Pyxis Oncology, Inc. (PYXS) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by. Welcome to Pyxis Oncology MICVO Monotherapy Phase I Clinical Update. [Operator Instructions] 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. And 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'm 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. And with the expected changes in the first-line, there will be inadequate options for these patients and finally, a considerable market opportunity with a total addressable market of over $4 billion in the United States. 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 we -- what seems likely to become the future standard of care. The study also evaluated key patient subgroups, including HPV status. Next, the results you'll 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. And finally, we will review our path forward toward potential Phase III initiation in mid-2027. I'm also very pleased to report now that we've 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 can 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'm Head of Translational Medicine and Research at Pyxis. I'm 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 EBD+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 4 key potential advantages. The first is that it is purpose-built. It uniquely targets EBD+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 4, which provides an improved therapeutic window via conjugation with the engineered cysteine, improve the ADC stability and result in reduced free payload detected in serum with a C-max of approximately 4 days after administration. The ADC is potent. It has 4 optimized cytotoxic auristatin 0101 microtubule polymerization inhibiting payloads, which have the potential to maximize tumor killing and biological potency in multiple solid tumor types. And finally, the ADC is designed for permeability. The auristatin 0101 payload has been optimized for membrane diffusion to enable efficient bystander killing as it's 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 a 3-pronged MOA, which I will tell you about next, differentiate MICVO from conventional cell surface targeting ADCs. By utilizing the noncellular targeting mechanism, MICVO offers a novel pioneering approach to deliver anticancer activity through a 3-pronged MOA. In the first prong, MICVO binds to EBD+FN 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 3 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. Nonclinical and preclinical analyses have shown that the tumor microenvironment has features such as robust EBD+FN 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 antitumor 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 anticancer activity and a synergistic effect with anti-PD-1 therapies. And lastly, clinical signals observed in both the MICVO monotherapy dose escalation in 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'm Tom Dorney, and I head up Strategy at Pyxis Oncology. I look forward to reviewing how the potential of MICVO and 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, but 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's 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 frontline. 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're 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. So a non-EGFR targeting mechanism is essential to address this unmet need in the second-line and beyond. And 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 the 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's 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 as presumed future standard of care, the majority of patients would only have decades-old chemo available for their treatment. And as you'll see, those therapies provide only a modest benefit for patients. On the next slide, I'll 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're showing control arm data for KEYNOTE-040 and CheckMate-141 trials, which were large Phase III studies in the second-line setting. We're showing these 2 control arm data sets 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'll pass it over to Brian Freeman.

Thanks, Tom. I'm 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 1 of our trial, which was a dose escalation basket study evaluating MICVO monotherapy at multiple doses in 9 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 2 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 progressed following treatment with EGFR-targeted therapy and the 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's 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 unlocks 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 4 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 0 or 1. 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 analysis. 33 of these 35 patients are efficacy evaluable. Note that we set the dose cap at 80 kilograms for males and 70 kilograms 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'll also notice that nearly 2/3 of patients in the 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 3 prior lines of systemic treatment and a median of 2 lines of prior therapy in the recurrent or metastatic setting. So 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 have received, which are particularly relevant considering that EGFR inhibitors are likely to move into the frontline 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 5 patients who had progressed on a prior novel EGFR inhibitor, such as petosemtamab or ficerafusp alfa. So 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 3 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, 2 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. And finally, in the third panel on the right, safety, you will see a profile that is expected and consistent with prolonged or statin exposure. Many of these adverse events are those that are routinely encountered and managed in our practice. And so 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 picks the individual patient responses observed. The different colors represent patient's HPV status with blue representing HPV-associated oropharyngeal carcinoma. And then 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 EBD+FN 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 3 prior lines of therapy compared to just 2 prior lines in the EGFR inhibitor naive group. Now importantly, the patient population also included 5 patients who received a prior novel EGFR inhibitor. And while the end is small, it is encouraging to see that all of those patients experienced tumor regression on MICVO with a confirmed response rate of 40%. And finally, response rates are very similar for patients who received a prior Taxane versus those that did not. Now the spider plot shown here reveals that responses with MICVO developed rapidly with 75% of the responders having response detected at the first 6-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 [indiscernible], 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 6-month PFS. Median overall survival has not been reached at this time with only 6 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 1 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 patient's 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 5 months was observed. Again, the end is small, but it is promising to see that the 5 patients who were previously treated with a novel EGFR inhibitor, either petosemtamab or ficerafusp alfa had a median PFS of 5.8 months. And patients who previously received a Taxane still achieved a 6.2-month median PFS, demonstrating that patients who've had prior exposure to microtubule inhibiting chemotherapies can still be susceptible to the antitumor efficacy of MICVO, which has a microtubule inhibiting auristatin payload. Overall, it's exciting to observe consistency between the response and PFS data among these key clinical [indiscernible]. Now 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 4 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 events 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. So first, the median time to onset of Grade 3 peripheral neuropathy was 5.5 months. For 5 of the 6 patients who experienced Grade 3 toxicity, the peripheral neuropathy has resolved or was resolving and 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. So 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 and 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 1:1 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 frontline. The rapid and deep responses are translating into clinically meaningful results and impressive survival benefit. The safety profile is well understood and manageable. And finally, we have a clear path forward toward a pivotal trial. For MICVO monotherapy, we have 3 important milestones highlighted on the bottom of the slide. Project Optimus feedback in Q1, updated overall survival in the first half of '27 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. And these results give us confidence to advance our thinking about the potential of MICVO beyond head and neck cancer. Thank you again for joining us today, and we will now open the call for your questions and comments.

[Operator Instructions] And our first question will come from Jeffrey LaRosa with Leerink Partners.

Congrats on the progress. I have 2 questions. I think I'll just start with one and wait for a follow-up. I think 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 retreat patients after these modifications?

Yes. It's Dr. Ho. Thanks so much for the question. These neuropathy events consistent with other agents we use in 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 retreated patients in those with Grade 3 events because, again, 5 out of the 6 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?

Yes. 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 and payloads like NAE have really been limited to HPV-positive in Taxane-naive patients. Do you think this is a function of the payload or target perhaps?

Yes. I mean I think this is why you do the experiment, Jeff, and we set out to evaluate whether or not MICVO would have broad applicability for multiple tumors. And you saw 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. And those 2 arms really inform the standard of care today versus the standard of care tomorrow. And 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 and we're quite pleased with the broad efficacy that we've seen in the trial at this point.

And our next question is going to come from Brad Canino with Guggenheim.

Congratulations on the strong and consistent data for MICVO. I do have one question though on ORR and prior EGFR. It's coming at 20%, 20 points less than 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?

Brad, thanks for the question. Let's do 2 things here. First, let's talk about how we think the treatment landscape is going to change. And Tom highlighted it before, there are 3 novel EGFR inhibitors in Phase III development for first-line -- looking for a first-line indication. And we think the odds are pretty high that one of them will make it, if not all, and it substantially changes what is available to patients in the second-line and beyond. So 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. But what that leads to is really not very good options in the second-line. And I think I appreciate you highlighting the subgroup analysis that we did to really allow you to dive in deep on how we 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. And I think what you'll notice there in the 18 patients that received a prior EGFR, which is Cetuximab, the 2 novel EGFR inhibitors. You'll see that 2 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 3 got them in the second-line. And in contrast to those patients that did not receive an EGFR, MICVO was delivered in the second-line for 8 of those patients, 8 of the 15 to the majority of them. So at this point, we're very confident in saying that we believe this is a line of treatment issue, not anything to do mechanistically, and 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.

That's helpful context. And 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 patients -- or sorry, in what line of therapy patients will be eligible for MICVO?

Yes, Brad, thanks. And maybe there's 2 parts to that question, sort of the clinical trial and then the commercial impact. So let me start with the clinical trial. First, really I'm 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. And it's safe to say that EGFR inhibitors likely will get approved at different times globally. So 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 within the Headliner trial. So 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. And 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.

Yes. 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 to 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. So 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 metastatic setting, given the ongoing OrigAMI-5 evaluation.

Thanks, Dr. Ho. Brad, did we get both of them?

And our next question will come from Derek Archila with Wells Fargo.

This is Hang calling in for Derek. So I guess my first one is on the Phase III. My question is like how the panel, the next-gen EGFR, how much are you expecting their involvement while your Phase III is ongoing and the impact to your base trial performance? And just among the checkpoint 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?

Yes. Hang, 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 frontline. And 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. So 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 Hang'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 will change the standard of care. And taking those things into consideration for this Phase III study is certainly relevant. But 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.

And just a quick follow-up. So the 12-month OS rate, 79%, it looks very promising. I believe like peto/pembro combo in first-line, that's very similar number that they demonstrated. So 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?

Yes. Hang, thank you so much for that question. I will say that when we first saw the KM curve for OS for MICVO in the second-line and beyond patient population. I can only tell you that we were so, so pleased. When you develop a novel drug, sometimes you're surprised and every once in a while, you're 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'll just amplify, it's early but very encouraging. And it's 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're seeing could play out quite nicely. And as you know, survival is really the most important endpoint for these patients. We are -- I'm 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're seeing from Hang's question?