Oncolytics Biotech Inc. (ONC) Earnings Call Transcript & Summary

Good morning, and welcome to The Oncolytics Biotech Key Opinion Leader Webinar. [Operator Instructions]. As a reminder, this call is being recorded and a replay will be made available on the Oncolytics website following the conclusion of the event. In addition, I'll remind all listening that today's webcast will contain forward-looking statements and note the disclaimer shown on this slide. I will now hand the call over to Oncolytics President and CEO, Dr. Matt Coffey, to begin the formal presentations. Please go ahead, Matt.

Thank you, and thanks to those who have joined our Key Opinion Leader webinar. Our topic today will be the exciting data from our HR+/HER2- breast cancer program randomized BRACELET-1 trial. These data showed pelareorep driving a robust improvement in progression-free survival with a hazard ratio of 0.29 and a nearly threefold increase in confirmed overall response rate when combined with paclitaxel. With BRACELET-1's results, we have substantiated our prior Phase II data showing a statistically significant near doubling of median overall survival when pelareorep was added to paclitaxel and brought our HR+/HER2- breast cancer program to Phase III readiness. We are now working to expeditiously advance to a 2-arm registration trial of pelareorep-paclitaxel combination therapy in HR+/HER2- breast cancer and are aided by these efforts by an FDA Fast Track designation and a special protocol agreement that indicates our phase -- our prior Phase II trial counts as one of the 2 pivotal studies needed to support approval. We expect to provide an additional update on pelareorep's registrational path in breast cancer in the second half of the year. As you can see on this slide, our HR+/HER2- breast cancer program represents one of our pipeline's 2 compelling registration opportunities with the second being our program evaluating pelareorep combined with nab-paclitaxel, gemcitabine and atezolizumab in first-line advanced pancreatic cancer. The breast cancer will be the focus of today's event, I'll remind those listening that our pancreatic cancer program is also advancing expeditiously towards a licensure-enabling study supported by an FDA Fast Track designation and Phase I/II data showing an objective response rate that is nearly triple the average objective response rate reported in relevant historical control trials. Like in breast cancer, we expect to have an update on pelareorep's registration path in pancreatic cancer by end of the year. Turning to the agenda for the remainder of today's event, I'll soon pass the call on to Oncolytics Chief Medical Officer, Dr. Tom Heineman. During his presentation, Tom will provide some background on pelareorep and HR+/HER2- breast cancer program before detailing BRACELET-1's data. These will include data showcased in an oral presentation at ASCO Annual Meeting this past weekend as well as additional data and analysis from the trial announced in our press release issued earlier today. After Tom concludes his presentation, we will be joined by 3 highly esteemed key opinion leaders for a roundtable discussion on BRACELET-1's results and our breast cancer program more broadly. These key opinion leaders include Professor Richard Vile, Director of the Mayo Clinic immuno-oncology program and Co-Director of the Gene and Virus Therapy Program; Professor Aleix Prat, Director of the Oncology Institute at Hospital Clinic of Barcelona and former President of the Spanish Breast Cancer Cooperative Research Group's Governing Board; and Professor Martine Piccart, who is formerly the President of ESMO and is currently an Honorary Professor of Oncology at the ULB and Scientific Director at the Jules Bordet Institute in Belgium. Each of these KOLs brings unique expert perspective on the current and emerging treatment landscape in breast cancer, and we are very grateful for their time today. With that, I'll pass the call off to Tom.

Thanks, Matt. Before moving on to discuss our breast cancer program and the BRACELET-1 data, let me first provide some background information on our first-in-class immunotherapeutic agent pelareorep or pela, as I'll sometimes refer to it. As you can see on this slide, pela is a nonpathogenic oncolytic virus that has demonstrated a favorable safety profile and tolerability profile in numerous clinical studies that have collectively treated more than 1,100 patients to date. Pela selectively replicates in tumor cells and is delivered intravenously, allowing it to directly access both primary and metastatic disease. This is a key advantage over many other oncolytic viruses that are administered intratumorally. Another key advantage of pela over other oncolytic viruses is the fact that it has a biosafety level 2 classification, which allows it to be administered via standard practices in an outpatient setting without any special handling procedures. As you can see on the right side of the slide, pela treatment leads to a robust increase in T-cell infiltration into tumors, which is a result of its multifaceted immune-mediated mechanism of action. An overview of this mechanism of action is shown on this slide, which highlights how pela addresses the myriad of biological mechanisms that prevent the immune system from recognizing and infiltrating tumors. We believe pela's ability to do this positions it as a platform therapy with the potential to synergize with a wide array of anticancer drug classes across many indications. Pela's mechanism of action has been demonstrated in multiple clinical studies that have shown pela-based combinations leading to the generation, expansion and activation of cancer-fighting immune cells. In addition, prior clinical studies have shown pela-based combinations remodeling tumor microenvironments in ways that enable immune cell access and are associated with improved patient prognosis. Collectively, these data provide mechanistic support for the promising efficacy results reported in our breast cancer and pancreatic cancer programs, which Matt referred to at the top of the call. With that brief overview of pela complete, I'd now like to turn your attention back to our HR+/HER2- breast cancer program. As Matt mentioned, BRACELET-1 results presented at ASCO substantiated data from a prior randomized Phase II trial, IND 213. The IND 213 trial randomized 74 patients with metastatic breast cancer across 2 cohorts; one, evaluating paclitaxel monotherapy and one evaluating paclitaxel combined with pela. Of these 74 patients, 57 had the HR+/HER2- breast cancer subtype, participants with HR+/HER2- metastatic breast cancer were divided roughly equally between the treatment groups with 29 patients receiving paclitaxel monotherapy and 28 receiving the paclitaxel-pela combination. The patient population for IND 213 was heavily pretreated with the trial's eligibility criteria specifying that participants must have received at least one prior line of chemotherapy for advanced or metastatic disease. Looking at the table on the left, you can see that in the full population of 74 randomized patients, median overall survival in the pela plus paclitaxel arm was 17.4 months compared to 10.4 months in the paclitaxel monotherapy arm. This difference was statistically significant when looking at the subgroup of patients with HR+/HER2- breast cancer. We observed a hazard ratio of 0.6, with a median overall survival of 21 months in the combination arm compared to 10.8 months in the paclitaxel monotherapy arm. This difference was also statistically significant providing proof of concept for HR+/HER2- breast cancer program and supporting the special protocol assessment agreement and Fast Track designation referenced by Matt earlier. On the right side of this slide is the Kaplan-Meier curve for survival in the HR+/HER2- subgroup of IND 213. As you can see, the survival benefit observed in the pela arm first became apparent around the 10-month mark. Seeing this delayed separation in the survival curve strongly suggested that the pela was working through an immunologic mechanism of action and that anticancer cellular immune responses were likely driving the observed clinical benefit. This actually contrasted with the prevailing belief at the time, which was that pela worked primarily through a lytic mechanism of action. When discussing these new insights with the FDA, the agency suggested that prior to moving to a licensure-enabling study we further characterize pela's mechanism of action to confirm its immunologic basis. In addition, after discussing IND 213's data with our collaborators at Pfizer, we decided also to see how pela-paclitaxel combination therapy would perform in a less heavily pretreated patient population and in combination with a checkpoint inhibitor. Answering these questions would allow us to optimize the design of a licensure-enabling Phase III study, including helping us to define the most appropriate patient population. This was a particular interest because patients at an earlier stage in their treatment compared to those studies in IND 213 would be expected to have healthier immune systems, which we hypothesized would lead to a more robust and rapid treatment effect that could perhaps be detected through an overall response rate or progression-free survival endpoint. Using PFS as an endpoint in a registrational study [ could ] in turn, allow us to get a readout 18 months or more sooner than the overall survival endpoint for which the data would take longer to mature. Following discussions with Pfizer and the FDA we went on to confirm pela's immunologic mechanism of action through the AWARE-1 study, which generated the translational data I referred to earlier, and we also initiated the BRACELET-1 trial, which is the main topic of today's webcast. As you can see on this slide, BRACELET-1 was designed to confirm IND 213's positive results and inform a subsequent registrational study. IND 213 and BRACELET-1 have similar designs with each, including a paclitaxel monotherapy control arm and a cohort evaluating paclitaxel-pela combination. In addition, BRACELET-1 includes a third cohort evaluating paclitaxel plus pela combined with the PD-L1 inhibitor, avelumab. On the right, you see the BRACELET-1's primary endpoint its overall survival at week 16 with secondary endpoints, including progression-free survival, immune biomarker data and safety and tolerability. The study was designed to enroll 48 patients across its 3 cohorts and was not powered for formal statistical comparisons. As I alluded to earlier, another key difference between IND 213 and BRACELET-1 was the patient populations enrolled as BRACELET-1 excluded patients who received prior chemotherapy for metastatic disease. In addition, all BRACELET-1 participants received prior hormone-based therapy with a CDK4/6 inhibitor which is the current standard of care. A more detailed comparison of the patient population from IND 213 and BRACELET-1 is shown on the table here. In addition, I'll note that more detailed data on patient demographics and disease characteristics from BRACELET-1 can be found in the copy of the slides from the ASCO Oral Presentation posted on our website's Posters and Publications page. So with that overview of our breast cancer program and BRACELET-1's design complete, let's get on to the most exciting part of today's presentation. Here, we have data on BRACELET-1's primary endpoint, which was overall response rate at week 16. As you can see, the overall response rate at week 16 increased from 20% in the paclitaxel-monotherapy arm to 31% and in the paclitaxel-pela combination arm. This result is even more impressive if you look at how the data matured since the confirmed overall response rate for the pela-paclitaxel combination cohort was 37.5% versus 13.3% in the paclitaxel-monotherapy cohort. Recall that a confirmed response is one that is corroborated by a follow-up scan at least 4 weeks later. If you now look at the overall response and disease control rates from Cohort 3, you can see that adding avelumab to pela and paclitaxel did not lead to an increase in anticancer activity compared to paclitaxel plus pela combination therapy. Translational data that I'll be speaking about shortly suggests that this may be due to inhibitory effects of avelumab on pela induced T cell expansion solidifying our decision now to move to a registrational study that will focus on the paclitaxel-pela doublet. Here on Slide 12, you can see the swimmer plots for the paclitaxel-monotherapy and pela-paclitaxel combination cohorts. Looking closely, you'll notice that included among the 6 patients who achieved a confirmed response in the combination cohort were 2 who improved from stable disease to partial response at later time points after week 16, which is consistent with pela's immunologic mechanism of action. And on this next slide, our data from the same cohorts presented as spider plots, which provide more specificity about the magnitude of tumor reduction over time. Again, the differences in the depth and duration of the responses between the cohorts is apparent. Turning to Slide 14. You can see the swimmer plots comparing the pela and the pela-paclitaxel and avelumab cohort. Given that there is no clear evidence of increased anticancer activity in the avelumab cohort, I won't spend much time discussing these data or the data on the corresponding slides, which show the spider plots for these cohorts. However, I wanted to share these data to provide a comprehensive look at the results from each of the cohorts of the study. Next, I'd like to turn our attention to BRACELET-1's data on progression-free survival, which is an endpoint that has been used in the past to support approvals of oncology drugs. As you can see in the Kaplan-Meier curve and the accompanying table, there was a robust increase in progression-free survival in the pela plus paclitaxel cohort compared to the control arm. As of March 3, 2023 cutoff date, median progression-free survival was 6.3 months in the paclitaxel-monotherapy group and increased to 9.5 months in the paclitaxel-pelareorep combination group with a hazard ratio of 0.29. Looking at 12-month PFS rates, this was 0% in the paclitaxel-monotherapy group and increased to 32.8% in the pela-paclitaxel combination group. Similar to the overall response data, results from Cohort 3 evaluating pela plus paclitaxel in combination with avelumab did not show increases in progression-free survival compared to the monotherapy control group. If we now look at BRACELET-1's progression-free survival and response rate data together, there are several important and exciting points I'd like to emphasize. First, these data are internally consistent with robust increases in both response rate, particularly the confirmed response rate and a median progression-free survival in the pela-paclitaxel combination compared to paclitaxel monotherapy. In addition, these data substantiate IND 213's positive results, which again showed a statistically significant near doubling of median overall survival in the pela plus paclitaxel combination arm. Second, the results from the paclitaxel-monotherapy arm in both BRACELET-1 and IND 213 are in line with expectations based on historical results. Therefore, the fact that the control arm in each study performed as expected increases our confidence in the positive results for our pela containing arms in both studies. And third, the overall response rate and progression-free survival data from BRACELET-1 are supported by translational data from the study, which indicate that pela enhances paclitaxel's efficacy by generating a robust anticancer immune response. These translational data are shown here on Slide 18 with the graph showing T cell expansion over time. As you can see, while T cell numbers remained relatively constant over time in the treatment -- with treatment in the paclitaxel-monotherapy group, adding pela to the regimen led to statistically significant increase in anticancer T cells by the fourth treatment cycle. This finding is consistent with pela's mechanism of action and provides a strong scientific basis for the robust increases in overall response rate and progression-free survival observed in the pela-paclitaxel combination cohort. Turning our attention to the right-hand panel of the figure. We see data on T cell expansion and BRACELET-1's cohort evaluating paclitaxel plus pela in combination with avelumab. As shown in the figure, there was no increase in T cell expansion in this cohort, suggesting that avelumab blunted pela induced increases in anticancer T cells. This provides a mechanistic basis for the observation that no increase in response rate or progression-free survival was seen in the paclitaxel plus pela plus avelumab cohort compared to the paclitaxel-monotherapy cohort. We'll hear more about the biological mechanisms underlying this finding through our KOL roundtable. Turning our attention to Slide 19. You can see safety data from BRACELET-1. In the interest of time, I won't go through this table in detail, but I will note that there are no unexpected findings and that pela displayed an acceptable and manageable safety profile consistent with that observed in past trials. I'll also note that the addition of avelumab to the treatment regimen appeared to lead to an increase in toxicity without an apparent increase in efficacy. To summarize, BRACELET-1's findings, we saw a robust improvement on the trial's primary endpoint with a 31% response rate at week 16 with the pela plus paclitaxel combination versus a 20% response rate at week 16 with the paclitaxel-monotherapy. This was complemented by an even more impressive increase in confirmed response rate from 13.3% to 37.5% in the pela plus paclitaxel arm. Equally impressive were the progression-free survival results, which demonstrated a 71% reduction in risk of disease progression in the combination group compared to paclitaxel monotherapy. Seeing such robust improvements in objective response rate and progression-free survival is exciting and will enable us to design a registrational study with dual primary endpoints that could allow us to get a T data readout at least 18 months earlier than would be possible with a single overall survival endpoint. These exciting efficacy data from BRACELET-1 are supported by translational results showing pela induced increases in T cell expansion that are associated with anticancer activity. In addition, pela displayed an acceptable safety profile that was consistent with what we have seen in prior studies. With these results, our HR+/HER2- metastatic breast cancer program is now Phase III ready. Before moving on to our key opinion leader roundtable, I'll reiterate that BRACELET-1 is just one of several clinical studies supporting our HR+/HER2- metastatic breast cancer program. Other trials include a Phase I study that demonstrated pela's single-agent activity in this indication, the AWARE-1 study confirming pela's immune-mediated mechanism of action and the IND 213 study I spoke about earlier. With all of these trials complete, we're now advancing to a licensure-enabling study. While we, of course, need to discuss this planned trial with the FDA to -- prior to finalizing its design, we envision a 2-arm study evaluating pela-paclitaxel combination versus paclitaxel alone with dual primary endpoints of progression-free survival and overall survival. As we advance towards that trial, we believe we have substantially derisked our program through each of the prior studies and we are fortunate to be supported by an FDA Fast Track designation. We expect to provide an update on our planned licensure-enabling study in the second half of the year. And with that, I'd like to offer my thanks to all those who participated in the BRACELET-1 trial as well as those who contributed to its conduct. I'll now ask Professor Vile, Prat and Piccart to join me for our key opinion leader roundtable.

Thank you, Tom. We have several questions here, and I'd like to kick off with the first one. Looking at the totality of data from BRACELET-1 and IND 213, how clinically meaningful for patients are the increases in PFS and OS observed with pela plus paclitaxel, assuming they are confirmed in a Phase III trial?

Thank you. I think I will ask Professor Piccart to start off with that, and then the other experts, of course, can offer their thoughts as well.

Yes. Thank you very much. So perhaps I would like to start by saying that the treatment of metastatic hormone receptor positive HER2 negative breast cancer has changed dramatically in recent years. With the addition of CDK4/6 inhibitor to first-line endocrine therapy, we can now control the disease of these patients for sometimes up to 2, 3 years. And we have seen also an improvement in survival for our patients. But once they progress on this combination of endocrine treatment and CDK4/6 inhibitor, things become a lot more challenging. And we have to switch to chemotherapy at a certain point There, there is no preference for a certain type of chemotherapy and in general, these cytotoxic drugs are not performing very well and are not able to control the disease for long periods of time. So there is a clear unmet need to improve therapies after CDK4/6 inhibitors. And this is where I can see this particular approach of trying to transform what is fully immunogenic disease into an [immunogenic] disease with this oncolytic virus as very innovative. Now clearly, in terms of what is important for patients, progression-free survival, of course, has some value, but in general, what is going to be of greatest importance is overall survival improvement and/or quality of life improvement. And this has been acknowledged in a tool that has been validated. It's called ESMO-Magnitude of Clinical Benefit Scale, which has been designed together with patients and where we can see that patients indeed will value these 3 endpoints with more emphasis, more weight given to quality of life and overall survival. And that's where I am really very supportive of the design of the registration Phase III trial with these 2 co-primary endpoints, progression-free survival and overall survival.

Thank you, Professor Piccart. Professor Prat, any additional thoughts perhaps?

Sure, Tom. And yes, I fully agree with what Martine said. I would think that after CDK4/6 inhibition and endocrine therapy, we have an unmet need. There is innovation arriving. For example, trastuzumab deruxtecan for HER2 low, but still, when you look at the data of DESTINY 04, there is still a lot of room for improvement. So definitely innovative approaches, such as the one that we are proposing here, I do think makes total sense. And the totality of the data, I think, as you pointed out very well, Tom, is that here, we have an innovative approach that has shown to make, as Martine said, a tumor cold, hot and not only that to improve outcomes and not only improve overall response on PFS, but also a hint that OS can be achieved and that for patients is a critical aspect. So I do think that further studies are needed and the registrational makes total sense. So I'm looking forward for that.

Thank you and Professor Vile, any other thoughts?

Nothing significant other than we've done a lot of preclinical studies with the virus, and it's really exciting to see. It's relatively rare that encouraging results in preclinical mouse studies sort of really translate into the clinic. And at least as far as we can see at this stage, that seems to be happening here, certainly from our own studies where we combined the virus with a drug, and this is looking very, very encouraging from that point of view.

Thank you.

Great. The second question and the topic is could the clinicians provide their thoughts on BRACELET-1's safety data, including the numerical increase in neuropathy and discontinuations in the pelareorep cohorts?

So perhaps we can start with Professor Prat this time, but of course, everyone will have an opportunity to comment.

Sure, Tom. So yes, there is an increase in neuropathy, it's small, but is there. I think the most likely explanation is that patients have been exposed to more doses of paclitaxel and I don't think it's a direct effect of the virus. And I think that has also been shown so the more the patients are treated with paclitaxel, the more peripheral neuropathy, the patient will have. Anyhow the increase, I think it's not major, but of course, more data in the pivotal trial, will allow to phase this out.

Thank you. And Professor Piccart?

Yes. Well, I agree with Aleix's comment. To me, it is really great that this proof-of-concept, relatively small study has been performed prior to jumping to definitive Phase III trial because what has been seen here is a relatively high rate of early discontinuation of pelareorep. It was 27% and in the presentation here in Chicago, the principal investigators recognized that they have not paid enough attention to supporting patients for the flu-like symptoms that they develop with this strategy. So what I see there is the possibility of improvement in the Phase III trial with better management of the side effects, which should then lead to less discontinuation of the treatment and even better activity, I suppose.

Excellent. Thank you very much. In the interest of time, let's go to the next question and then -- from here if you don't mind.

Sure, Tom. Could the speakers speak very briefly about the current standard of care for metastatic breast cancer and how you envision pela would fit into the treatment paradigm if Phase II safety and efficacy data are confirmed in Phase III?

Yes. I believe we touched on this briefly, but perhaps our clinicians Professor Piccart and Professor Prat can weigh in briefly on this. If you don't mind -- Martine, if you wouldn't mind starting off at that would be great.

Yes. So I view this particular strategy as one very attractive possibility upon progression on endocrine treatment and CDK4/6 inhibitors. Of course, like Aleix alluded to, we have antibody-drug conjugates entering the scene now sacituzumab govitecan is one and trastuzumab deruxtecan is another. But I don't see why pretreatment with one of these antibody-drug conjugates would affect the antigen activity that we see here because these antibody-drug conjugates have, as a payload, cytotoxic agent, which is irinotecan, which is not at all a microtubule inhibitor like paclitaxel. So I'm not at all afraid that if some patients in the Phase III trial will have been exposed to one of these drugs, that we will have any risk in terms of the anticancer activity of paclitaxel and pelareorep.

And Aleix, please?

Yes. Just -- and I fully agree with Martine's comment. At the end of the day, whether after CDK4/6 inhibitor endocrine therapy and whether a second endocrine-based therapy is administered at the end of the day, patients go into chemotherapy-based strategies. Of course, as Martine pointed out, ADCs are coming, but the data also suggests there is room for improvement. And eventually, Taxol will be a treatment that we will use and of choice for patients. So having a way to improve what the efficacy of Taxol is giving to these patients, I think, makes total sense.

And Dr. Vile, just because Professor Piccart brought it up, can you think of any reason why prior treatment with an antibody-drug conjugate would have any impact on pelareorep's combination therapy's efficacy?

Yes. I mean I think anything that generates -- helps to generate a pre-existing T cell response against the tumor could then -- the virus would then act as a very powerful boost of that because if there are pre-existing T cell responses, certainly in our animal models, we've seen that when we give the virus subsequently and we get on an additional stimulation of antigen release through the activity of the virus, we see a dramatic increase actually in the efficacy there. So I think that could be very much a sort of a prime boost mechanism going on in vivo in these patients -- in-patient.

Thank you very much. Appreciate it.

Great. Next question. BRACELET-1 showed a clear increase in PFS while the increase in PFS in IND 213 was much smaller despite the statistically significant survival benefit. What may be the reason for this difference?

Okay. Good. Well, perhaps Professor Prat, maybe you could start off on this if you'd be so kind?

Sure, Tom. And I don't think we have a clear answer on this or at least I don't have a clear answer. I mean crucial comparisons are always difficult in these studies. BRACELET is a more modern study. And I think I would like to point out that all patients received prior CDK4/6 inhibitors, whether that's a variable to take into account whether it's others, I think it's difficult I think the fact that at the end of the day, improvement in survival is shown is critical. Also PFS can be somehow subjective in some aspects. So I do think, at the end of the day, OS is probably the most objective variable. But again, seeing in BRACELET this PFS effect and also not only the PFS effect, it's the overall response, it's the clinical benefit rate. It's the spider plots. It's 2 patients being without progression now for 13 months. I think it speaks that the activities there and these minor differences across trials maybe are good to chance.

Yes. And Professor Vile, any thoughts on why the IND 213 may not have shown a PFS benefit compared to the BRACELET study?

Not really anything significant to add. I think with these sorts of immunotherapies, there are all sorts of variables which kick in in terms of numbers and so on. So I would agree, I think it's probably due to small differences that are not significant.

Yes. And Professor Piccart, any thoughts?

No. I think that, of course, the patient population in BRACELET is less heavily pretreated so -- compared to the other patient population. But other than that, I cannot find a very good explanation.

Okay, thank you.

This is a related question. So Tom, if you want to move on, we can. So what can we say about the significance of the PFS benefit in the paclitaxel plus pela group compared to the paclitaxel group alone?

Well, I think we've more or less addressed that.

That's what I thought. Okay.

Yes. We can go ahead.

Fair enough. And the last question here is, could you provide your thoughts on findings from Cohort 3, paclitaxel plus pela plus avelumab and possible reason avelumab appear to attenuate the effect of combining pela with paclitaxel?

Okay. Very interesting question. I think for that one, why don't we start with Professor Vile?

Sure. I think this is really an interesting finding. Our prediction was that adding a checkpoint inhibitor would further boost the T cell mediated effects of the virus. And I think we clearly see that that's not the case in this case. We've looked at it, and that could be for a variety of reasons, and it's difficult at this stage to be definitive. But certainly, our preclinical studies have shown that the effects of immune checkpoint inhibitors are highly dependent upon timing, the virus versus the checkpoint inhibitor whether the checkpoint inhibitor is working on the antitumor response or the antiviral response, can be influenced. But probably my personal view at this stage is that avelumab has been shown clearly to be cleared faster and has a much shorter half-life than other anti-PD-L1 antibodies such as durvalumab. Mechanisms have been investigated, and there's a clear literature showing that the checkpoint inhibitor causes the rapid internalization -- sorry, is rapidly internalized, mainly through Fc receptors. So given that the preclinical now, I think the clinical data is showing that the virus is working clearly through expanding T cell clones, probably antiviral as well as antitumor. If you have an immune checkpoint inhibitor, which is actually being internalized and cleared much quicker, that could be actually exerting a negative effect on that T cell response, which the virus is expanding. So I can't answer the question definitively at this stage. But certainly, I would think that it could be that this particular checkpoint inhibitor is cleared faster through Fc receptor clearance, and that then is actually inhibiting what is the key driver of this therapy, i.e., the T cell expansion. And clearly, the correlative studies with T cell expansion are showing that, that is the case, that it is inhibited in the presence of the anti-PD-L1 -- of this particular anti-PD-L1. So those would be my thoughts at this stage.

Thank you very much. Professor Piccart, any additional thoughts?

Well, I think it's -- Dr. Vile here, who is the expert. But my thought on this is that for combination immunotherapies to enter the clinic, we will have to see a dramatic improvement in outcome because of the cost. We should not forget that cost can be an issue. And so clearly, here in this relatively small study, we don't see a signal, and that makes me confident that for the definitive registration trial, we can go ahead with this 2-arm design and not add a third one, which often complicates things. And as I said, you would have then to really show a dramatic improvement above the -- what you see with the doublet combination.

Yes. Thank you and Professor Prat, any thoughts?

No. I think everything has been said. I do think that the data strongly suggests that the combination is not for -- not worth further pursuing. Whether other combinations with other immune checkpoint inhibitors might be of interest. I think it is future work. And it's true that in the AWARE trial, we had a cohort of atezolizumab, right, another anti-PD-L1, and we did see some immune effects -- additive immune effects compared to just pela. Of course, that was a window of opportunity trial with just 3 weeks of therapy, but still maybe that tells us that maybe depending on the combination, things might be different, but for the current data, I do think that should not -- this combination should not be pursued.

Okay. Tom, so that does conclude this part of the presentation. So I'd just also like to offer my congratulations to you and the team on getting to this point, and we're excited about what's coming. So I will now turn it over to my colleague, Tara, to handle the analyst portion of the Q&A.

Great. Thanks, Tim. Please hold for a brief moment. So our first question comes from John Newman from Canaccord.

Thanks for the presentation. Thanks to all the KOLs as well this morning for participating. I just had one question to start on the statistics. I'm wondering if you happen to look at the statistics for progression-free survival for the pelareorep and paclitaxel on PFS versus paclitaxel alone and what that looks like? And the second question is the physicians, I think, made some comments regarding the third arm with the checkpoint inhibitors. I'm wondering if in the future, you would consider looking at a different checkpoint inhibitor or at this point you are more comfortable just focusing on the paclitaxel combination?

Okay. So with the statistics, well, Professor Piccart, maybe you can comment. I think the -- what we've shown here in the presentation were the hazard ratios with the confidence intervals, I think is what we've actually presented, yes.

Yes. If I understood well, there was no intention to do a formal comparison. That would have required a larger sample size, I guess. But what we see with this hazard ratio is a strong suggestion that PFS is improved with the dual combination.

Yes. And Aleix, I don't know if you had other -- any comments related to that?

No. I think I said before, a formal compilation cannot be done, but the data strongly suggests that the direction of more efficacy with pela is clear, the suggestion...

No, sorry, Aleix, I didn't mean to interrupt.

No, regarding the second point, brought up by John Newman, is yes, the combination with an immune checkpoint. I think as we previously stated, we think that the current data does not suggest that the combination should be for the [ presumed ] meaning pela with avelumab. But it's true that potential other combinations could be explored, not for the registrational trial in my opinion, but for other studies. But at the same time, we need to acknowledge that immune checkpoint inhibitors are not showing high efficacy in this disease, right, monotherapy with pembrolizumab in PD-L1 positive. Hormone receptor positive HER2 negative has shown an overall response of 12% monotherapy, avelumab even less, 5%. And in a randomized trial of eribulin plus minus pembrolizumab in hormone receptor positive HER2 negative, this trial was negative. So I do think, so far, they are not available, the activity with immune checkpoint inhibitors doesn't seem to be there. So I don't see an argument to try to -- for the registrational trial to try to investigate this. Other potential combinations may -- we are interested in may be in a small Phase II trials.

Yes. When we heard a minute ago, Professor Piccart pointed out that a substantial efficacy benefit would be needed to justify adding a checkpoint inhibitor. I don't know from just from a mechanistic perspective, Professor Vile, do you think a different checkpoint inhibitor may be something that could in principle add value?

I do. I think for the registrational trial, I don't think that the data warrants that. But I think there's a lot of very exciting science that can be done with different checkpoint inhibitors and particularly from our data with the virus, the timing could be very important. So I personally believe that the virus is an extremely good way of either timing and non-existing antitumor T cell response or boosting it if it's already there. And so with those sorts of things in mind, there's a lot of preclinical studies that could be done in terms of when the checkpoint inhibitor is given relative to the virus. Now those are sort of lengthy experiments to do. And I don't think they are warranted for the registrational trial. But I do think additional checkpoint inhibitors working on different stages of the priming and boosting the timing of that offers a huge opportunity with the virus as well.

Thanks for the questions, John. Our next question comes from Soumit Roy from JonesTrading.

Good morning, everyone, and congratulations on the data. One question on the registrational trial. We keep getting a physician's comment around a big use of ADC in this population. So do you think paclitaxel alone would -- is the right control arm? Or would you prefer a physician's choice? Or will that increase too much variability?

Thank you very much. I think that would be a good question for Professor Piccart to get us started on, if you would be so kind.

I think I shared my opinion with you. I think for the Phase III trial to be relevant, we need to allow for exposure to an antibody-drug conjugate. Now in many regions of the world, patients will not yet have access to these expensive drugs. But they probably will at least in the United States. So for the trial to be meaningful. We need to have a subset of patients exposed, and we can then double check in a forest plot that this prior treatment with an antibody-drug conjugate does not affect the anticancer efficacy of this particular strategy. Paclitaxel is a fantastic drug. If you think about, it has been around for a long time. It is well known by oncologists all around the world, and it is cheap. It's a key drug today. So I can see a value in choosing this particular drug for the combination with the oncolytic virus. And I think that this will just be an additional possibility to treat our patients, the more possibilities we have, the better.

Professor Prat, any additional thoughts?

Fully agree with Martine. I do think that for the trial, sticking to Taxol makes little sense for the comments that Martine made. That doesn't mean that potential combination with disease could be of interest down the road, no doubt. But then, of course, here is where the type of chemo, the type of payload might matter in combination with pela and that's probably more preclinical work, more studies like AWARE would, I think, help better understand if another combination beyond Taxol makes sense, and there's a huge potential to explore that. But not for the registrational trial in my opinion.

Okay. Thank you. Why don't we move on to the next question here, if we might.

Our next question comes from Louise Chen from Cantor Fitzgerald.

Congratulations on the data here. So I wanted to ask the doctors where you think overall survival will actually shake out for this drug in the study? And then secondly, maybe a question for the company. How do you think this data or why does this data shorten your development times? And how much could you save here with the shortened development time? And have you discussed this with the FDA? And then last question is just an update on partners for breast and pancreatic and any timing on that now, especially with this positive data, do you think that will speed things up?

Okay. So Professor Prat, given the IND 213 data, which have the survival benefit and the BRACELET data and any other data you wish to bring into mind, can you make any kind of guess or projection of how pela might affect overall survival in this population?

Sure, Tom. So I think the overall data and, of course, more data from BRACELET regarding OS will also help us. But I think that the magnitude that we should expect should be high. And when we say high, magnitude of benefit in terms of overall survival, in my opinion, is more than 3 to 6 months. And I do think that based on the current data we've seen, that could be achieved. One particular aspect is that, yes, there is a change in the course of the disease. So I do think that when this will be evaluated, and I think Martine also pointed out this before, the ESMO clinical benefit scale matters here because it's not just the absolute increase in survival, [ it's also ] hazard ratio and the design is also quality of life also being there. So I do think that achieving what we call among the ESMO clinical benefit rate and the scale of 1 to 5, 5 being the highest benefit. I do think that the trial should aim for achieving the highest which is 5.

Thank you. And Professor Piccart, any thoughts?

No. Nothing to add to these thoughtful comments.

Thank you. Yes. And if I may comment just very briefly on the second part of the question related to how these data might impact the timelines for development that we would anticipate that a Phase III study, as mentioned, would have a dual primary endpoint of progression-free survival and overall survival. Clearly, progression-free survival, the events needed to trigger the analysis would come earlier than overall survival. And the devil is in the details, but we would anticipate that those events that the progression-free survival endpoint would be triggered somewhere around 18 months, give or take, earlier than an overall survival endpoint. And so it would give us an opportunity to achieve a potentially licensable endpoint earlier by about that magnitude. And I'm sorry, I'm blanking on the last part of your question. Could you remind me?

Yes, sure. I was just curious if you have an update on partnerships for breast and pancreatic especially in light of this strong data you've shown?

Yes. I think I might defer to...

I can take that, Tom. We've actually been very busy over ASCO talking with potential partners. I think very much like our pancreatic results, we had very much signaled that we were expecting an OS benefit with not much of a PFS. But I think by going to an earlier-stage setting, we were able to capture the benefits. So we've been very engaged with pharma partners to talk about these results. With the changing landscape of breast cancer, I think we've got a unique position that fit in after CDK4/6 failure, especially if we really look at the HER2-zero patients I think we have a very clear line of sight to a registration program. I think pharma partners see this. The parties that we spoke to this week, and I think we're very surprised to see a hazard ratio as low as 0.29. I think there's very few instances where we can see a hazard ratio that low, especially when the confidence intervals are less than 1. I think it's a very strong read out for a study this small. I think on the back of 213, I think what we're offering now is 2 randomized studies that show us moving in the same direction with a clear line of sight to a registration path. I expect nothing but more interest from pharma partners as we move forward as we start to expose parties to this data. Like literally, this came out today. We share this information with groups under confidence. I think everyone was very pleasantly surprised with the strength and the quality of this data. So I would expect it to accelerate our timelines quite dramatically.

Our next question comes from Patrick Trucchio from H.C. Wainwright. Patrick, we can't hear you. No, we cannot.

What about now?

Yes, we can hear you.

Great. Sorry about that. Congrats on the data. Earlier, there was some discussion around the potential to improve the discontinuation rate with improved support of flu-like symptoms with the possibility to improve responses as well. I'm wondering if you can elaborate a bit more on how this support differed from prior studies and what changes could be expected in the registrational trial as well how responses could be expected to be improved from what has been demonstrated in BRACELET-1. And finally, just what would need to be demonstrated at 18 months on PFS in this registrational trial to achieve approval?

Right. Well, for the first part of that, especially related to management of adverse events, I think Professor Piccart, you brought this up earlier, would you be able to comment on Patrick's question?

Well, in the protocol of the BRACELET study, there was nothing specified in terms of managing these side effects, like fever, chills. So if we pay attention to this in the Phase III, my expectation is that the early discontinuation rate will drop and that this probably will further improve the results because in many studies, you have early discontinuation rates, but when they reach 27%, to me, it's a signal that it's too high that you need to do something to decrease this. And this shouldn't be too difficult. So I think it's an important message for the Phase III.

And regarding the magnitude, I believe you asked, Patrick, the magnitude of PFS that might be suitable for registration. Is that -- did I say it correctly?

Yes.

I don't know. I mean, Professor Prat or I guess, Professor Piccart as our clinicians, did you -- is there any number that comes to mind for that? Or how would you -- what do you think might be appropriate?

I think we discussed that there, the ESMO-Magnitude of Clinical Benefit Scale really helps. So we should aim for PFS at a score of about 3 or 4 hoping then that we -- overall survival improvement, we will go higher in the scale. I cannot remember by heart, but I think it's probably going to be the need for a 3-month improvement in median PFS, which is exactly what we saw in the BRACELET study.

And then Professor Prat, any additional thoughts about that? For either part of the question, anything you...

Yes. I mean, regarding the first part regarding [ itching ], the side effects, the chills. In AWARE trial that I participated and treated patients myself, we implemented prophylactic administration of [antidermics] like paracetamol or -- and like Tylenol or anti-inflammatories and it worked very well. We saw a dramatic change here. So again, that was only one cycle of therapy. But I do think that looked very, very, very encouraging.

Yes. And regarding the magnitude of PFS, I don't know if you can point to an exact number. My recollection and don't quote me on this precisely, was that in the HER2 study, their PFS, I believe, had a hazard ratio of 0.62 or something like that. But anyway, I'm just throwing that out there as a comparator, there are many other potential things you could look at.

Great. I'll now turn it back over to Tim to read the written questions from the webcast.

Thanks Tara, so in interest of time, we have one more here, Tom. The questioner noticed that some patients had responses later in treatment even past week 16, and wanted to know how to interpret that in terms of the combination with pela and paclitaxel?

Yes. So that sounds immunologic to me. Why don't we ask Professor Vile to start out on that, if you don't mind, Richard?

Sure. No, I think that's one of the fascinating parts of this data is the initial observation that the improvements start to kick in at a later time point, which is indicative that the virus is not just going in lysing cells, the sort of the classic paradigm of oncolytic viruses, but it's really stimulating an immune response, which then kicks in later. And I think this is the same sort of effect. I think there's very much likely to be a prime boost, boost type mechanism of this virus. We've seen these patients who develop later responses, I think, is indicative of that. I think it will be fascinating to see -- just to follow up on the T cell data, looking at expansion of clones. And it -- I don't know that this is the case, but certainly, I think about it, a hypothesis would be that as tumor lysis via immune-mediated mechanisms continues there is a continual sort of boosting effect of that. So as it may even be that as tumor sort of starts to recur that provides an in vivo boost of the T cell responses generated by the virus. And so that's why you see these sorts of effects. And certainly, in preclinical models, we can show that subsequent additions of the virus will boost a preexisting response and we'll get -- as tumors start to come back, they will start to regress again in those mice which were treated with the virus. So I think it all points towards a developing T and possibly B cell response against the tumor. And as you boost that response in various ways, either by tumor or indeed by viral boosting, you can get very effective T cell control of tumors.

And Professor Prat, any additional thoughts related to that question?

Not really. I think Dr. Vile has the expertise and he said it all.

Thank you. And Martine, of course, if you have anything you'd like to add, I'd be very happy to hear.

No, just that the investigators participating in the Phase III will be -- will have to be made aware of this so that they don't stop the treatment too soon.

Yes, excellent point, actually.

Okay. Well, that concludes the Q&A portion. I turn it back over to Matt for some closing comments.

Matt you're on mute.

Well that would help. I just want to thank everyone who joined us today as well as a special thanks to Professors Vile, Prat, Piccart for taking the time to provide their expert perspective on our data. We very much look forward to advancing both our breast and pancreatic cancer programs, to licensure-enabling studies and to provide updates on these efforts as we progress. And I just want to wish everyone a great day. Thanks very much for your time.

Thanks.