Ladies and gentlemen, thank you for standing by. Welcome to Pyxis Oncology MICVO monotherapy phase I clinical update. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question- and- answer session. To ask a question during the session, you would need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would like now to turn the conference over to Tom Civik, Chief Executive Officer. Please go ahead.
Good morning, and thanks for joining us today for our clinical update on MICVO. My name is Tom Civik, and I am the CEO here at Pyxis Oncology. I am so pleased to be here representing the extraordinary team at Pyxis Oncology. Before we begin, I want to share my deep thanks for the patients who put their trust in us, investigators who helped shape this program, and a long list of partners who have supported and encouraged us through this important journey to unlock the potential of MICVO. As you saw in the press release that went out this morning, we are thrilled to share with you the updated data from our phase I study evaluating MICVO in second line and beyond head and neck squamous cell carcinoma.
Please note that today's presentation includes forward-looking statements, and we encourage you to review the related disclosures, which are available on our website. Joining me today on the call from Pyxis Oncology are Marsha, who heads up our Translational Medicine and Research group, Tom, who heads up our Strategy and Finance, Brian, our Chief Program Officer, and Hongwei, who heads up our Clinical Development team. I am also very pleased to have Dr. Alan Ho from Memorial Sloan Kettering Cancer Center joining us today. Dr. Ho is Chief of the Head and Neck Oncology Service and an Attending Medical Oncologist specializing in the treatment of head and neck cancers. He is also a translational clinical researcher focused on developing innovative and personalized therapies for patients with head and neck malignancies.
Today, Dr. Ho will present the clinical data from our phase I study of MICVO in second line and beyond in head and neck squamous cell carcinoma. He will also join us at the end to answer your questions. Okay, let's get started. I am extraordinarily excited to report that based on the data you will see today, we believe MICVO is uniquely positioned to become a meaningful treatment option for patients with cancer. Let me walk you through the agenda for today. First, the program. MICVO is a first-in-concept ADC with a novel ADC target in the tumor extracellular matrix. Second, the need, and it is significant.
There is a large number of patients in the second line and beyond. With the expected changes in the first line, there will be inadequate options for these patients. Finally, a considerable market opportunity with a total addressable market of over $4 billion in the U.S. Third, the study. Our team built and executed an innovative global study that allowed us to evaluate MICVO either after the current standard of care or after what seems likely to become the future standard of care. The study also evaluated key patient subgroups, including HPV status. Next, the results you will see presented from Dr. Ho show that MICVO as a monotherapy with a 5.4 mg per kg dose cap demonstrates substantial efficacy improvement with a safety profile that is consistent with other approved auristatin ADCs.
Finally, we will review our path forward toward potential phase III initiation in mid-2027. I am also very pleased to report now that we have accomplished our first goal of clearly showing that we have an active therapy and a manageable safety profile in a hard-to-treat cancer. We are actively thinking about where else MICVO could deliver benefit for patients beyond head and neck. With that, let me turn over the presentation to Marsha to walk through the scientific rationale behind MICVO.
Hello, my name is Marsha Crochiere. I am Head of Translational Medicine and Research at Pyxis. I am happy to describe our first in concept antibody-drug conjugate, Micvotabart pelidotin or MICVO, to present its novel extracellular matrix targeting mechanism of action and review why head and neck was an ideal cancer for MICVO to pursue first. MICVO is the first ADC targeting a protein in the tumor extracellular matrix rather than on a cell surface like conventional ADCs. MICVO's target is extra domain B of fibronectin or EDB-FN, a non-cell associated splice variant of fibronectin localized predominantly in the tumor ECM with little to no expression in normal tissues and has been shown to be associated with tumor growth, angiogenesis, and metastasis. MICVO is an intentionally designed ADC construct that offers several key potential advantages over conventional ADCs that bind to cell surface target antigens.
The rendering of the construct is on the left. It is a fully human IgG1 monoclonal antibody that has been purposely designed with four key potential advantages. The first is that it is purpose-built. It uniquely targets EDB-FN in the tumor ECM and is engineered for structural integrity with high avidity-driven binding and has site-specific extracellular protease cleavable valine-citrulline linkers. The second is that the ADC is predictable. It has a uniform drug-to-antibody ratio of four, which provides an improved therapeutic window via conjugation with the engineered cysteine, improve the ADC's stability, and result in reduced free payload detected in serum with a Cmax of approximately four days after administration. The ADC is potent. It has four optimized cytotoxic auristatin E microtubule polymerization inhibiting payloads, which have the potential to maximize tumor killing and biological potency in multiple solid tumor types. Finally, the ADC is designed for permeability.
The auristatin E payload has been optimized for membrane diffusion to enable efficient bystander killing as it is released from dying cells, as well as for fast clearance to reduce off-target effects, resulting in better tolerability compared to other auristatins. Collectively, these optimized features for this novel target, along with the three-pronged MOA, which I will tell you about next, differentiate MICVO from conventional cell-surface targeting ADCs. By utilizing the non-cellular targeting mechanism, MICVO offers a novel pioneering approach to deliver anti-cancer activity through a three-pronged MOA. In the first prong, MICVO binds to EDBFN in the tumor ECM, where extracellular proteases active at the low pH cleave the linker to release the payload, which diffuses into nearby proliferating cancer cells and kills them directly.
In the second prong, dying cancer cells release the free payload, which diffuses into nearby cancer cells to promote additional cancer cell killing via the bystander effect, thus initiating a cascade of cancer cell killing throughout the tumor. Finally, in the third prong, MICVO induces an immunostimulatory effect where dying cancer cells also release neoantigens, which stimulate immune cell infiltration and elicit immunogenic cell death. Together with its purpose-built design and these three mechanisms, MICVO is differentiated to have the potential to maximize tumor killing and biological potency compared to conventional cell surface targeting and internalizing ADCs. Head and neck squamous cell carcinoma, or HNSCC, is a difficult to treat cancer. Pyxis has identified it as a tumor type that is sensitive to MICVO based on several lines of evidence.
Non-clinical and preclinical analyses have shown that the tumor microenvironment has features such as robust EDBFN target expression, immune inflammation, and mature stroma with straight angular ECM fibers that are conducive for responding to MICVO. Data from preclinical studies show broad anti-tumor activity across multiple HNSCC patient-derived xenograft models with gene expression signatures indicative of proteins involved in linker cleavage and ECM remodeling. Data from an immune refractory HNSCC syngeneic mouse model showed MICVO promoted a more favorable immune microenvironment important for anti-cancer activity and a synergistic effect with anti-PD-1 therapies. Lastly, clinical signals observed in both the MICVO monotherapy dose escalation and combination with pembrolizumab studies showed HNSCC to be responsive to MICVO regardless of HPV status or prior therapies.
These features are not unique to HNSCC and have also been observed in multiple types of solid tumors, suggesting the broad potential for MICVO to benefit patients with other cancer types. Before I turn it over to Tom to discuss the head and neck unmet need, I want to say how proud I am to be working on this truly novel program with broad potential to help a significant number of patients with cancer. Tom?
Thanks, Marsha. I am Tom Dorney, and I head up strategy at Pyxis Oncology. I look forward to reviewing how the potential of MICVO in HNSCC that Marsha just shared translates into an important opportunity to address an unmet need for a significant number of patients. Head and neck cancer is the seventh most common oncology tumor type. Despite this large patient population, there are relatively few therapies available in the recurrent metastatic setting. Most patients receive either an immune checkpoint inhibitor, chemo, or an EGFR inhibitor. On the left side of this slide, you see head and neck cancer epidemiology estimates for 2030 in the U.S. broken out by line of therapy. 30,000 patients in the first line, 21,000 patients in the second line, and 8,000 patients progressing to the third line.
While EGFR inhibitors are predominantly used in the second line today, we think it is likely that next-gen EGFR inhibitors will graduate this mechanism from the second line up to the first line in combination with immune checkpoint inhibitors. This is a promising time for patients, with new first-line options potentially becoming available soon. However, this will create significant unmet need in the second line. Although cetuximab is an EGFR inhibitor and the current treatment of choice in second line for many patients, we expect this will change when the EGFR immune checkpoint inhibitor combinations move into the front line. Investigators and physicians report that sequential retreatment with an EGFR inhibitor in the first line and then second line is very unlikely. Let me amplify that.
There is no scientific rationale and no clinical evidence that we are aware of to support EGFR inhibitor treatment in the first line and then again in the second line in head and neck squamous cell carcinoma. A non-EGFR targeting mechanism is essential to address this unmet need in the second line and beyond. With 21,000 patients in the second line alone, there will be a significant population with very few and very poor options. On the right side of this slide, we estimate this opportunity for a non-EGFR targeting mechanism in the second line and beyond as greater than $4 billion in the U.S. alone by 2030, and that is not accounting for the global opportunity in this setting. With our plans to develop MICVO globally, we see a significant opportunity for MICVO here.
As I mentioned, there are relatively few therapies available for these patients, and in a presumed future standard of care, the majority of patients would only have decades-old chemo available for their treatment. As you will see, those therapies provide only a modest benefit for patients. On the next slide, I will put that current standard of care in better context. Here are the limited options in second-line head and neck that I was referring to that provide modest benefits for patients. We are showing control arm data for KEYNOTE-040 and CheckMate 141 trials, which were large phase III studies in the second-line setting. We are showing these two control arm datasets because these are the options that would be available for patients in the second line if the standard of care changes in the first line. The control arms for these studies include cetuximab, docetaxel, and methotrexate.
Unfortunately, with an overall response rate in the mid to high single digits, only a couple of months of median progression-free survival, and roughly half a year of median overall survival, there is a massive opportunity to improve the care for these patients. This opportunity to improve the standard of care for a significant number of patients in the second line and beyond, plus the data supporting MICVO's potential in head and neck squamous cell carcinoma, directed our clinical development strategy. For more on that, I will pass it over to Brian Freeman.
Thanks, Tom. I am Brian Freeman, and I am the Chief Program Officer at Pyxis Oncology. I am thrilled to share a bit about the robust plan we implemented to unlock the full potential of MICVO and to share the background for the patient population you will see today. Let me start with the escalation study. MICVO first entered the clinic in 2023 in Part one of our trial, which was a dose-escalation basket study evaluating MICVO monotherapy at multiple doses in nine different solid tumor types. in November of 2024, we disclosed the results of this portion of the study, where we identified 3.6 to 5.4 mg per kg as the efficacious dose range and head and neck squamous cell carcinoma as the tumor type with the strongest efficacy signal.
In early 2025, we then initiated the Part 2 dose expansion portion of the study, evaluating MICVO monotherapy in second-line and third-line head and neck squamous cell carcinoma at 5.4 mg per kg. This portion of this innovative global study design has two arms. The first arm included patients who progressed following treatment with platinum and anti-PD-1 therapy, which is the current frontline standard of care. The second arm includes patients who have progressed following treatment with EGFR-targeted therapy and anti-PD-1 therapy, which is emerging as the standard of care for a large subset of frontline patients. In December of 2025, we disclosed early results from this portion of the study, where we showed a very compelling 46% confirmed overall response rate for MICVO regardless of HPV status and also made the decision to implement a dose cap to mitigate toxicities observed in high body weight patients.
Dose capping is a common practice with many other approved ADCs and is a well-understood approach by both physicians and regulators. This allowed us to implement dose capping with both speed and precision. I should also mention it is no coincidence that when we shared the impressive efficacy data along with the plan to transition to a dose cap, that was the exact moment we saw explosive enrollment in our expansion trial. It is safe to say that this combination of compelling efficacy with a well-established dosing approach to address the toxicities in high body weight patients drove investigator and patient enthusiasm for our trial.
That brings us to present day, where we are excited to share more mature results from the dose cap patients in the study and how this dosing strategy unlocked the full potential of MICVO at 5.4 mg per kg with compelling efficacy and a manageable safety profile. Today's data will focus on patients treated at or below the dose cap. In the data we will share today, we will focus on the patient population we plan to move forward with in the pivotal study of MICVO monotherapy in second-line and beyond head and neck cancer. These are patients with confirmed head and neck squamous cell carcinoma arising from the mucosal lining in the upper aerodigestive tract, with primary tumors in the four typically studied disease locations. Patients must have progressed on prior platinum and anti-PD-1 therapy, have had RECIST-measurable disease, and had an ECOG performance status of zero or one.
All data presented today are from our August 18, 2026, data cutoff. 44 such patients have been treated in the study at 5.4 mg per kg, 42 of whom are efficacy evaluable per the common definition shown at the bottom of this slide. Of the 44 patients in total, 35 of them are in the dose cap subgroup and are included in our safety analyses. 33 of these 35 patients are efficacy evaluable. Note that we set the dose cap at 80 kg for males and 70 kg for females. These cutoffs were established based on our clinical experience as well as robust PK analysis. These dose cap subgroup patients are the population you will see in the data moving forward in this presentation. Before I turn it over to Dr. Ho, let me share with you the demographics and disease characteristics for the patients enrolled in the study.
For the 35 patients in the dose cap subgroup, you should notice a few things that will help put the results in context. We enrolled an almost equal number of patients with HPV-positive and HPV-unrelated disease. This will be informative as we look at how these subgroups performed in the study. You will also notice that nearly two-thirds of patients in this study were performance status 1 at the time of enrollment, which is slightly higher than you'd expect and higher than what you see in many other head and neck studies. Also note that this is a very heavily pretreated patient population. With a median of three prior lines of systemic treatment and a median of two lines of prior therapy in the recurrent or metastatic setting. The majority of the patients enrolled in the study were treated with MICVO in the third-line setting.
Finally, take note of the prior treatments these patients had received, which are particularly relevant considering that EGFR inhibitors are likely to move into the front line in the near future. 71% of patients received a prior taxane. All patients had received prior platinum and anti-PD-1 therapy, and 57% of patients had progressed following prior EGFR targeting therapy, including five patients who had progressed on a prior novel EGFR inhibitor, such as cetuximab or Ficlatuzumab. In summary, the data results of this study represent a heavily pretreated patient population with a median of 2 prior lines of treatment in the recurrent or metastatic setting. I'm thrilled now to hand it over to Dr. Ho to share the study results.
Thank you, Brian and the Pyxis Oncology team. I am Dr. Alan Ho, Chief of Head and Neck Oncology at Memorial Sloan Kettering Cancer Center and an investigator on the current trial. It is my pleasure to share with you impressive data for MICVO in patients with second-line or later recurrent metastatic head and neck squamous cell carcinoma. Let me start by summarizing the data you will see. MICVO's activity is impressive for three reasons. A 36% confirmed response rate in a challenging trial population, including achieving those responses on the first scan for 75% of responders and with 83% of responders experiencing greater than a 50% reduction in tumor volume. The disease control rate of 94% is also extremely high and reflects the broad efficacy of MICVO. The middle panel demonstrates that survival is very encouraging as well.
While single-arm trials are sometimes hard to interpret, two data points are quite compelling. A median PFS of 6.2 months, which is impressive relative to other second-line and beyond head and neck data. The overall survival data here is also quite interesting, with a 79% 12-month overall survival probability. To explain, the lower bound of the confidence interval for this 12-month overall survival probability is 58%, supporting this encouraging durability signal of efficacy. If realized, this survival benefit would be extraordinary for this heavily pretreated population. Finally, in the third panel on the right, safety, you will see a profile that is expected and consistent with prolonged auristatin exposure. Many of these adverse events are those that are routinely encountered and managed in our practice.
After reviewing the data, I am quite excited about the next steps for MICVO and look forward to participating in the pivotal trial that the team at Pyxis Oncology has designed. On this slide, let me first orient all of you to the information describing MICVO efficacy. In the table at the top, I want to direct your attention to the overall confirmed response rate of 36% and disease control rate of 94%, as well as the specific patient outcomes that contributed to both those statistics described on the last row of the table. The waterfall plot below the table depicts the individual patient responses observed. The different colors represent patients' HPV status, with blue representing HPV-associated oropharyngeal carcinoma.
Below the waterfall plot, you can see whether each patient received a prior taxane or a prior EGFR inhibitor, the number of prior lines of therapy, and the EDBFN H-score. On the right of the slide is data that summarizes the consistent efficacy with MICVO observed across different clinically relevant patient subgroups. First, you can see MICVO had similar efficacy regardless of HPV status. There was also impressive efficacy regardless of prior EGFR inhibitor therapy exposure. The slightly lower response rate in the prior EGFR inhibitor therapy group is likely related to those patients being more heavily pretreated with a median of three prior lines of therapy, compared to just two prior lines in the EGFR inhibitor-naive group. Importantly, the patient population also included five patients who received a prior novel EGFR inhibitor.
And while the N is small, it is encouraging to see that all of those patients experienced tumor regression on MICVO with a confirmed response rate of 40%. Finally, response rates are very similar for patients who received a prior taxane versus those that did not. The spider plot shown here reveals that responses with MICVO developed rapidly, with 75% of the responders having response detected at the first six-week scan. Responses were also deep, with 83% of the responders achieving greater than a 50% tumor reduction. So this therapeutic profile of rapid and deep responses is particularly critical for these patients since aggressive treatment refractory cancers in the head and neck region can often cause debilitating pain and functional impairment of swallowing, breathing, and speech that first urgently requires drugs to quickly produce tumor regressions.
This often is necessary in such scenarios for treatments to impart clinical meaningful and durable benefit for patients. This slide here depicts the impressive progression-free and overall survival outcomes observed to date with MICVO. With 22 events at the time of analysis, MICVO demonstrated a 6.2-month median progression-free survival and a 54.9% probability of six-month PFS. Median overall survival has not been reached at this time with only six events, but as you can see, the KM curves look quite encouraging, which is statistically being projected to be a probability of overall survival at one year of 79%, a truly remarkable survival outcome for patients with head and neck cancer being treated in the second line and beyond.
To further emphasize this point, the lower bound of the 95% confidence interval for 12-month overall survival is well above 50%, which provides optimism for where mature overall survival could read out for this study. Here is the breakdown for median PFS in various patient subgroups of interest. As you can see, median PFS is promisingly high regardless of patients' HPV status, prior treatment with an EGFR inhibitor including novel EGFR inhibitors, or prior treatment with a taxane. For HPV positive and HPV-unrelated patients, the median progression-free survival is 6.2 and 5.9 months respectively. For patients who progressed on prior EGFR-targeted agent, in addition to a platinum and an anti-PD-1 therapy, a median PFS of five months was observed.
Again, the N is small, but it is promising to see that the five patients who were previously treated with a novel EGFR inhibitor, either ficlatuzumab or cetuximab, had a median PFS of 5.8 months. Patients who previously received a taxane still achieved a 6.2-month median PFS, demonstrating that patients who have had prior exposure to microtubule-inhibiting chemotherapies can still be susceptible to the anti-tumor efficacy of MICVO, which has a microtubule-inhibiting auristatin payload. Overall, it is exciting to observe consistency between the response and PFS data among these key clinical subgroups. The safety profile of MICVO is consistent with that of other auristatin ADCs and is generally manageable. At the time of this data cut, patients had a median treatment duration of 120 days. 14.3% of patients had to discontinue MICVO for treatment-related AEs, and 40% of patients required a dose reduction.
Importantly, median time to discontinuation was almost 5.5 months, which is a meaningful amount of time on treatment prior to discontinuation and well after early responses were already frequently observed. There were no Grade 5 treatment-related events reported. There are four categories of known auristatin payload-related AEs of interest described here. Cutaneous reactions of Grade 1 or 2 were reported for 48.6% of patients, Grade 3 for 5.7% of patients. Peripheral neuropathy, Grade 1 or 2, was reported for 40% of patients, Grade 3 for 17.1% of patients. The median time to onset was 82 days for Grade 1 or 2 peripheral neuropathy, while the median time to onset for Grade 3 neuropathy was 166 days. Again, reflecting that patients were able to be maintained on therapy for a meaningful amount of time before the development of these events.
28.6% of patients experienced Grade 1 or 2 ocular AEs, while 5.7% experienced Grade 3 ocular AEs. 11.4% of patients had Grade 1 or 2 pneumonitis, and no patients experienced Grade 3 or higher pneumonitis. All in all, the safety profile combined with the efficacy data I just reviewed is quite exciting. Here's more in-depth analysis that puts the peripheral neuropathy event into better clinical context. The important thing here is that MICVO-related peripheral neuropathy has late onset, is often reversible, and appears to be accompanied by a meaningful patient benefit. First, the median time to onset of Grade 3 peripheral neuropathy was 5.5 months. For five of the six patients who experienced Grade 3 toxicity, the peripheral neuropathy has resolved or was resolving, and one patient's Grade 3 event is ongoing at the time of this analysis.
The patients who experienced Grade 3 neuropathy also achieved very good efficacy outcomes, with 67% of these patients experiencing confirmed response and their median progression-free survival being 8.8 months. In my view, this later, largely reversible risk profile for peripheral neuropathy is clinically manageable given that patients can still experience rapid deep benefit before its onset. More than anything, highlights the need to manage this toxicity early so that patients can have the opportunity to experience dramatic clinical benefit for as long as possible. Finally, to put these results in context with the caveats we must always remember when making cross-trial comparisons, MICVO's response rate, progression-free survival, and overall survival appear favorable compared to those of single-agent chemotherapies or cetuximab observed in the KEYNOTE-040 and CheckMate 141 studies. As a result, the next logical step is to study MICVO versus these therapies in a randomized trial.
I will now hand it back to Brian to discuss this in more detail.
Thanks again, Dr. Ho. With those compelling clinical trial results as context, let's review our plans for the next stage of MICVO's clinical development. To start, we are making strong progress towards completing dose selection, consistent with FDA's Project Optimus initiative. In addition to 35 patients dosed at 5.4 mg per kg with a dose cap, we have enrolled more than 20 patients at 3.6 mg per kg. At present, the emerging data support 5.4 mg per kg with a dose cap as our go-forward dose for the MICVO phase III monotherapy study. Following alignment with the FDA on dose selection, we plan to move as quickly as possible to initiate the phase III trial. Results we have shared today reinforce our confidence in MICVO's profile for this large patient population with significant high unmet need and in our phase III study.
I'm happy to report that we have aligned with regulatory authority advice on the design of the phase III study, called Headliner. We plan to evaluate MICVO versus current standard of care treatments in second-line and beyond head and neck squamous cell carcinoma. We designed Headliner in partnership with investigators around the world. It will be a global phase III trial in the second and third line setting. The study will enroll approximately 500 patients who have progressed following both a platinum-based therapy and an anti-PD-1 therapy, and randomize them one-to-one to MICVO monotherapy or investigator's choice of single agent cetuximab, docetaxel, or methotrexate. The co-primary endpoints of the study will be overall response rate and overall survival. The study design has been aligned with both FDA and EMA advice and is planned to begin in mid 2027. Now, I'll send it back to Tom for some closing remarks.
All right. Thanks, Brian. With these data now disclosed, I'm excited to share our plans to further advance MICVO in clinical development. What I hope you took away from today's discussion on the MICVO monotherapy data is this novel mechanism of action fills an important treatment gap as the first-line landscape evolves and EGFR inhibitors move to the front line. The rapid and deep responses are translating into clinically meaningful results and impressive survival benefit. The safety profile is well understood and manageable. Finally, we have a clear path forward toward a pivotal trial. For MICVO monotherapy, we have three important milestones highlighted on the bottom of the slide. Project Optimus feedback in Q1, updated overall survival in the first half of 2027, and the first patient enrolled in the Headliner trial in mid 2027.
While we didn't talk about our combination study today, the program also continues to advance. We expect to provide an update on our progress in the fourth quarter, followed by an update on initial durability and our recommended phase III dose in the second half of next year. Let me finish with where I started, with my deep gratitude for my colleagues at Pyxis Oncology, our partners, and most importantly, the patients and investigators who have made this possible. I also want to thank Marsha, Tom, Brian, and Dr. Ho for representing the tremendous work of so many people who have brought us to this point. Based on the data we shared today, we are incredibly excited about the potential for MICVO and our path forward to a pivotal trial in the second-line head and neck cancers.
These results give us confidence to advance our thinking about the potential of MICVO beyond head and neck cancers. Thank you again for joining us today, and we will now open the call for your questions and comments.
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. We ask that you please limit to one question and one follow-up. Our first question will come from Jeffrey La Rosa with Leerink Partners. Your line is open.
Hi. Thank you for taking my questions, and congrats on the progress. I have two questions. I think I'll just start with one, then wait for a follow-up. First on the safety, I think for both the company and Dr. Ho, if you could talk a little bit more about your strategy and experience managing peripheral neuropathy with those modifications. How quickly are these phase III events resolving, and have you been able to successfully re-treat patients after these modifications?
Yeah. Hi, it's Dr. Ho. Thanks so much for the question. These neuropathy events, consistent with other agents we use and standard practice, I think the key is always early recognition and potentially dose modification or hold in order to delay or prevent other Grade 3 events from happening. In this particular trial, yes, we have successfully re-treated patients, even those with Grade 3 events, because again, five out of the six of those patients, the Grade 3 events did reverse and decrease in grade, allowing continued treatment for patients. So in all those ways, quite manageable, and particularly with early recognition and with the reversible nature of the toxicity.
Jeff, what was the second question?
Yeah, the second question is, what do you think is driving the consistency of MICVO's clinical benefit across patient subgroups, especially HPV status and prior taxane exposure when, I guess, other ADCs with microtubule-hitting payloads like auristatin have really been limited to HPV positive and taxane-naive patients? Do you think this is a function of the payload or target, perhaps?
Yeah, I think this is why you do the experiment, Jeff. We set out to evaluate whether or not MICVO would have broad applicability for multiple tumors. You saw in what I believe is an innovative global study that we did in the expansion arm, it gave us the opportunity to look at patients who either received platinum plus PD-1 as a frontline treatment, or an EGFR inhibitor plus PD-1 as a frontline treatment. Those two arms really inform the standard of care today, versus the standard of care tomorrow. I think Marsha did a great job of explaining the scientific rationale behind MICVO and why we've got so much excitement for this program, not only for its application in second line head and neck cancer, but possibly beyond. The data speak for itself.
There's consistent benefit across multiple subgroups, and I think this is why you do the experiment. We're quite pleased with the broad efficacy that we've seen in the trial at this point.
Great. Yeah, thank you.
Okay. Thanks, Jeff.
Thank you. Our next question is going to come from Brad Canino with Guggenheim. Your line is open.
Morning, and congratulations on the strong and consistent data for MICVO. I do have one question, though, on ORR and prior EGFR. It's coming at 28%, 20 points less than the no prior EGFR. Is that a real spread between the effect size, do you think, or are there other factors that could be driving that as you look at the data? Thanks.
Yeah. Hey, Brad. Thanks for the question. Let's do two things here. First, let's talk about how we think the treatment landscape's going to change. Tom highlighted it before. There are three novel EGFR inhibitors in phase III development looking for a first-line indication. We think the odds are pretty high that one of them will make it, if not all. It substantially changes what is available to patients in the second line and beyond. First off, we believe we're in the midst of a really important and could be very valuable time for patients to have better treatments in the earlier lines. What that leads to is really not very good options in the second line. I appreciate you highlighting the subgroup analysis that we did to really allow you to dive in deep on how we've performed against multiple subgroups.
On slide 19 in the deck that you saw, the waterfall, I think it's worth spending a little bit of time looking at the prior lines of treatment. I think what you'll notice there in the 18 patients that received a prior EGFR, which is cetuximab and the two novel EGFR inhibitors, you'll see that two of those patients didn't get MICVO until the fifth line. 13 of those patients did not get MICVO until the third line, and only three got them in the second line. In contrast to those patients that did not receive any EGFR, MICVO was delivered in the second line for eight of those patients, eight of the 15, so the majority of them. At this point, we're very confident in saying that we believe this is a line of treatment issue, not anything to do mechanistically.
It gives us a lot of confidence with the Headliner trial moving forward as a really important patient group to be able to address. So we're quite excited with the results and think that it's more driven by the line of therapy than anything else, Brad.
Thanks. That's helpful context. That actually leads into my second question, which is if the EGFR bispecifics are approved in combo with PD-1, how do you expect the platinum chemo pretreatment requirement in your phase III and likely label indication for that to impact in what line of therapy patients will be eligible for MICVO? Thank you.
Yeah. Brad, thanks. Maybe there's two parts to that question, sort of the clinical trial and then the commercial impact. Let me start with the clinical trial first. Really excited for the lengthy conversations we've had with the agencies across the globe, specifically the FDA and the EMA, to help design this trial. It's safe to say that EGFR inhibitors likely will get approved at different times globally. It's important that we have a design of a trial that can meet the current treatment standards across the globe, and that's how we've designed the Headliner study.
As you saw in the comparator arms that are always dangerous to do cross-trial comparisons, but both Tom and Dr. Ho showed you that the combination of cetuximab, methotrexate, and docetaxel doesn't deliver much for patients in this group, and that is the control arm that we are moving forward with in the Headliner trial. The first step, we have a global design trial that we think answers the question of how MICVO performs in the second line and beyond, and we're quite excited about our ability to deliver for that patient population. As it gets to the commercial aspect of hopefully if MICVO were to get approved and be available in the second line and beyond, I think those treatment decisions become really important for physicians who maybe have had a patient who's experienced platinum in the neoadjuvant or adjuvant setting.
This becomes a really important discussion for physicians and their patients about a novel mechanism of action in the second line. Maybe let me ask Dr. Ho if he'd like to contribute to this question as well about both the clinical trial as well as how it might impact use when approved.
Yeah. I think the salient point is really the unique mechanism of action, apart from how platinum works or how anti-PD-1 works. I think the point made about the use of platinum in the neoadjuvant adjuvant setting is quite relevant. The only other thing I would also point out, too, is with the ongoing phase III evaluations of the novel EGFR bispecifics, for instance, OrigAMI-5, there are still opportunities if that is a positive trial for patients to receive carboplatin or platinum in the first line setting as well. I think it's hard to anticipate exactly how that's going to influence the lines of therapy that patients will receive enrolling into the trial. But there are multiple opportunities to receive platinum, either in neoadjuvant adjuvant setting or even in the first-line recurrent/metastasis setting given the ongoing OrigAMI-5 evaluation.
Great. Thanks, Dr. Ho. Brad, did we get both of them?
That was excellent. Thank you.
Yep. Thank you.
Okay. Our next question will come from Derek Archila with Wells Fargo. Your line's open.
Good morning. This is Hao calling in for Derek, and thank you so much for the question. My question is on the phase III. My question is how the panel, the next-gen EGFR, how much are you expecting their involvement while your phase III is ongoing and impacting to your base trial performance? Just among the physician choice, cetuximab and chemo or maybe some combo use, what do you think about will be the split among all these standard of care treatment and how that's going to impact the placebo response rate?
Hao, thank you for the question. Let me get started and I'll ask Dr. Ho to contribute as well. I think the most important thing to take away from today's discussion is that we fundamentally believe EGFR inhibitors plus a checkpoint inhibitor are likely to move into the front line. This is an opportunity that needs to be well understood that a novel mechanism of action is extremely important here. Every physician we've talked to across the globe has said that retreatment, sequential retreatment with an EGFR inhibitor doesn't make scientific sense and would not be their treatment of choice. The novel mechanism of action for MICVO and these broad and consistent results across the trial that you're seeing today give us a lot of confidence that our data supports moving very quickly into a pivotal trial. Dr. Ho, anything to add to Hao's question?
Nothing except to say I think it is very relevant that we take into consideration all those first-line EGFR bispecific phase IIIs because indeed, I agree, the data looks quite promising and we all expect that those trials have a very good chance of being positive. It'll change the standard of care, and taking those things into consideration for this phase III study is certainly relevant. I think the important point, just to be restated, is the complementary mechanism of action with MICVO, the non-overlapping mechanism of action, both in terms of target and the cytotoxic payload, which I think makes it a really promising second-line and beyond option.
Thanks, Dr. Ho.
Yes. Thank you. Just a quick follow-up. The 12-month OS rate, 79%, it looks very promising. I believe like pembrolizumab combo in first line, that is very similar numbers they demonstrated. I guess my question is in the first half, more OS data update. How confident. How mature is the data right now, and how much we will be able to see on the first half update?
Yeah. Hao, thank you so much for that question. I will say that when we first saw the KM curve for OS for MICVO in this second line and beyond patient population, I can only tell you that we were so pleased. When you develop a novel drug, sometimes you are surprised, and every once in a while you are very pleasantly surprised, and that was the case here.
The 12-month OS probability of 79% is a really encouraging signal, and I think I will just amplify. It is early, but very encouraging. It is even more so encouraging because you can see the bottom end of the confidence interval on the 12-month OS is 58%. So it gives us confidence that what we are seeing could play out quite nicely. As you know, survival is really the most important endpoint for these patients. I am going to amplify what Dr. Ho said earlier.
The rapid and deep responses that we see early are really attractive for this patient population for a lot of different reasons. But the fact that we have rapid and deep responses followed by this really interesting and important survival benefit give us a lot of confidence that moving forward into the Headliner trial with the primary endpoints being response rate and overall survival, that our odds for success are quite high. So Dr. Ho, anything to add about survival benefit that we are seeing from Hao's question?
Clearly very promising. Of course, early, so we definitely want to see that data mature. But I would just reemphasize, I think depending upon what series you look at, one of the unique challenges of these patients is particularly the functionally debilitating aspects of the disease that recur local regionally, and this is a major problem for these patients. So correlating to the overall survival benefit is the need for drugs that will give you deep and rapid responses, which the data here demonstrates MICVO can elicit. So that aspect of it, I think, really gives the drug an advantage, and hopefully translating to overall survival benefit, particularly those patients that have these very devastating local regional recurrences.
Yep. Thanks, Dr. Ho.
Yeah, great. Thank you so much.
Thanks, Hao.
Thank you. The next question will come from Sam Slutsky with LifeSci Capital. Your line's open.
Hey, good morning. Thanks for taking the questions. Two quick ones from me. I guess to add to the 12-month survival question, it looks to me like you're showing a rate that's been seen with kind of key EGFR competitors, but in the frontline setting. Any theory from your end on what's driving such a high rate as you consider things like baseline characteristics, subsequent treatments, or just the status of their cancer following discontinuation? Just quickly, for the control arm in phase III, what would you expect the mix to look like for percent of patients on cetuximab versus docetaxel versus methotrexate? Thanks.
Yeah. Hey, Sam. Thanks for the question. Let me do the second question first. We've done a lot of analysis. Obviously, it's easy to look at trials like KEYNOTE and CheckMate to figure out what the split was there as it relates to cetuximab, docetaxel or methotrexate. In many ways, these are sort of global decisions where the treatment options are a little bit different based upon the U.S. or Europe. We've done our best to project out what we think will happen as the treatment options change. We remain extraordinarily confident that the profile that you've seen today with broad efficacy and a manageable safety profile is positioning us for success moving forward. As it relates to the OS, Dr. Ho, do you want to maybe add to anything else here to Sam's question?
Yeah, I think it's a really intriguing question that we really don't have an answer to. You might speculate about how the next generation EGFR bispecifics may be contributing to those overall survival outcomes. But a couple of things is all of those have different mechanisms of action that's hard to group together. In this particular trial, only five of the patients in this cohort had exposure to the next generation bispecific. So I think you're left with mixed prior treatment histories that really make it hard to kind of correlate back to how prior therapies might have contributed to the survival outcomes we're seeing. You're kind of left with just the broad activity we're seeing across subgroups. Again, as I mentioned, the rapid and deep responses that are contributing. So I think it's an interesting question.
It's something we're going to have to really investigate once adoption of the next generation EGFR bispecifics occur. But for this particular data set, it's hard to associate any of those survival benefit with those next generation agents.
Yeah. That is right, Dr. Ho. I would just maybe add to it that, Sam, I hope what you picked up from Brian's review of the demographics of the patients in the study is they are heavily pretreated. To see this sort of survival benefit in a group that is second line and beyond in head neck cancer gives us a lot of confidence on what this program could do for a lot of patients. Coupled with the fact that if the EGFR inhibitors plus the checkpoint inhibitors move into the front line, there is an enormous need for over 21,000 patients that are looking for a novel mechanism in the second line. The overall survival is really important, but it is really the combination of rapid and deep responses combined with really consistent and impressive survival and a manageable safety profile that is well understood.
Sam, anything else?
No, I think that is it. Thanks.
Yep. Appreciate the question.
Our next question is going to come from Stephen Willey with Stifel. Your line is open.
Yeah, good morning. Thanks for taking the question. Maybe just a couple of clarification questions around the proposed phase III. Can you talk about the stratification factors you're going to be deploying in this trial and just whether or not there's going to be any kind of attempt to maybe proactively limit the representation of patients on the basis of HPV status? Then can you clarify if response rate and survival, are those dual or are they co-primary endpoints?
Steve, as always, I appreciate the question, and unfortunately, we're not disclosing that level of information today. I think our aim with the Headliner trial is twofold. One is we believe the profile that we showed today is worthy of moving as quickly as we possibly can to starting this trial. Then our job once we start it, is to ensure that it moves along as quickly as possible. But as it relates to further stratification, we're not disclosing that at this point. I would imagine at a future conference, medical conference or publication, that that information will become available.
Yep, understood. Then just on the Project Optimus discussion with FDA and the amount of data that you're generating with the 3.6 dose, is there a specific duration of follow-up that you are aiming to achieve before you engage with regulators on the topic of dose selection?
Steve, let me answer the question this way, that we would not have it as a milestone for the first quarter of 2027 if we weren't confident that we had the data to fulfill our commitment for Project Optimus. While I look forward to providing that update then, unfortunately, that's all I can share at this point. We have a lot of confidence at 5.4 mgs, with the dose cap is the dose. We also, as you've seen in our dose escalation study, we are also equally confident that 5.4 all the way down to 3.6 is an active drug. We've got a lot of excitement right now behind 5.4 mg per kg with a dose cap.
All right. Understood. Thanks for taking the questions.
You bet. Thanks, Steve .
Our next question will come from Swayampakula Ramakanth with H.C. Wainwright. Your line is open.
Hey, RK.
Hey, Tom. Thank you very much for this and really interesting data. Two questions from me. The first question, this is on the full 5.4 mg per kg population. You dosed 44 patients at that dose. 42 are efficacy evaluable at this point. Of them, out of that, you showed us today data on the 35 patients who were at or below the cap. Could you talk regarding the efficacy data and safety data on the full population, the 42 and 44-patient population, and also among the nine patients who obviously are above the cap. Is there any evidence of added efficacy as well as toxicity with that additional exposure?
Yeah. Thanks, RK. This has been an area of focus for us since December's data release last year. As many of you will recall, we quickly implemented a dose cap for our patient population based upon the clinical data that we were seeing, combined with some really robust PK analysis. Where we ended up was the dose cap that you saw at 80 kg for males and 70 kg for females. The reason we shared the data with you today, exclusively on the 35 patients that were safety evaluable and 33 that were efficacy evaluable for 5.4 mg per kg with the dose cap, is this is the patient group that we are excited to move forward into a clinical trial with.
The information as it relates to those patients above the dose cap, we expect to share at a medical conference or a publication down the road. I would just say that the data that we have in-house gives us a lot of confidence that the selection of a dose cap at 5.4 milligrams is the right move forward. We have not given up efficacy, but we have maintained. I'm sorry, we have not given up any efficacy, but we have significantly improved the safety profile for those patients of high body weight. More data coming down the road, RK.
Okay. As a follow-up, just as you said, your cap is sex specific in the sense 432 mg for males and 378 for females. When we look at the other ADCs, whether it's PADCEV, TIVDAK, or datopotamab deruxtecan, they all had a single 90-100 kg cap. Have they commented on sex-specific cap, and does that cap get used in the pivotal, or you're still thinking of adjusted ideal body weight, or both?
Yeah. I think, RK, we are fully committed to 5.4 mg with the dose cap that you've seen here. The PK analysis combined with our clinical data is extraordinarily clear. We have a lot of confidence that the cutoff is right and it's the right dose for us to move forward, both from an efficacy and a safety standpoint for patients. So, that is our plan. 5.4 mg with the dose cap.
Thank you. Thanks for taking all my questions.
Yeah. Thanks, RK.
Thank you. Our next question is going to come from Leonid Timashev with RBC. Your line is open.
Hey, guys. Thanks for taking my question. Maybe two quick ones here. I guess I just wanted to return first to how physicians actually treat this. Obviously, MICVO is working broadly, but I guess to what extent do physicians prefer to segment either by HPV status or anatomical location? Is that ultimately going to drive the degree to which the market's accessible for you guys? Secondly, I know at the start of the presentation you hinted at MICVO working broadly. I guess, is there any hints you'd give us to date on what other indications you may want to pursue the drug in? Thanks.
Yep. Dr. Ho, do you want to answer the first question for Leo?
Yeah. We do take into consideration HPV status for subsites if the data leads us there. I think the classic issue with cetuximab and the differential efficacy in HPV positive and negative populations is sort of an example of that and how a lot of the development of the novel EGFR bispecifics has been guided. Here, if we can demonstrate good efficacy across different subgroups, and looking at the data that we just presented today, we wouldn't really take into consideration HPV status in thinking about the selection of patients for this drug, given the broad efficacy across all those cohorts. It's really just led by the data more than anything else.
Yeah. Leo, I'll take your second question, and do so with a smile on my face around are we considering pursuing MICVO outside of second-line head and neck cancer. As I said in my prepared remarks, we look forward to updating you on the combination trial with MICVO plus pembrolizumab later this year in the fourth quarter and more mature data at the second half of 2027. As you might expect, as a small biotech, we had to be focused, and we were focused on where the signal was strongest, which was head and neck cancer. You may also recall in our dose escalation basket study, we had quite a few tumors that showed activity while we were still dose escalating.
Now that we've shared this really compelling data on how we can fill a huge unmet need in the second line if the EGFR is moving to the front line, I think it gives us the opportunity to really think about where else we can and should take MICVO. I think Marsha did a great job of outlining the attributes of head and neck cancer, but also letting you know that there's lots of other cancers that look a lot like head and neck cancer. We're excited about the next steps, but our focus has got to be getting the Headliner trial up and running so that we can get this drug to patients as quickly as possible. Leo?
We-
Yep. Leo, anything else?
All good for me. Thank you.
Okay. Thank you.
Thank you. That is all the time that we have for questions today. I will now turn the call back over to Tom Civik for closing remarks.
All right, [Inaudible]. Thank you. Thanks for all the questions, and I really appreciate you all joining us today. We are looking forward to continuing to advance this important potential therapy, and we will continue to update you on our progress. Thank you for joining us today, and I hope you have a great day.
This concludes today's conference call. Thank you for participating, and you may now disconnect.