors, as listed in the bottom box in the table, including 8 of them who had that first-generation tyrosine kinase inhibitor, osimertinib.
At the planned interim analysis, which we performed recently with these 15 patients, they had received a median of 11 doses of AFM24, over a median duration of 11 weeks, but up to 34 weeks, if you look at the range. Again, they had a median of two prior lines of therapy, which is heavily pretreated for this patient population. The safety profile in this group of patients was no different than we saw earlier in the dose escalation part of the study. The majority of the treatment-related adverse events were mild to moderate, and mostly infusion-related reactions, that occurred mostly with the first dose, sometimes with the second, but did not recur after that.
When we look at higher grade treatment-related adverse events, grade three, meaning a treatment-related adverse event, there were seven of them, they were decreased neutrophil count, lymphopenia, which was asymptomatic, and one infusion-related reaction. We've already discussed the one case of pneumonitis and death. Next slide. We are now on slide 18. Again, you see the swimmer plot on the left, highlighting that the majority of these patients had durable stability or response on study. You see that a high proportion of them went beyond three and a half months, as we had summarized earlier. In the table are also listed the variety of EGFR mutations that these patients harbored.
To the right is a exciting waterfall plot, where you see the reduction in the size of target lesions, including the two patients that met the official criteria of partial response that was confirmed. Next slide. Actually, if you go back one page to the slide. What I also wanna mention specifically, that besides the response, right, that we had a disease control rate. This includes patients who had a response plus stability of disease, that the disease control rate in the aggregate was 47%. Roughly half of the patients were clinically benefiting from this therapy. Next slide. Back to slide 19. This is showcasing one of the patients who derived significant benefit.
This is a 49-year-old patient, male, diagnosed in April of 2020 with non-small cell lung cancer, adenocarcinoma subtype, with metastatic disease and have a mutation in exon 19. It's actually an exon 19 deletion. Patient was previously treated with a EGFR TKI, afatinib, with a partial response, then progressed, had chemotherapy for a short while with progression of disease, developed brain metastases that were treated with whole-brain radiation, then had a response to atezolizumab with subsequent progression. Came onto the study with the first treatment in August of 2022. You see the baseline scan from July 2022. I know it's probably hard to see, but the green bar is highlighting one of the lymph nodes that we were following in this patient that in the subsequent scan in October of 2022, showed significant reduction.
To the left, the bars are the addition of the diameters of the target lesions. You see that the total went down significantly from July to October, meeting the partial response criteria. That response was sustained on the subsequent scan, what we call the confirmatory scan, in November of 2022. Next slide. Another of the patients who has benefited significantly. This is a patient with what we call stable disease. Some tumor reduction. A 55-year-old Asian male, diagnosed as well in January 2020, another exon 19 mutation, metastatic disease to various organs, including lymph nodes, the contralateral lung, adrenal gland, and bone. Initially treated with the third-generation TKI osimertinib, with a partial response. Had progression of disease. Had chemotherapy in combination with atezolizumab and bevacizumab, with a partial response.
Could not continue the chemotherapy from toxicity, was maintained on atezolizumab, bevacizumab alone, and then subsequently had progression of disease. Started treatment on AFM24 in August of 2022. You see the some of the target lesions on August third, what's called the screening scan. You see a reduction on the subsequent scan in September, and it's sustained in November, in January, and then finally, the patient progressed in March of 2023. The patient did not meet the criteria for partial response, but had meaningful, prolonged clinical stability after failure of two regimens of therapy. Next slide. In summary, on slide 2021, AFM24 shows meaningful clinical activity in this group of patients who are heavily pretreated with EGFR mutant non-small cell lung cancer. Our overall objective response rate is 13%, the disease control rate is 47%.
In addition to the responses, we have patients with prolonged stability of disease. Although this expansion cohort did not meet the formal criteria to be expanded further, it did provide proof of concept from the activity perspective, that we're seeing clinical benefits from the safety perspective and from the pharmacodynamic perspective, where we saw actually activation, again, of NK cells in the periphery, and as we showed earlier. The drug has a well-managed safety profile, as we've talked about. Again, while these clinical results are promising, we believe, based on the mechanism, the antitumor activity will be further enhanced or may be further enhanced in combination with other therapies, including those that target PD-1. I think this is the, my last slide, and I'll hand it over back to Andreas.
Yeah. Thank you for sharing this really exciting data with us. I think you have treated quite a number of patients and seen patients who will really benefit, even late-line, who was very heavy pretreatment. Let me try to put this data into perspective and outline the way that we will take from here, and I'm restarting again with the unit, the cycle, where AFM24 basically provides the starting signal on the left side, so initial tumor destruction, activating of NK cells and macrophages. Our underlying hypothesis is then that we should see activation also of T cells and infiltration of T cells in the tumor microenvironment. If we move to the next slide, I think one of the key findings of this study is that what we postulated when we started out this program is exactly happening in patients.
What you see here is that, on the left side, paired, data set from patients at screening and then at cycle one, day 24. We do see a increase in, both NK cells as well as in cytotoxic CD8 positive T cells in tumor biopsies. I think paired biopsies, even though quite hard to do, are the gold standard, really, for proving your hypothesis that what you postulate is happening in the tumor. This is, I think, the strong rationale and the strong basis for us to focus on the combination of AFM24 with checkpoint inhibitors that, target PD-1 or PD-L1. We can go to the next slide.
We have started, as Anthony said, our dose escalation study of AFM24 in combination with atezolizumab and have published first data, and I think one of the very first patients that we put on this trial also confirmed clinically our hypothesis of the synergy between AFM24 and PD-L1 inhibitors. As you see on the right, this is a patient with gastric carcinoma, heavily pretreated, starting out with oxaliplatin, capecitabine, and pembrolizumab. Had a very short-lasting partial response, but then a documented progression while still receiving pembrolizumab. Received second-line paclitaxel, third-line irinotecan, so really went through the whole armamentarium of possible chemotherapy, and then on a clinical trial of a PD-L1 inhibitor, was enrolled with really disfiguring massive skin metastases at baseline.
What you see from left to right, already after two doses of AFM24, 1 dose of atezolizumab, and I have to mention here that this was low dose AFM24. This was part of the dose escalation, so 160 milligrams. Clinically, a very meaningful reduction in tumor burden. This patient also had significant tumor-associated pain, which was reduced significantly. She continued to show basically a reduction in shrinkage of her metastasis down to a 72% reduction in the target lesions. No change in non-target lesion, but no progression anywhere. This was maintained for roughly 8 months when she finally started to progress again. Very meaningful, I think, response in a very heavily treated patient, who, at that point when we enrolled her into the study, had no other treatment option left.
Second patient, also an interesting case on the next slide. This is a patient with pancreatic adenocarcinoma, a disease type where immune modulation up to this point has never shown any signs of reactivity. Again, a patient who had received three prior lines of chemotherapy. Even though this patient did not achieve a reduction in tumors that met the criteria for a partial response, you can see that this patient had stable disease with good tolerability for more than six months, we arrived real clinical benefit from this type of treatment. Very early data, but we believe that they point into the right direction, that the combination of AFM24 with a checkpoint inhibitor is really capable to induce clinically meaningful responses across a number of different indications. If we move to the next slide, this summarizes where we stand today.
I think what we have shown is that AFM24 monotherapy shows promising single-agent activity, across a variety of tumor types. At this point, most strikingly in patients with non-small cell lung cancer, EGFR mutated. We have also seen that responses and stable disease can maintain for clinically meaningful periods of times of six months and longer. When we go to the field of EGFR mutated non-small cell lung cancer, there is, as Anthony has shown, clearly a significant unmet medical need. EGFR-targeting TKIs are currently standard of care, but limited options exist once patients have exhausted the TKI option with chemotherapy plus/minus CPIs currently being used, but not with really satisfactory results.
What we also have shown, and the reasons to believe why AFM24 plus CPI may be really a meaningful treatment option for these patients, we have seen clinical activities with AFM24. We also have, and we can make some cross comparisons, shown with another ICE with AFM13, that there is very significant synergy between ICE molecules activating the innate immune system and CPIs activating the adaptive immune system, highlighted by our study in Hodgkin lymphoma, that showed an 88% overall response rate and a 46% complete response rate. What's always important for immunomodulating therapies, especially for combinations, is that we are not seeing any enhancement of the classical immune-mediated side effects by AFM24, either alone or in combination with CPIs.
If we can move to the next slide, this shows our reformulated, refocused program for AFM24, where we will focus now on the combination with atezolizumab. We are actively recruiting, as we have announced, into the three expansion cohorts that were the original part of the study. We are recruiting patients with non-small cell lung cancer, EGFR mutant. We are recruiting patients with gastric carcinoma. We have the cohort of hepatocellular and pancreatic carcinoma, which, in fact, recruited very fast, and here we temporarily put enrollment on hold to really assess the activity in the initial patients. Based on the data that we have presented today, we decided to add a fourth cohort, which will focus on patients with non-small cell lung cancer, EGFR mutations. With that, I think I am...
Oh, one more slide to go, but this is just summarizing what we have seen during the presentation. AFM24 monotherapy in solid tumors, I think a very important milestone, a very important step, as there has always been some concern whether the innate immune system really can attack and can shrink and can control solid tumors. I think with the data we have provided today, we can answer this question clearly with a yes. The innate immune system can control solid tumors. The near-term focus will now be on the combination with atezolizumab in the four different cohorts that I mentioned. I think with that, we conclude our presentation and open the line for questions.
Thank you. Ladies and gentlemen, if you have a question or a comment at this time, please press star one one on your telephone. If your question has been answered or you wish to remove yourself from the queue, please press star one one again. We'll pause for a moment while we compile our Q&A roster.
Our first question comes from Srikripa Devarakonda with Truist. Your line is open.
Hi, thank you so much for hosting this event and providing all the details and strategy for AFM24 going forward. You know, regarding the path forward for the EGFR mutant patients, the cohort that you're planning to add, can you just talk about any steps you need to take in order to open this new cohort? Do you need to have a discussion with the agency, or is that you can just go ahead and open it? Doctor, maybe you can talk a little bit about, you know, this is a PD-L1 combo trial that's ongoing, not suggesting that you start another cohort, but I was wondering if you have any thoughts on whether there could be a difference between PD-1 and PD-L1 in these non-small cell lung cancer patients? Thank you.
Yeah. I can take the first question. No, we do not need interaction with the agency. We are in the process to submit amendment to the existing trial, just adding an additional cohort. Again, this is a process that is ongoing, and we're expecting to have first patients or to be able to enroll first patients into this new cohort in the second half of this year, most likely in the third quarter of this year.
I'll take the second part of the question about PD-1 versus PD-L1. You know, again, my expertise is in drug development across solid tumors, and there's this ongoing debate whether PD-1 and PD-L1 agents are really different across tumor types. I don't think that question really has been settled or answered, in my opinion. The good news is that for non-small cell lung cancer, there is clear activity for anti-PD-L1 agents. Here we are using atezolizumab, which already has shown activity in this disease, and so has durvalumab, the other anti-PD-L1 agent. I think we are safe from that perspective.
Great, thank you so much.
One moment for our next question. Our next question comes from Daina Graybosch with SVB Securities . Your line is open.
Hi, thank you for the question. A couple of them for me. The first is in both cases.
Dana, can you speak up a little bit? It's very difficult to hear.
Yeah. Let's just pick up my headset. Is this better?
Yeah. Yes, much, it's much better now.
Great. Both the case studies you showed of benefit, the patients had both also had some prior benefit with atezo, plus or minus bev. I wondered if you saw any trend with that more broadly. Is there something about coming after atezo that seems to be enriching for patients who respond to AFM24 or had some long, stable disease benefits? The second question I have is about this new cohort combining of atezo. I think we all know that probably the best benefit in this patient population, atezo included chemo and bev, and I wonder whether you'll give an option for bev as well in this new cohort. Thank you.
Yeah, thank you. Both excellent questions, and I currently cannot answer the first question, but your observation is spot on. The two patients that we are presenting here were both coming from a PD-1, PD-L1. We have not formally analyzed all of our patients in accordance to previous treatment, but that's an excellent observation, and we will clearly do so, but we don't have the data then yet.
I would note, though, that for the first patient, the exposure to atezo was in the earlier line.
Yeah
Had subsequent other lines of therapy. It's a, it's a valid observation we have to look into.
Yeah. So I think it's really a good question, and we'll make us analyze the pretreatment and the possible differences according to pretreatment. Now, I agree that in general, VEGF inhibition has been shown to be beneficial in combination with CPI. I think it's not only true for bevacizumab. You also know the data with ramucirumab in non-small cell lung cancer. We currently do not plan to include a VEGF inhibitor in one of the existing cohorts, but this is definitely something that could be one of the next steps, as I think there is likely synergy between the three mechanisms of action.
Great. Thank you.
One moment for our next question. Our next question comes from Maury Raycroft with Jefferies. Your line is open.
Hi, this is Kevin on from Maury. Congrats on the update. Thanks for taking my questions. I just had a first question on the AFM-24 atezo update in the second half. I just wanted to see what the latest you were saying is, in terms of the totality of data we could see per cohort. I know enrollment is going well, as you mentioned. If you could make any go, no-go decisions at that point in the first three cohorts. Lastly, anything you're seeing on internal benchmarks for these different cohorts?
I'm gonna start from the back. We have never disclosed our internals, our benchmarks for continuation, discontinuation. This is something we cannot share. In terms of enrollment, as you have seen, we have already reached a sizable number of patients in the cohort four, which is pancreatic HCC and biliary tract, and we are starting to analyze the data. We have also seen robust uptake in the gastric cancer cohort. Non-small cell lung cancer has just started, and as we had non-small cell lung cancer, EGFR mutant, it is about to start. I think what we will report in the update will be a sizable number of patients, probably across the three cohorts that currently exist. Again, by definition, the EGFR mutant cohort will always lag a little bit behind.
This may not necessarily be enough patients to reach the formal interim analysis criteria across all cohorts, but I think we should have a good understanding of the initial activity when we report the data.
Great, thanks. That's helpful. just one more. you know, there's some other NK engager data this weekend at ASCO. I just wanted to get your take on how your innate cell engagers are differentiated versus these other engagers, and particularly in the CD123 space, given the AFM24, sorry, AFM28 is in the clinic. Then anything on AFM28 in terms of enrollment color that you could share as well?
Yeah. maybe I take the first part, and then I hand over to Arend, our Chief Scientific Officer. The enrollment that we see in our AFM28 study is really encouraging, and that we are progressing as planned or maybe even a little bit faster as planned. That's a very well conducting study. Now, in terms of differences or comparison between our CD123 targeting agent, AFM28, and the other CD123 engagers, I'd probably hand over to Arendt.
Yeah, happy to. Kevin, thanks for the question. First of all, as you rightly said, you know, these are, of course, belong in the same class, but we stand by our strong belief that really activating CD16A is probably one of the biggest, strongest activators in K cells, as we do, bivalently is a good way to do. We have seen preclinically, very clearly, that, through the very high affinity that we have, higher than other molecules, we see this very high retention. You know, we see that as the biggest difference to the other molecule. What's also important, you know, maybe just one to add, what we've shown consistently across our ICE molecules, that they do work down to very low levels of CD123.
That's been a important, characteristics of our, of our, platform. You've seen that with all of the molecules, you know, shown in cell lines and animal models, that, they do work down to low levels, very different than other engagers, but also ADCs. You know, we believe we can reach cells also with very low CD123 expression. Hope that answers your question.
Great. Thank you. Yes, thanks.
One moment for our next question. Our next question comes from Lee Wei. Wei, your line is open.
Hey, thanks for taking our questions. I guess for the new cohort of EGFR mutant patients that you're going to add to the combo, maybe help us understand, you know, what will be the benchmark for atezolizumab in these patients, and what will be the efficacy bar that you need to clear? Maybe also talk a little bit about the key inclusion criteria for these patients.
The benchmark for atezolizumab, I would say the benchmark for PD-1 inhibitors as a whole, because I don't think, as also as Anthony said, there are meaningful differences clinically at least, in patients who have really failed third generation TKIs, is probably not higher than 10%, depending a little bit on the different studies. I think that is probably a relatively good benchmark. You will see an occasional response, but again, the majority of patients do not really benefit from CPI- from PD-1 inhibitors. That may in part have to do with the fact that the tumor mutational burden in tumors that are driven by a strong dominant mutation, often is relatively low, which is a negative predictor for PD-1, PD-L1.
Again, this is one of our hypotheses, that by destroying tumor cells, by making tumor-associated antigens accessible to the macrophages, which we are also activating, that we may see really a spread of tumor-associated antigens, and therefore an expansion of reactive T cell clones. In terms of the inclusion/exclusion criteria, for our trial, by definition, it has patients that have to have an activating EGFR mutation. They have to have documented failure to third line or third-generation TKIs. They basically have exhausted this TKI option. Patients can have chemotherapy after TKI, so they would be allowed to go into study.
I think what we expect to see is probably a mixture of patients who may be second line, so come directly from a TKI, and patients who have had the sequence of TKI, followed by chemotherapy and then go on to trial.
Okay, great. The second question is for the NK combo with an off-the-shelf approach. Is that something you are discussing with your partner, Artiva, and when you might be in a position to test this combo?
I think we cannot specifically comment on discussions that we have with individual companies. I think it's fair to say that we are currently looking at a number of options to get access to an off-the-shelf allogeneic NK cell product, but cannot go more into detail at this point in time.
Okay. Got it. Thanks.
One moment for our next question. Our next question comes from Swayampakula Ramakanth with H.C. Wainwright. Your line is open.
Thank you. Good afternoon, and I appreciate you giving us this update. The question to Dr. El-Khoueiry, in your observation among these 15 or so patients that you analyzed, do you have any feeling for what mutations, you know, do you think there's any correlation between the mutations and the response that you're seeing?
That's a great question. You know, as you saw, the list of mutations is quite diverse and a very small number of patients, so it is too early and quite impossible to really look at any trends or specific signals depending on mutations. We have a quite a broad range, including the, you know, the resistance mutation that happens in exon 20, T790M, which is a known resistance mutations to the third generation osimertinib. I take that as a good sign, but I don't think really we can comment more with this small number of patients.
Thank you, Doctor. Thanks for taking my question.
One moment for our next question. Our next question comes from Yanan Zhu with Wells Fargo. Your line is open.
Hi, thanks for the update and for taking the questions. The first question follows one of the discussions earlier. I think you mentioned that it's intriguing that the responding patients with EGFR mutant lung seems to, you know, have, you know, both patients had a prior Atezol exposure. In the enrollment criteria for the new cohort in 102 study, I think there is no requirement for prior PD-1, and I think it sounded like you don't expect a lot of prior PD-1 patients to enroll.
I guess, would you analyze the data further and, you know, decide and you know, make any adjustment to enrollment criteria if prior atezol does somehow predict response?
Well, at this time, again, we do not have any specific guidance. Patients can have had PD-1, but can also be PD-1 naive, which I think in this early stage allows us really to cover a patient population that is as diverse as possible. Of course, when you see clear trends, you always have the option to narrow down on the patient population that looks most exciting. For the time being, we really want to include a relatively diverse patient population to cover all possible clinical situations that may occur in second, third-line, EGFR mutated non-small cell lung cancer.
Got it. Yep, thank you. My other question is for the doctor. Could you talk a little bit more about the pneumonitis case and whether you are at all concerned about this AE?
Personally, I'm actually not concerned at all. I was one of the physicians that felt that this was not related to the study therapy. This patient came onto the study with significant lung disease and some signs of inflammation in the lung already at baseline. This happened very quickly after getting on study. There were several confounding factors, including infection and other comorbidities. We did not see any other signs of anything close to pneumonitis or immune-mediated events in any other patient. I am personally not concerned at all.
Got it. Thanks for the comment.
One moment for our next question. Our next question comes from Bijan Mekoba with Stifel. Your line is open.
Hi, this is Bijan, on for Brad Canino. Thanks for taking the question. When we're thinking about the EGFR mutant cohort, there's currently a lot of development in the post-Tagrisso lung cancer space with ADCs, bispecifics, and new combos. It's what response rates would you need to see in a larger data set to consider it as competitive in the likely new treatment paradigm?
Good question. Again, I would say our current baseline, where available therapies are, is probably 10%. Again, chemotherapy, combinational chemotherapy, will give you a little bit higher response rate, more into 25% range, but with a very limited duration. I think what you need to do in a situation, and also Anthony can comment on this, is not simply only at the response rate. I think you have to look at the totality of the data, which response rate is one important factor, but also the durability of tumor control, whether it's a formal response or a reduction in tumor that is initially progressive, and also duration of responses and side effects. Everything, I think, goes into the decision-making later in the clinic, when physicians decides what treatment alternative to take.
It is not necessarily always the regimen with the highest formal initial response rate. You have to really look at a multitude of factors. At the end of the day, it has to be a treatment that provides meaningful clinical benefit to the patient.
Yeah, I mean, I fully agree with the answer. I would add that this is a population that's, I mean, biologically it's fraught by the development of resistance, because of the EGFR pathway being activated and the cell responding, depending on the pressure that it encounters by developing different resistance mechanisms. The durability of the benefit, whether it's stability or response, is critical here, as was stated by Andreas.
Gotcha. Thank you. That's helpful. Just one more question. There was a PD-1 Tagrisso combo that was discontinued previously due to immune-related AEs. A question on that: Do we know why those AEs were caused? Is this something that occurs relatively quickly with the combination, or is it something that we could see in longer follow-up? I know we aren't seeing it in these initial data, but I'm curious if it may occur in the future.
Yeah, I think it would be pure speculation to try to predict. Based on the mechanism of action and our initial data that we have seen, we do not have any indications that we see a synergistic toxicity between PD-1 and an ICE like AFM24. Again, different disease, but if you recall our Hodgkin lymphoma study, where we combined AFM13 with pembrolizumab, what we did see is some infusion-related reactions very early, as Anthony mentioned, and we have seen across studies which are very well treatable. There's a clear trend that these infusion-related reactions happen early, first, second infusion, and then basically do not reoccur.
In this patient population, due to the high effect, 88% response rate, we also have many patients on long follow-up, up to a year and beyond. We did not observe any of these synergistic immune-mediated side effects. The side effect profile in this cohort of patients, where we have significantly longer follow-up, was very benign. We expect the same, to see the same with AFM24 and PD-1 here.
Gotcha. Thank you.
Again, ladies and gentlemen, if you have a question or a comment at this time, please press star 11 on your telephone. I'm not showing any further questions at this time, and this also does conclude today's presentation. You may now disconnect and have a wonderful day.