Immutep (ASX:IMM) ESMO Congress results webinar, October 2023




Immutep Limited (ASX:IMM) CEO Marc Voigt and Senior VP Strategic Development Christian Mueller present on results from the 2023 ESMO Congress.

Paul Sanger: Good day ladies and gentlemen and thank you for joining us for the Immutep (ASX:IMM) webcast to discuss the company’s new clinical data released at the European Society of Medical Oncology 2023 meeting. My name is Paul Sanger, and I will be your moderator today. The format today will be a presentation delivered by Immutep and at the end, we will open the call for analyst questions. I will also relay any other questions received via email prior to this call. I would now like to hand the call over to Marc Voigt, Immutep’s CEO to start the presentation. 

Marc Voigt: Welcome everyone. We appreciate you taking the time. With me from the Immutep management team are: Prof. Frédéric Triebel, Immutep’s Chief Scientific Officer; Dr Florian Vogel, Chief Medical Officer; Mr Christian Mueller, our Senior VP of Strategic Development.

Today, it is our pleasure to walk you through the exciting new results from our large Phase II trial focused on first line treatment of metastatic non-small cell lung cancer, which exceeded our own optimistic expectations. The unique chemotherapy-free combination of our proprietary lead clinical candidate in oncology called eftilagimod alpha, or efti, with the anti-PD-1 therapy pembrolizumab was shared via an Oral Presentation by Dr. Enric Carcereny of the Catalan Institute of Oncology at the ESMO Congress on Saturday.

We will also briefly walk through data from the Phase 1 trial evaluating efti combined with both pembrolizumab and doublet chemo in non-small cell lung cancer. We will be limited in what we can say, given there will be new data from this promising INSIGHT-003 study presented tomorrow at ESMO. Stay tuned for that.

This is our usual forward-looking statement.

Before we dive into the clinical data, I would like to take a moment to discuss our lead candidate efti, along with the LAG-3 landscape, and the very unique position that Immutep finds itself in.

As a pure-play LAG-3 company, we are very pleased to see the increasing attention being paid to this unique gene, and how its interaction with MHC Class II can have a profound impact on our immune systems to fight both cancer and autoimmune diseases.

It has been roughly a year and a half since LAG-3 joined PD-1 and CTLA-4 as the only immune checkpoints in the field of immuno-oncology with approved therapeutics. As the worldwide leading company in LAG-3, it is validating to see this approval as well as the increased focus by the biotech and large pharma industry on this promising checkpoint. With this said, we believe our own programs stand apart from the field, and more important than our own beliefs, the clinical data has done nothing but strengthen our conviction in that assessment.

Moving to our deep pipeline on Slide 4.

Our extensive knowledge and understanding of LAG3 has led to the creation of multiple first-in-class clinical and preclinical candidates shown here. Behind this diverse pipeline is our Chief Scientific Officer and Board member, Dr. Frederic Triebel, the worldwide leading scientist who discovered LAG-3.

Our diversified product portfolio harnesses LAG3’s ability to stimulate or suppress the immune response either to fight cancer or to silence the T cells at the cause of autoimmune disease. Staring from the bottom of this slide we have two assets in autoimmune diseases:

  • IMP761 is the world's first agonist to LAG3 designed to target the causes of autoimmune disease as opposed to dealing with its symptoms. The use of checkpoint agonists against autoimmune diseases is an area of rising interest within the industry given the work of Eli Lilly with their PD-1 agonist, as well as Gilead’s acquisition of MiroBio for $400 million roughly a year ago. We hope to bring this important candidate that can address well over 50% of all autoimmune diseases into the clinic by mid-2024.
  • Moving up the slide you see two clinical candidates that have been out-licensed to large pharma, the first to GSK is GSK781, a depleting LAG-3 antibody for autoimmune diseases, and the second is leramilimab or LAG525, an anti-LAG3 antibody to Novartis.
  • Next up is an early preclinical program in the middle of this slide that we are working on with Cardiff University in the UK. This is an anti-LAG-3 small molecule that could offer cancer patients the convenience of a tablet at a fraction of the cost of existing antibody-based anti-LAG-3 candidates. We have significant work to do here, yet the upside from an orally available LAG3 checkpoint inhibitor we feel is worth the effort.
This brings me to currently the most significant candidate in our pipeline and the focus of our webcast today…efti. This proprietary first-in-class soluble LAG3 and MHC Class II agonist is our wholly-owned asset for which we have global rights everywhere except China, where it has been out-licensed to EOC Pharma.

As detailed on the pipeline, efti is being tested across numerous solid tumor indications with different combinations, from early to late-stage development.

The next slide provides specific details on the multiple first-in-class therapeutic approaches Immutep has designed around LAG-3 and its interaction with MHC Class II that plays such a vital role in the immune response. This slide also shows what makes efti so unique among all other LAG-3 approaches in oncology today.

At the most basic level, you can see that efti does not target T cells like all other companies are doing with their antibody approaches; as well as what we are doing with our 2 clinical and 2 preclinical assets on the right side of this slide in the orange boxes. Instead, in the green box on the left-hand side of the slide, you can see that efti targets antigen-presenting cells or APCs. Importantly, efti targets the most potent professional APCs…dendritic cells.

As a soluble LAG-3 protein, efti is a key that unlocks broad activation of the adaptive and innate immune system. It accomplishes this through its high affinity for a subset of the MHC II ligand found on dendritic cells. Once it pairs with this ligand, efti leads to a cascade of anti-tumor cells including cytotoxic CD8 T-cells, NK cells, and monocytes, as well as a significant increase in Interferon-gamma and CXCL10 that further enhance the anti-cancer response from the immune system.

Turning to Slide 6. That powerful anti-cancer immune response that efti drives is shown here across multiple clinical trials and different indications, either as monotherapy in renal cell cancer, in combination with chemotherapy in metastatic breast cancer, or in combination with anti-PD-1 therapy in non-small cell lung cancer.

The one constant among these three trials --- where you see significant increases in cytotoxic CD8 T-cells and other anti-tumor cells, as well as important chemokines and cytokines like interferon-gamma enhancing the anti-cancer immune response --- is efti.

As shown in the middle of the slide, even in the 226-patient randomized Phase II trial for HR-/HER2+ metastatic breast cancer, a notoriously cold and non-immunogenic tumor, subcutaneous administration of efti drove a broad systemic anti-cancer response. Importantly, the statistically significant increase in killer CD8 T cells was directly linked to Overall Survival in these patients.

With respect to efti’s impact on overall survival, we believe a similar positive impact may be unfolding with efti when combined with the largest checkpoint inhibitor on the market today, the anti-PD-1 therapy called pembrolizumab or Keytruda.

More important than our belief is the compelling clinical data in terms of Overall Survival and other key efficacy metrics that was just presented at ESMO. With that I will turn over the call to Christian Mueller, our Senior VP of Strategic Development.

Christian Mueller: Thank you Marc and thank you all for joining us on this important call today to discuss the new exciting results from Part A of the TACTI-002 / KEYNOTE-798 trial for patients with metastatic first line non-small cell lung cancer that were just presented at ESMO in Madrid.

For all those who were not present when Dr. Caracareny presented, the session was completely crowded with people not finding space even in the overflow areas.

I will provide an overview of these very strong clinical results, along with perspective on our registration strategy in this important indication in the next few minutes. After that I will hand back to Marc.

With that, let's jump right into the data.

Slide 8 provides an overview of the study design of TACTI-002, for which we have a clinical supply and collaboration agreement with Merck, also known as MSD outside the US. This Phase 2 trial evaluating the combination of efti with MSD’s anti-PD-1 therapy KEYTRUDA or pembrolizumab, is a multi-center, multi-national study across Europe, Australia, and the United States. Part A is focused on first line therapy for metastatic non-small cell lung cancer patients and as one of the very few trials without chemotherapy recruiting patients of their PD-L1 expression level.

It is worth noting TACTI-002 was established as a Simon’s two-stage design with just 17 patients initially. There were pre-established response levels that needed to be met before expanding to 36 and then to 114 patients. The trial exceeded those levels, and a total 114 patients have been enrolled. This sizable patient population makes the KaplanMeier curves stronger and more robust statistically, and also narrows the confidence intervals, providing assurance in the statistical strength of the encouraging results we will discuss shortly.

One more thing I would like to mention here before moving on is that PD-1 expression levels have a large impact on clinical outcomes for anti-PD-1 therapy. In short, the higher the PD-L1 expression, the better anti-PD-1 therapy works in patients. Conversely, the lower the expression, the less effective or even ineffective anti-PD-1 therapy is. TACTI-002 had only 22 % of pts with high PD-L1 expression with TPS levels above 50 % and then 42 and 36 % with TPS o 1-49 % or < 1 % respectively.

Turning to Slide 9, here we present the encouraging efficacy results in the entire patient population also called ITT of Part A. The strong response rate of 40.4% and high 21.6 month duration of response helped generate an impressive median Overall Survival of 20.2 months in the ITT patient population, after a median follow up of over 2 years. Additionally, we saw an excellent 12-month progression free survival rate of 37.7% and a 3-year overall survival rate of 35.8% in the ITT.

As detailed, the ITT population includes roughly 75% of patients with PD-L1 expression below 50%, meaning it is not expected that anti-PD-1 therapies alone will work.

These results are very encouraging for a chemotherapy-free immuno-oncology combination in an all-comer PD-L1 patient population. Frankly, the overall survival data is superior to many chemo-immune checkpoint combinations in this same patient group for instance as it was reported here at ESMO from the PERLA study with GSKs/MSDs anti-PD-1 plus chemotherapy in a comparable pt population.

Moving to Slide 10. We see what we believe to be the strongest survival data from any dual immuno-oncology combination in a sizable Phase II like this one. Unlike so many IO-IO combinations that are limited to high PD-L1 expressors, the benefit from efti extends across the entire PD-L1 spectrum including to low and negative PD-L1 expressing patients.

On the Overall Survival chart to the right you can see the exceptional durability and high quality of responses exhibited through overall survival across all PD-L1 sub-groups.

The table to the left provides a detailed overview of the superior data in terms of response rates, progression free survival, durability, and overall survival, which truly differentiates efti from most other immuno-oncology candidates being tested with anti-PD-1 therapy.

Let's discuss the three TPS subgroups separately for a moment. In TPS < 1 % where Pembro is not expected to work at all, we have observed an ORR of 31 % translating into median OS of 15.5 months which matches almost the 16.4 months which are reported for pembro for pts with TPS score of 1 % or higher.
In TPS 1-49 % the ORR was 45 % leading to median OS of 23.4 months and then in TPS >= 50 % the ORR of 55 % lead to median OS which is not yet reached and is expected to be well beyond 35 months.

Overall we are more than happy to see that the initial hypothesis we had, that efti could overcome if you want to call it primary resistance to pembro seems to work in all three TPS subgroups. So for us the study is a great success which we would like to turn in to BLA/MAA.

For this let's have a look how it tracks if you combine TPS 1-49 % and TPS >= 50 %. 

Next slide please. In this population we report a median OS of 35.5 months which is unprecedented together with a strong median PFS of 11.2 months, ORR of 48.3%, and an excellent median Duration of Response of 24.2 months. This significant 35.5-month median Overall Survival stands in a class by itself, and we will provide some more context on that shortly.

As shown on the two charts, the 12-month PFS rate and 3-year Overall Survival rate at 46.8% and 45.6%, respectively, are also very promising and highlight the quality and extended duration of these responses.

As this basically means you lift the tail of the curve it could be a key USP for this combination especially compared to chemo-containing regimen.

Of note, we present here data for central TPS measurement but the data for central and local TPS testing provides similar outcome.

Additionally, as you can see here unlike many other IO-IO combinations that only target high PDL1 expressing patients as their results in the low expressing TPS 1-49% group are very weak. This is not the case with efti as is evident with the strong efficacy data in these low expressors, which contributed significantly to overall results in TPS >1%.

So here you can see a very powerful set of clinical data around patients that express any PD-L1, who make up approximately 70% of the non-small cell lung cancer population. This represents a key area for efti’s future development where we have Fast Track designation.

Here on Slide 12 we provide some context on the strength of these results by benchmarking efti+pembro to reported historical results from pembro monotherapy in comparable patient subsets. I would call it Proof of Concept by historical comparison.

As the charts show, Efti+pembro is leading to superior response rates, PFS and Overall Survival across all PD-L1 levels, and this combination is doing so in a relevant fashion with efficacy increasing anywhere from a range of roughly 1.5 to over 2 times the levels for pembro monotherapy.

What is key and again a differentiator for efti as compared to other clinical assets being combined with anti-PD-1 therapies, including anti-TIGIT and even anti-LAG-3, is that the data clearly shows that our results are not only clearly better in high PD-L1 expressing patients, where anti-PD-1 therapies are known to work very well, but also in patients with low expression or TPS 1-49%, where anti-PD-1 therapies have suboptimal responses.

We have often talked about driving superior results through the combination of efti with anti-PD-1 therapies. We have also discussed how we believe we can expand the patient population that can be addressed with anti-PD-1 therapies. Here is an excellent opportunity to highlight that point PD-L1 TPS 1-49% makes up ~35% of the non-small cell lung cancer population. This substantial patient population does not have a viable effective chemo-free immuno-oncology option in the first line setting.

The transformational results that you see here in TPS 1-49, as well as the strength of the results in TPS >50%, offer compelling evidence that efti can substantially increase the number of patients that respond to anti-PD-1 therapy and translate this into improved overall survival.

To provide even further evidence of how powerful the combination of efti plus anti-PD-1 therapy can be, Slide 13 provide benchmarking of efti+pembro versus different chemo containing PD1 regimen across the four key efficacy endpoints: ORR, PFS, DoR and most importantly Overall Survival.

This comparison centers on 1st line NSCLC patients with PD-L1 expression >1%, to focus in on where efti+pembro has received Fast Track designation and we envision further development as we will explain in a sec.

As is clear from the chart on the right, the addition of chemotherapy has a deleterious effect on the duration of response for all therapies shown here. This has been key for us as to why the prospect of a chemo-free regimen of efti+pembro is so enticing and holds so much promise to positively impact patient outcomes in 1st line NSCLC. We are glad to be able to share with you today, that without the use of chemotherapy, the response rates together with the excellent durability of these responses has culminated in a substantially better Overall Survival result for these patients in this historical cross trial comparison. In the end the 35.5 months are unprecedented in this patient population.

Moving to Slide 14, here we benchmark the long term effects in terms of 12 months PFS and 36 months OS rates. The 3-year OS chart shows the 45.6% OS rate at 3 years is well above pembro mono and all chemo-containing regimens, and offers initial evidence that the combination of efti with anti-PD-1 therapies may be uniquely positioned to lift the tail end of the survival curves and lead to more long-term responders.

Moving to the final benchmarking dataset on Slide 15, this one slide sums up the immense potential of efti in the world of immuno-oncology. Simply put, the ability to drive meaningful efficacy without adding toxicity is what every biotech company, including Immutep, strives for. As depicted in the figure the discontinuation rates are similar to pembro alone and much lower than for any chemo containing regimen.

That is what we see here with efti + pembro generating vastly superior Overall Survival results that extends well beyond all standard-of-care regimens, and efti is doing this with an extremely favorable safety profile This is something that we believe the regulators and other stakeholder will consider in the future.

Now we would like to briefly cover the INSIGHT-003 Phase 1 trial

Slide 17 provides an overview of the investigator-initiated Phase 1 trial design that is testing the first triple combination approach utilizing efti in combination with carboplatin/pemetrexed & anti-PD-1 therapy in metastatic non-squamous first line non-small cell lung cancer.

The study is focused predominantly on 1st line nonsquamous NSCLC patients with PD-L1 TPS of less than 50% and is assessing safety, tolerability and initial efficacy. As reported in the abstract at ESMO last week, which has a cutoff date of April 2023, 21 patients have been enrolled and treated. A strong 67% ORR and 91% DCR were detailed in ESMO abstract, which also noted that patients with negative or low PD-L1 status (TPS) showed promising efficacy signals and that the triple combination appears to be feasible and safe.

These results give us continued confidence in the flexibility of efti to be safely combined in various novel formats and enhance various therapeutic approaches for multiple solid tumours. Importantly, INSIGHT-003 may also help to further inform the late-stage trial design options for efti in first line non-small cell lung cancer especially for pts with TPS < 50 %. We will have new data presented in the next 24 hours at ESMO on this promising trial, so stay tuned. This was the last slide with data.

Let's now move to the next steps regarding our registrational strategy and how we see it.

Slide 19 provides a high level overview of the non-small cell lung cancer market, which unfortunately impacts roughly 1.9 million people annually and is the most frequent cause of cancer death.

Well-tolerated treatment options that synergize with SOC and improve outcomes across PD-L1 status, including negative & low PD-L1 tumors, are necessary in frontline NSCLC. Lets have a look into the unmet needs a bit deeper.

Turning to Slide 20, this slide shows how efti is uniquely positioned to address all unmet needs with different concepts presented before. As we have detailed throughout today’s webcast, PD-1 expression levels have substantial impact on clinical outcomes for anti-PD-1 therapy, and the strength of the clinical data presented not only at ESMO but also SITC and ASCO in 2022 shows efti has significant potential to address all PD-L1 levels.

This is important as many dual immuno-oncology combinations that do not rely on chemotherapy have shifted to the high PD-L1 expressors due to sub-optimal results in low PD-L1 expressing patients. This means they are focused on just 25-30% of the market. That is not the case with efti + anti-PD-1 therapy as this powerful combination is driving results even in PD-L1 negative patients.

Based on INSIGHT-003 efti has the potential as shown in Strategy B on the right side of the slide, to create a new standard for 1st line NSCLC patients with TPS <50%. These patients represent 70% of the patient population, and in particular for the PD-L1 negative patients there is a very high unmet need for better therapies.

But pour current focus as we have the largest dataset and the most mature data incl. Overall Survival here is creating an efficacious chemo-free regimen for 1L NSCLC patients with TPS ≥1%. This is where company will move forward in terms of registrational setting as I will explain on the next slide. This part of the population represents about 65 % of the total population and the approach is named here strategy A. Efti would ne uniquely positioned as usually IO only approached do not comprise TPS 1-49 %. So how will a potential P3 look like? Lets move to slide 21.

Turning to Slide 21, Immutep is preparing to conduct a Phase 3 study and has multiple options given the strength of new data presented at ESMO 2023. Before we get into the details let us start of with the principles for the trial design as we see them.
  • Aim is to capture US and EU markets (70-80% of global 1st line NSCLC market)
  • Trial design/timelines subject to Regulatory Authority interactions, Competent Authority approval, stakeholder feedback, as well as partnering discussions
  • Practical implications are:
    • Primary objective will be overall survival and it will have a robust statistical power of 90 % and an alpha of 5 %.
    • Choice of comparator arm will influence sample size, feasibility, commercial aspects
    • Comparator arm should be NCCN 1 category 1 and ESMO recommended
    • Patient population: strength of the data allows for TPS >1%, and also for a potential focus on 1-49% or >50%
  • Sample size & comparator arm will be based on acceptance by Competent Authorities in key global markets, including the US and Europe, and design to ensure good likelihood of success
  • On the right an example is depicted where efti plus anti-PD-1 would be tested against the CM9LA protocol meaning 2 Cycles of chemo plus ipi plus nivo in a 2:1 randomized setting with in total 630 patients. The study would also have a futility build in for a favorable risk/investment approach.
We these details I would like to release you from the data heavy part of the webcast and hand back to Marc.

Marc Voigt: Thanks Christian for that detailed overview.

Slide 23 offers a summarized view of the data covered here today. In summary we are very excited with the excellent overall survival data in front line treatment of metastatic non-small cell lung cancer (NSCLC) achieved by combining efti, our proprietary soluble LAG-3 and MHC Class II agonist, with anti-PD-1 therapy.

The strength of the data across all levels of PD-L1 expression truly differentiates efti + anti-PD-1 from other chemotherapy-free IO-IO combinations, and opens to the door to not only stronger clinical outcomes for patients, but also for significant expansion of the number of patients that respond to anti-PD-1 therapies.

Looking ahead, we have multiple development options to capture the entire NSCLC market by PD-L1 status through chemo-free IO+IO combinations in TPS greater than or equal to 1% or IO+IO+chemo combinations that target low and negative PD-L1 (TPS <50%) patients. Planning around our registrational Phase 3 trial is in progress and under discussion with regulators.

The maturing data from TACTI-002 and the initial data from INSIGHT-003 continues to build our understanding of efti’s ability to boost the innate and adaptive immune system and provides important insights into how efti may ultimately meet diverse 1st line NSCLC patient needs in both chemo and chemo-free settings. In the chemo-free setting, the strength of new data affords us multiple options for efti + anti-PD-1, and our final trial design and patient population will depend on feedback from agencies and other stakeholders.

As you can see on Slide 24, 2023 has been an active year for Immutep, and we are very encouraged with how the clinical data has matured throughout the year culminating with the compelling data we shared today from TACTI-002 as well as the promising initial data from INSIGHT-003 that will be further elucidated in the next 24 hours at ESMO. Stay tuned for that.

One of the key milestones in 2023 was the closing of an $80 million capital raise that provides us a strong cash position and runway to early 2026.

We have several upcoming milestones through the remainder of this year and into 2024 including:
  • New data from INSIGHT-00.
  • Completion of patient enrolment in the randomised TACTI-003 Phase IIb trial, with top-line results to follow
  • Updates from investigator-initiated INSIGHT-005 and EFTISARC-NEO studies
  • IND-enabling studies of IMP761 and the start of clinical development of IMP761
  • Updates from partnered programs
  • Updates regarding expansion of clinical trial pipeline
In summary, the breadth of efficacy and safety data from the large number of metastatic NSCLC patients in the Phase II TACTI-002 trial offers compelling evidence of efti’s substantial impact in safely stimulating the patients’ immune response to fight cancer. As a pure-play LAG-3 company we are quite excited about what the future holds for LAG-3 and its potential positive impact on the lives of patients with cancer and autoimmune diseases by utilizing the power of their own immune systems.

I will pass back to Paul for questions from the analysts who kindly joined us today, so thank you very much.

Paul Sanger: Thank you, Marc, and thank you to your team members. So, as Marc said, we will now open the call for analyst questions. We have quite a lot of analysts on the call today, so please try and keep your questions just to one to start with, and if you don't mind rejoining the queue. If you do want to ask a question, please just raise your hand and I'll get to you as soon as I can. The first question to Marc and team comes from Ahu Damir from Ladenburg. Ahu, over to you.

Ahu Demir: Thank you very much for the presentation and, first of all, I want to say congratulations to the whole team. It's great to see the impressive data, and it hasn't disappointed. It just keeps improving. And also great to see the positive outcome of everyone's hard work. So, wanted to say that first. I'll ask two questions, if I could. My first question is, looking at the ESMO abstract and the data presentation, the data cutout, there is a six months difference that we have noticed, and looking at the improvement on the median overall survival data is significant, especially for the TPS equal and higher to one, one to 49, and as well as 50%. So I am just curious if you could comment on the follow-up periods. What is the longest and shortest period you have followed the patients? Does six months make such striking differences for the data set that we have from 114 patients?

Marc Voigt: Thank you, Ahu. Much appreciated. And, of course, also a very important question to understand the data and how the data tracks. I will make some initial comments and then pass over to Christian. So, last patient in, if I recall correctly, was in November 2021. And when you move forward and observe the patients, some of the patients are, of course, censored, and the longer follow-up time you have, the less censoring occurs. So, the more mature the data is, it shifts the curve based on the Kaplan-Meier formula to the right, so that also the move to the right on this curve can be longer than the difference of the data cut-off, which has been six months, let's say six months. But the move to the right can be much more than those six months. But, Christian, maybe you can explain that in better terms.

Christian: Thank you, Marc, and thank you, Ahu, for the question. I think the easiest is explained on slide number 10. If you look at the blue and the yellow line, you can see that there's quite a plateau between 24 and 36 months, and if this is below the line or above the line can make the difference for the median. And we have seen it in the past that certain patients having longer follow-up can lead to a much more significant impact, as Marc just explained, than the six months. So, that's the main reason. As you just look for one number, the curve itself has moved to the right. And then it's always the question when it basically hits this 50% mark, and this is, obviously, a little bit can move differently than just by the follow-up time increase, if that makes sense.

Ahu Demir: Yeah, it does. Thank you. That's helpful. My second question is more general. So, you have provided some colour on the registrational study. Could you maybe comment on the squamous versus non-squamous? And it sounds like the TPS levels, that you have not finalised the decision yet, so we are curious when you would make the final decision, what would be the timeline for the commencement of the trial, and also the futility analysis, which would be crucial for the trial?

Marc Voigt: Yeah, also very important questions, obviously. So squamous versus non-squamous, we haven't seen material differences between the two, so we wouldn't necessarily split up, but go there with, if you like, a joint patient population. We have, of course, a scenario for the Phase III clinical trial, which we have been showing. It's important to understand that this scenario is subject to further discussions. We had, of course, some with regulators and other stakeholders. The typical discussion points you have there, of course, patient population, TPS greater equal one, which would be very nice to cover as we would then practically double the chemo-free addressable market or, which would also be very validly feasible, focus on one to 49 or greater or equal to 50.

The comparator arm is, of course, always a discussion point. We had a press release earlier this year in May. Also, a discussion with the FDA, and it's pretty clear if you would like to recruit patients in the United States that you have to include as a comparator arm NCCN-1, category one comparator. But there are, of course, a few different ones. We would like to have one which is registered in the European Union in the United States. So, these are discussions where we have a proposal, a robust one based on the statistics. But, of course, we need to listen. We need to see how the precise feedback is based on the data and what is reasonable in order to capture the United States and Europe, so 70% to 80% of the market. And, of course, also to be on target with the patient population and bring together, and this has been our effort from start and we are working on this obviously since a few months.

In terms of feasibility of the trial, if you look at the comparator arm of ipi plus nivo plus two cycles of chemo, in the real world, it's not used that much, but from a feasibility point of view it would be feasible to run a clinical trial. You have to include the marketing perspective, the label, and so on and so forth. So it's a process where you need to carefully listen, adjust. We will definitely not be stubborn. The beauty is that our data allows us to move validly in so many different directions, and we have to balance then our resources and, of course, also some third-party perspectives, which are quite important for decision-making. And we will have a very busy year-end, and we will certainly update the market on how we are tracking and how it will look like till end of this year and early next year. I don't know, Christian, if I forgot any aspect there.

Christian Mueller: No, nothing to add for my side.

Paul Sanger: Ahu, many thanks for your questions. We'll now move to Melissa Benson from Wilsons. Melissa, over to you.

Melissa Benson: Thank you. Morning, team. I just had one particularly focusing in on the PDL-1 negative patients where you saw the median of 15.5 months, you know, with only a third of those patients really responding. Can you give us a flavour, I guess, because we recognise that that might be a bit skewed, the median, can you give us a flavour for that third of patients who did respond? What was their overall survival range looking like?

Marc Voigt: I don't know, Christian, Florian, if one of you would like to take that question.

Christian: Yeah, I can give a general answer. What we have observed in this study is that that's the beauty of that combination, I think, we tried to address in the webcast here and there, that if a patient responds, he or she responds for a very, very long time. And that means also… And this is regardless of TPs. So, also for the patients in TPS less than one, the duration of response is not different than to the other subgroups. And interestingly… not shown here, but interestingly you can suspect that from the data being on the slides, that patients who have a stabilisation of disease also can have a very substantial overall survival.

So, what I'm trying to say here is, for overall response rate, the duration of response, as you can see here also in line number four, it's not much different for TPS less than one. And then if you add the patients with longer duration or longer stabilisation of disease, you also get… some of those will have a pretty good overall survival. Otherwise, you could also not explain the nice overall survival we have as we do not have overall response rate about 50% in two out of these three groups.

Melissa Benson: So, is it correct in saying that that 15 and a half months is undercutting it, if you like, because the non-responders are skewing that down?

Christian: I think it depends a bit. I think the 15.5 looks pretty good and, as said, if you compare it to Pembro alone, where there's no data, but you can compare it against Pembro [indistinct] to 1%, those 15.5 track really well. I think for us, if you look from a development point of view, the initial idea here or the initial good signal is that you see responses which you wouldn't expect with Pembro alone. And now if you think further and you add chemo to it, you may come to a regimen where you have a response rate of 65%, 70% maybe, which then would, obviously, exceed what is out there in the market.

Melissa Benson: Thank you. That's helpful.

Paul Sanger: Melissa, many thanks for your question. We'll now move on to Chris Redhead from goetzpartners in London. Over to you, Chris.

Chris: Yeah. Hi there. It just comes down to… I mean, the lifting of the tail seems to be remarkable that you are seeing the overall response rates at 12 and 36 months being quite similar. That's a very extraordinary result. But the question I wanted to focus on was this idea of the triple therapy and how you think that'll fit in. Because clearly you see, when you add chemo, you get a decrease in the duration of response and just kind of… I don't know what your thoughts are in terms of, maybe it's too early to say, but how you think that would fit into a treatment regime? Because clearly you'd start off without chemo, because that's what's going to get the best duration. At what point do you switch to chemo if the patients don't respond? Just getting your thoughts.

Marc Voigt: Yeah, this is, of course, a very reasonable question as well. We believe, first of all, that we have - this is what the data suggests -- more robust, given the number of patients, also the follow-up time for the chemo-free market. And based on INSIGHT-003, subject to the data tomorrow, for the patients below 50 TPS, that we could capture the whole market, and that the different settings may require different approaches or solutions. So, for a TPS score greater equal one, the chemo-free solution seems to be very valid. And having said that, we, of course, as just explained a minute ago, we see also very strong results below one. But one has to, of course, see what is the competition, what can reasonably be done. And for patients that would potentially require a chemo backbone, this could be an individual question for patients with one to 49. But definitely, typically, for patients below one TPS score, we potentially have also a solution there so that we provide different approaches for different medical problems here. I don't know if anyone from the team, Frederick, Florian, or Christian, would like to add to that.

Christian Mueller: Maybe just quickly from my side, the way I think the investigators and also patients look at it, first of all, you want to have an effective therapy, and for TPS less than one, there are some therapies out there which lead to median overall survival of more than 15.5 months. So, taking the chemotherapy away would not lead to a more efficacious or at least equally efficacious therapy. So, it would probably not be good to do so. And that's why we believe for this subset probably a chemotherapy backbone would be best. And the good thing with efti is, as Marc pointed out, we could address then the whole non-small cell lung cancer market with different approaches and just shift the use of chemo to TPS less than 50 or even only TPS less than one, dependent on the data we see.

Paul Sanger: Thanks for your question, Chris. Let's move on next to Benjamin Paluch from Baird. Benjamin, over to you.

Benjamin Paluch: Hello. Thank you so much for taking the question. Congrats on the data. With the presentation yesterday at ESMO, I was just curious if there was any feedback from doctors that you'd like to highlight.

Marc Voigt: Well, that's a very good question, Benjamin. As Christian said, it was very, very crowded. I believe it's fair to say we got a lot of attention, but why not hear from the horse's mouth, from Christian and Florian?

Christian: Yeah. What you usually have on these conferences is you have two abstracts presented and then you have a discussant, and I think the discussant did a pretty good job in explaining, where's the difference of efti compared to others? And then also pointed out that what we basically do here is we overcome primary resistance to Pembrolizumab as we enlarged the number of patients who could benefit from that part of therapy. She was also impressed by the data, and the only question she had, and that's also what we get from all the PRs we talked to, "Let's make a Phase III."

Benjamin Paluch: Got it. Thank you so much.

Marc Voigt: Thank you, Benjamin.

Paul Sanger: Thanks for your question, Benjamin, and thanks for being patient, David. David Stanton from Jefferies, over to you.

David Stanton: Thanks, team, very much for taking my question. I guess my question's a follow-up and an extension of the previous question. I'd be interested in any feedback you've got from your partner from Merck regarding this data. Thank you.

Marc Voigt: Yeah, of course. Thank you, David. I have to be a bit general here. I believe everyone seeing and discussing the data has a very good reason to be excited and is excited. I mean, if you would like to wish for data, this is almost what you would wish for, I would say. So there, I believe, is a good level of excitement for a variety of different partners, and, of course, we are honoured that we worked here together with Merck, with Keytruda, Pembro being in general a powerful drug and we have a very good relationship since years. And I believe it's fair to say that they are excited as well. But, of course, they would need to speak for themselves.

David Stanton: Thank you and congratulations.

Marc Voigt: Thank you so much.

Paul Sanger: Okay, we've got time for just a couple more questions. Let's move to Thomas Wakim from Bell Potter.

Thomas Joaquin: Thank you all for the presentation and congrats again on this data. I'd just like to focus in on the TPS group greater than 50%. I noticed in the presentation the median overall survival data for this cohort was not yet reached based on the follow-up period, but then in the abstract that was released, I think the data was around 39 months. So, just wondering if you could provide some additional colour there as to that cohort and the overall survival. Thanks.

Marc Voigt: Christian, would you like to take that one?

Christian Mueller: I was offering directly to take that one. We can go exactly to the same slide we just had. It's slide number 10. It shows us pretty nicely. So, if you talk about median, it's always important to keep in mind the per cent of events. And we have 40% of events in the TPS larger or equal to 50, which means that the median itself can move around. You have 60% of the patient are still censored. That's one thing. And the second is then the follow-up time of certain individuals change. And then if you look into the figure, you can see that the black line is right above the median after around above 38 point or 36 point something. That's probably 38.8 months, which means just certain follow-up has been increased. So this curve has basically been lifted, was probably just slightly underneath the 50% mark because of different censoring at the time of the abstract.

And what happens, you see the steps in the curves and the steps get bigger over time, and that's because the patients at risk are less. And then when a patient dies, the percentage basically of that number of patients at risk is bigger. So the impact is bigger. So, if you increase follow-up, those steps get smaller and also at the end of the curve. And then you can have those situations as we have observed here, that we had a median at the time of the abstract and now we don't have a median and it's not yet reached. I think the bottom line for that, I know everybody likes to compare numbers, is the median overall survival for that subgroup will be really, really great, unprecedented, and it may be 39 in the end or it may be 40 something. So, I think time will tell, but the data is unprecedented and really great in that subgroup as well.

Thomas Joaquin: Thanks for your answer.

Paul Sanger: Thanks to everybody for all those questions. That's all we have time for. And on that note, I'll pass back to you, Marc, for final comments.

Marc Voigt: Yeah. Thank you so much and apologies if there were any remaining questions we could not have been answering. But, on behalf of the Immutep team, I would really like to thank everyone for listening today in the United States on a Sunday, very late in Europe, and Monday morning in Australia. And as a reminder, an archive of the webcast will be available shortly on our website. Thank you so much and goodbye.



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