Immutep TACTI-002 and INSIGHT Clinical Results & Update

Company Presentations

Immutep Limited (ASX:IMM) Executive Director and CEO Marc Voigt, Chief Scientific and Medical Officer Dr Frédéric Triebel, and Director of Clinical Development and Regulatory Affairs Christian Mueller present on Immutep's latest clinical results. 

Clive Tompkins: Good morning, everyone, and thank you for joining us at the Immutep (ASX:IMM) investor call today. Where we'll discuss the company's clinical results from the TACTI-002 and INSIGHT-004 studies of its lead product candidate, eftilagimod alpha. Clive Tompkins here. I'll be your moderator on the call today. The format will be a presentation delivered by Immutep. At the end of the presentation, we'll open the call for analyst questions. I'll also relay any other questions received via email prior to this call. I'd now like to hand over to Marc Voigt, Immutep's CEO, to start the presentation. Marc, are you there?

Marc Voigt: Yes. Thank you, Clive. Actually, I'm here, and welcome everyone. So, here you can see our forward-looking statement. Before we dive into the data, just briefly an overview. And also, of course, I should mention that joining me from the Immutep management team today are Frédéric Triebel, who is our CMO and CSO, immunologist and oncologist. And Christian Mueller, our Vice President of Strategic Development. So, we are very pleased to walk you through the encouraging data we reported from two clinical trials, as Clive said: TACTI-002 and INSIGHT-004. And, of course, we have a number of other clinical trials running, and we will focus, however, today on those trials which have been presented recently at ASCO.

Our company, as you know, is operationally active in the United States and Australia and Europe. We are active in immuno-oncology as well as an autoimmune diseases. And possibly most importantly, we have a global leadership position for LAG-3. You will not find any other company, including big pharma, with four programs around LAG-3, and also a broad intellectual property and know-how basis.

First of all, I have to mention Frédéric again, and would like to highlight him here. He is the worldwide leading scientists for LAG-3, devoted 30 years of his career to LAG-3. Immunologist, oncologist, well over 140 publications. And has been obviously contributing to the medical change, and also is a pioneer in immuno-oncology.

Turning now to slide six, you see that already over the years LAG-3 has drawn increasing interest from pharma and different academic groups. On the left-hand side, you can see the acceleration in the number of scientific papers published on LAG-3. And this increase goes hand in hand with an acceleration in the number of clinical trials and of LAG-3-related products that have been contacted. And our expectation is, especially now given the validation by Bristol Myers Squibb, that the interest and the investment will continue to accelerate and will be stronger in the future. And we are significantly contributing to the data, and obviously to the knowledge around LAG-3.

This is also a very important slide, the LAG-3 therapeutic landscape. Our programs are visible here in green, the green arrows. Two at the bottom in autoimmune diseases, two unique programs. Unique is also eftilagimod alpha, we will come to that. And then middle of this page, you'll see a number of blue bars and one green bar. These are the antagonistic antibodies or blocking antibodies. Our licensee Novartis, with their program. And clearly leading in that specific space is Bristol Myers Squibb with Relatlimab. And it's great that they reported clinically meaningful data and first-line melanoma in a trial called Relativity-47. Has been delivering results in terms of median progression-free survival. More than double the median progression-free survival versus OPDIVO monotherapy. No overlap of the confidence intervals, so they delivered in a clinically meaningful way. And this means that the LAG-3 MHC Class II interaction has now been validated. And this is, of course, an important point. It doesn't happen too often in the space. You may recall 2011, CTLA-4, 14, 15 PD1. And then it took another six, seven years to come now to LAG-3.

Back to what we are doing, which is exciting enough. Here you see our four different programs, two on the right-hand side, positioned in autoimmune diseases, depleting cytotoxic antibody exclusively worldwide out-licensed to GlaxoSmithKline. And then the world's first agonist to LAG-3, temporarily silencing the T cells troublemakers in more than 90 per cent of autoimmune diseases. Obviously chronically LAG-3 activated in a unique program at the preclinical stage. And then on the left-hand side, you see at the bottom the program we have been out-licensing some years ago to Novartis, traditional concept of blocking LAG-3 on the T cell. And today we will focus, of course, on our flagship eftilagimod alpha, or efti, which is a unique antigen presenting cell activator. And with that, I would like to hand over to Frédéric.

Frédéric Triebel: Thanks, Marc. First of all, I would to talk a bit about the LAG-3 biology, especially as we have been frequently asked about this in the past weeks. On slide nine, look at LAG-3 and the interaction between MHC Class II and LAG-3 in greater detail. As we can see, LAG-3 is a homodimer expressed on activated T cell, and a co-inhibitor receptor, now called an immune checkpoint, physically associated with the T cell receptor in the immunological synapse connecting a T cell to an APC. There LAG-3 down regulate this receptor signaling, but only when it is engaged by its ligand, MHC Class II molecules. In vivo, LAG-3 is expressed on a few cells. It's expressed on activated T and NK cells in a few inflamed tissues in the body as its expression is strictly regulated.

In practice, LAG-3 is found on memory effector CD4 or CD8 cells, as well as on induced Tregs, which are antigenic experienced T cells as well, at sites of chronic inflammation-like tumours. The T cell at the tumour sites or in the draining lymph node have been repeatedly stimulated through the T cell receptor with one or a few immunodominant tumour peptides. And then they become exhausted and express LAG-3. So, LAG-3 is an exhaustion marker. This makes it a very good target for immuno-oncology as LAG-3 expression is in fact mainly restricted to a tumour-specific memory T cells that infiltrate the tumour bed.

We will now talk more about efti. Slide 11 gives more detail on efti's unique approach. On the right-hand side, you see an antagonist antibody, like of course Relatlimab from BMS, or leramilimab from Novartis that blocks MHC Class II / LAG-3 interaction

I would like now to comment on the recent Relatlimab placebo phase III PFS results in first-line melanoma. Besides the validation of the physiological importance of the LAG-3 / MHC Class II interaction at controlling tumour growth, the question now is not really whether the rela plus nivo combination will replace the ipi plus nivo in melanoma, but rather whether this new combination will work in many different carcinomas as well. Personally, I am pretty optimistic. And this combination has a good chance to work in these less immunogenic tumour types. Indeed, good prognostics markers in melanoma, like high expression of LAG-3 on T cells at the tumour site, or high PDL-1 expression on tumour cells, are not required to see the full activity of the combination, auguring well for future use of this combination in carcinomas.

Either way, on Immutep's side we announced recently we have identified small molecules that mimic the action of this blocking LAG-3 antibodies. And this, through a collaboration with Cardiff University. We believe that these new LAG-3 / MHC Class II blockers may represent the next wave of IO products in a more distant future. Their development in the clinic will, in any case, be greatly facilitated by the results of the ongoing clinical research testing, different blocking LAG-3 antibodies in many different indications.

Going back to efti in the left-hand side, efti is the only antigen presenting cell activator targeting MHC Class II receptors in clinical development. Its mode of action is different to the blocking LAG-3 antibodies, which we see here on the right. Essentially, efti pushes the accelerator on the body's own immune responses the physiological way by first activating dendritic cells that become in a few hours better and more professional antigen presenting cells. This systemic activation of the dendritic cell network in the body boosts memory CD8+ T cell responses, and activates its multiple immune cell subsets, including NK cells, leading to a broader immune response compared to the blocking LAG-3 antibodies you see on the right-hand side.

Now, based on our clinical and preclinical research to date, we believe efti offers a pipeline in a product, and has disruptive potential across a number of indications. It has strong potential synergies with all our therapeutic agents, such as other immuno-oncology agents like PD-1 or PD-L1 antagonists, or chemotherapies. Efti also has several other potential benefits. It has a very strong safety profile, it has a unique IP position, not like the blocking antibodies. To date, all efficacy data has been encouraging. And it has a low cost of goods, which is very important when considering drug pricing. So, overall, efti has a very compelling profile.

Turning to slide 13, these tables show our diverse program of clinical trials for efti. A key objective of efti development has been to pursue multiple trials, multiple indications, and to evaluate multiple combinations.

We will now provide you with a short overview of the TACTI-002 clinical trial, and the results we reported over the weekend at ASCO. But first, I would like to comment on slide 15. In terms of clinical trials testing new IO-IO combinations, it is important to first assess the status of the pre-existing natural T cell response at the tumour site, as these T cell responses vary widely from one patient to another.

The best marker for a strong ongoing immunosurveillance that may limit tumour growth is the production of interferon gamma by activated T cells recruited at the tumour site. As interferon gamma is a labile cytokine difficult to detect by immunohistochemistry, oncologists are now used to quantifying the percentage of tumour cells expressing PD-L1, a surrogate marker in use by interferon gamma locally.

In carcinomas, it is well known that the patients more likely to response to anti PD-1 therapy are the ones with the so-called "hot tumour" phenotype. And, very often, with more than 90 per cent of tumour cells expressing the PD-L1 marker. Due to the strong pre-existing T cell responses at the tumour site, just removing one inhibitory interaction is then enough to induce long-lasting clinical benefit.

As mentioned before, efti is an APC activator, and has therefore a different mode of action by pushing on the accelerator of the immune response. And this could be beneficial to other tumour subtypes, namely the "tepid" or "cold" tumour subtypes. And this is relevant for our TACTI-002 study, which is a PD-L1 all-comer study. Meaning that patients could participate without being pre-screened for their PD-L1 expression at the tumour site, and was open to patients with hot, tepid and cold tumours. For the trial design and actual results, I will turn it now to Christian.

Christian Mueller: Turning now to slide number 16. Our TACTI-002 study is being conducted in collaboration with Merck Sharp & Dohme, known as MSD. TACTI-002 is testing a combination of efti with MSD's drug Keytruda, also known as Pembrolizumab, in up to 183 patients at sites in Europe, the US and in Australia. More importantly, the trial recruits in three different settings. Part A comprises treatment naive patients with advanced/metastatic non-small cell lung carcinoma. Part B enrols with advanced non-small cell lung carcinoma who have progressed on prior PD-1 or PDL-1 therapy. And very important to you to know is that this is confirmed by two consecutive scans before enrolment, allowing only truly refractory patients to be recruited. And finally, in part C, we have recruited patients with recurrent metastatic head and neck squamous cell carcinoma after failure of prior platinum-based therapy.

The primary endpoint, so overall response rate, is measured according to iRECIST, which is an accepted standard in trials involving only immunotherapies. It is an open label trial with a Simon's 2 stage design, and this has the advantage that cohorts can be expanded in case positive results are observed. We have completed stage one for all the three different parts, and all parts have been expanded based on positive data previously reported. Stage two of part A and C are fully recruited as well. And this is where we actually show data here today. Currently, the trial is recruiting into part B stage two, and into a 74-patient extension for part A.

We will now today present safety results and efficacy updates of part A and C during this webcast.

Let's start with the safety aspect on slide 17. This data reflects results from all 115 patients who were enrolled in the study at the time of data cut-off, which was 16th April 2021. Of all, we have continued to be very happy with the safety profile here, reported from efti in combination with Pembrolizumab. There have been no treatment related death, and the percentage of patients discontinuing the therapy due to adverse reactions remains very low. The strong safety profile compares favourably to other combination treatment regimens containing two immune therapies, or chemotherapy and immunotherapy, as illustrated on the table on the right-hand side, and we believe this gives us a great advantage on the competitive edge.

Looking more closely now at the non-small cell lung cancer landscape. There's a high unmet medical need amongst these patients for well tolerated and efficacious treatment, despite all the progress made in the last decade. There are approximately 1.8 million diagnoses each year worldwide, and approximately 1.3 million develop metastatic disease, and are generally eligible to receive anti-PD-1 or anti-PD-L1 therapy, such as Pembrolizumab. The flow chart on the bottom of the slide shows the typical treatment path for patients. Existing treatments have considerable challenges. There's, on the one-hand side, single anti-PD-1, PD-L1 therapy, which has only modest efficacy in about 70 per cent of patients who have a PD-L1 expression of less than 50 per cent. And on the other-hand inside, the combination of doublet chemo + PD-1 or PD-L1 is more efficacious, but leads to substantial additive toxicity. And doublet chemo alone doesn't provide the same efficacy as the combination with anti-PD-1.

So, overall, there's still a huge unmet medical need, as already described before. Moving to slide 19 now, here we outline the baseline characteristics for part A. So, the first-line non-small cell lung cancer patients. The trial was designed to be unselected for PD-L1 expression, as Frédéric explained. Which is quite rare actually, as most of the trials focused on patients with PD-L1 expression larger or equal to 50 per cent TPS. In TACTI-002, we had patients across the whole PD-L1 expression spectrum. In general, the median age was 65 years, and about 58 per cent had an ECOG of 1. The vast majority were previous and current smokers, and around 40 per cent of the patients had squamous disease, and close to 60 had a non-squamous type.

Let's now move to the right side and to the results. The patients were staged locally, first of all, and treatment decisions were based on the local read. The results for that are shown in column number 2 and have been published previously. Then, the tumour scans were analysed by blinded independent central read, abbreviated here as BICR. This was done retrospectively. According to the BICR, the overall response rate for the full analysis population was 41.7 per cent, including two patients with a complete response. And the disease control rate was 69 per cent. Both are slightly higher compared to what has been reported by investigators locally, which is quite encouraging. As there were a few patients who left prior to the first staging on the trial, we also calculated the overall response rate for all patients who had at least one post baseline scan. This population is the evaluable population. And here, the overall response rate, according to BICR, is about 48 per cent.

To see responses is important, but even more important than that is the duration and the deepness of the responses, as this is decisive for the long-term efficacy and the benefit in the end. And this is presented to you in slide number 20. In the left figure, the so-called spider plot illustrates the individual patient's response over time. The different colours indicate the best response of a particular patient. White indicates progression, grey indicates stable disease, yellow/green indicates partial response, and blue indicates a complete response. And the arrows shown here indicate that the patient is still on treatment, or progression-free survival follow-up if the treatment is completed. As you can see, seven patients are continuing on therapy, and one patient has actually already completed the full two years of therapy.

Let's have a look now into the quality of the responses. So 92 per cent of the responses were confirmed, and 58 per cent of the confirmed responses are still ongoing. More importantly, none of the responses progressed within six months after the response was observed, and the expected median duration of response is expected to be 13 plus months. The graph on the right-hand side, the so-called waterfall plot, shows the deepness of the responses and the detailed PD-L1 status. As you can see, there were responses in the 1- 49 TPS group, and notably also a complete response in a patient with 0 per cent PD-L1 expression. Overall, 72 per cent of the patients had a decrease in target lesions.

And then the question is, what does this mean? And we have been asked frequently by analysts to benchmark our data. As TACTI-002 is an non-randomised trial, we do this here against historical controls from published keynote studies. We'll also be aware that historical comparisons should be interpreted with caution. But nevertheless, we believe it's important. We would like to make two distinct comparisons. First of all, against pembrolizumab monotherapy, to see if there's a potential synergistic effect of adding efti to pembro, which is why the trial has been conducted. In the keynote 42 study, a comparable patient population was involved, except they didn't allow PD-L1 negative patients. And, as a second comparison, we are benchmarking our data against the current standard of chemo + pembro, to show how the combination efti plus pembro may compete here.

Let's start with the combination against pembrolizumab alone, which is the most important one for us. Pembro alone has an overall response rate of about 17 to 20 per cent, if you look at a PL-L1 all-comer setting, as displayed in the bar on the right side. And as this is derived from two different studies, as the keynote 42 didn't include PD-L1 negatives, there's a little bit of a range shift for pembrolizumab alone. As you can see, the response rate for efti plus pembro is a little bit more than double what you would expect with pembro alone. And then if you look into progression-free survival, you can have a look into patients with a high PD-L1 expression, which means a TPS of 50 per cent or more. And here, the median PFS for pembro alone is about 7.1 months. And for efti plus pembro, this is about 11.8 months, so quite a substantial increase here.

Overall, the overall response and PFS are increased and we have seen responses in PD-L1 negative patients, which is not seen frequently with pembro alone, and the safety profile seems to be comparable. So, overall, we are quite encouraged by the data we have seen here in TACTI-002, compared to pembrolizumab alone.

If you now come to the second comparison against the current standard of care, the addition of pembro to chemo increases its efficacy, as you can see in the two columns on the right side. And there are two columns here for pembro plus chemo, as there's a different chemo backbone for squamous and for non-squamous. That's why this is split up here.

The addition of pembrolizumab to chemo introduces a substantial additional toxicity and decreases the duration of response pembro has alone, if given alone. So, there remains a high unmet medical need for these patients. The median PFS, if you look at it, for the overall population is in the same range. So, you have 8.2 months for pembro plus efti, and then you have 9.0 months for the non-squamous part and 6.4 for the squamous part if you look for the chemo plus pembro combination, and this is also true if you look at the high PD-L1 expressors, where, in the TACTI-002 trial, the median PFS is about 11.8 months versus 11.1 and 8.0.

As a conclusion, we are really deeply encouraged by the data observed so far, and looking forward, having the data from the extension as quickly as possible to decide on the next steps.

Turning now to head and neck squamous cell carcinoma on slide 22. There are over half a million people diagnosed with the disease each year and approximately 350,000 develop metastatic disease. Despite many recent improvements, especially with PD-1 in the first and second line setting, the high unmet medical need persists. And median overall survival rates are barely above 12 months for the first line setting. Essentially, the need for an effective treatment is even higher than for non-small cell lung cancer.

Looking at slide number 23, we present the results from the second line head and neck squamous cell carcinoma patients. As reported previously, patients are pretreated with platinum-based chemotherapy and almost half with cetuximab. About 66 per cent have an ECOG of 1, and the median age is 62 years, and about 90 per cent are males. In the trial, patients with all different pathologies were enrolled. Responses according to iRECIST are detailed on the right-hand side with the cut-off date 16th April 2021. And we are pleased to report that out of the 11 patients with a response, which in itself is quite substantial, five had a complete response. The overall response rate is 30 per cent in the full analysis set and 36 in the valuable patient population. We are really truly excited about the OR, which is double the OR one could expect from pembro alone, as reported in historical chemo trials.

And again, the same story here. It's not about a response itself. It's really about the quality of the responses. And on slide 24, the spider plot follows the individual patient response again, with blue indicating the complete responders. The responses are long-lasting, and some patients will reach the two-year treatment landmark soon. At the time of cut-off, nine patients were still on the treatment. The waterfall plot on the right shows the patient responses are deep and are also occurring in patients with a low CPS score. And in total, as mentioned, we have five patients with a complete disappearance of all target lesions. The median duration of response cannot be estimated yet, as shown in the Kaplan-Meier plot on the right bottom, but we are encouraged that 80 per cent of the confirmed responses are still ongoing. And then the two patients with an event, the progression occurred well beyond the six months landmark.

On slide 25, we look further at the efficacy results. in this case, PFS. In the full analysis set unselected for PD-L1, median PFS is about 2.1 months, and the overall median OS is about 12.6 months at data cut-off. If you then select only the patients with a CPS score of one or higher, the overall response rate increases to 46 per cent, and the median PFS to 4.1 months, as indicated by the green line in the Kaplan-Meier plot. Even though this is already really encouraging, we feel that the PFS rates at six and 12 months are decisive and may be a potential key differentiator, and obviously quite encouraging.

Let's have a look what it means against historical controls and how one could potentially position efti plus pembro in the current treatment landscape.

As for the non-small cell lung cancer part, we were asked to benchmark the data, and I would like to point to the same disclaimer I made for the non-small cell lung cancer part. The bar graph on the right-hand side compares to pembro monotherapy activity in patients with CPS of one or higher compared to the results in TACTI-002, and you can see that the overall response rate increases from 17 to 46 per cent, and the complete response rate increases from 2 to 21 per cent. And, as we discussed, this is also seen in the PFS and DOS. We are very pleased by the results, which also paved the way for the fast track designation we received from the USFDA for the first line head and neck in this combination. It also enables us to extend the collaboration with MSD and start TACTI-003 in the first line setting.

We are very eager to start recruitment, and Marc will give a quick update on this part, and then he will also elaborate a bit on the current treatment landscape. But before we come to this, let me just quickly summarise the data the IKF presented for the INSIGHT Trial.

INSIGHT-004 is a phase I dose escalation study evaluating efti in combination with the anti-PD-L1 avelumab, conducted under our collaboration agreement with Merck KGaA Germany and Pfizer, who are co-developing and co-commercialising avelumab. INSIGHT-004 is the fourth arm, also called Stratum D, of the investigator-initiated INSIGHT trial, which is conducted in Frankfurt, Germany. Twelve patients participated in the trial, which was conducted in Frankfurt. They received six months of combination treatment, followed by six months of avelumab monotherapy. Safety was the primary objective, and efficacy was reported as secondary outcomes.

Let's have a look on the data. On slide number 29, we present the key final results from the INSIGHT trial, as they were presented during the ASCO from the investigator and discussed during an oral presentation. With regards to safety, there were no dose-limiting toxicities and no new safety signals from the combination of efti with the standard dose of avelumab. Forty-two per cent of patients showed a partial response, and responses were observed across a range of indications, including gastroesophageal cancer and mesothelioma, which are not typically responding to anti-PD-1/PD-L1 therapy. The majority of the patients are still alive, and the IKF concluded that the treatment with efti and avelumab was safe, with promising signals of efficacy, and efti avelumab seems to be a potent combination for enhancing PD-L1-directed therapy and needs further evaluation.

Separately, we have announced recently a new collaboration agreement with Merck Germany to conduct a new phase I/IIa trial, evaluating efti and bintrafuspalfa, called INSIGHT-004. Marc will elaborate on this soon.

I would like to thank you for your attention, and will now hand over to Marc, who will start with the competitive landscape and then come to the outlook. Marc.

Marc Voigt:
Yes, Christian. Thank you. And, first of all, looking here at slide 31, we have mapped out the cancer therapy landscape. I think most of you are aware of that, including checkpoint inhibitors, or CAR T cell therapies. And you'll see that eftlagimod sits within the group of antigen presenting cells activators, or APC activators, and it has no direct competition on its mode of action. So, it's not an ME2 approach. As powerful as anti-PD-1 is, as great as we are excited about anti-LAG-3, these are only two approaches. So, eftilagimod is unique. No one else is doing that. And, of course, this is explained by the fact that we have very strong intellectual property and know-how. There is no other MHC class two agonist under development.

So, efti has an excellent safety profile, as we just learned. And this is, of course, key looking at the different combinations with chemotherapy, with other IO options. Frédéric pointed earlier on to the potentially low cost of goods and the ongoing pharmacoeconomical debate. And, especially in the post-COVID era, if we are allowed to talk about that already, of course drug pricing will be in question, so that eftilagimod not only fits into today's treatment landscape, but, from a potential cost of goods point of view, also route of administration -- it's given subcutaneously -- a point of view also into the treatment landscape of tomorrow. So, given all this, we believe efti is very well positioned and has a chance to become the next big thing in oncology, actually.

So, this brings us now to the summary and our outlook. On slide 33, Christian has been pointing to that earlier on, we have been putting together some, if you like, benchmarks, or some data for first line head and neck cancer. So, obviously, the setting we aim to improve with TACTI-003. Despite some good progress in the past years, there is still a high unmet medical need for a therapy with good duration of response in combination with a higher overall response rate and an improved overall survival, with a comparable safety profile, for instance, like Keytruda alone.

And, regarding the response rate, it's noteworthy that Keytruda had 19 per cent overall response rate in >=1 CPS, or if you like PD-L1 expression, in the keynote study. So, this slide here shows obviously the first line head and neck cancer setting, and you may recall the second line data, which has just been presented, with, for instance, median overall survival in second line of 12.6 months, or a response rate of round about 30 per cent. Of course, one always has to be careful with comparisons based on paper, but I can just say that we are very, very eager to start TACTI-003 and to report data in the next year.

Now turning to slide 34, this is the trial design of TACTI-003 in first line head and neck cancer. It's an important study for us. We have been granted fast-track designation, as Christian mentioned, by the FDA in April. And while fast track in the US is granted in oncology, let's say, relatively often, it's maybe not so often that you receive it in absence of data. So, we haven't treated, obviously, first line head and neck cancer patients, but second line head and neck cancer patients. Still, we received fast track. And this is, of course, good and would enable us to more frequent interactions with the FDA, to a potentially accelerated approval if the data is good enough. So, it's quite useful and valuable to have that in place. The study will be conducted in collaboration with US Merck or MSD. It will be a randomised study involving up to 154 patients across multiple sites worldwide. And, you would certainly agree, we can rely on the clinical trial site network from TACTI-002, and the primary endpoint will be the overall response rate.

You see here also, there are two cohorts. Cohort A is a main cohort. So, this is the randomised part where the vast majority of the patients will be recruited. And then we have satellite cohort B, looking at patients with practically no PD-L1 expression, so a more experimental arm. And we are rapidly advancing our planning, or, I should say, study startup preparations, and it should commence very soon. So, it's practically around the corner. Now, this is another new clinical trial at the phase I/IIa INSIGHT-005 clinical studies. So it's an investigator-initiated trial where Merck, KGA, and GlaxoSmithKline, and Immutep are supporting IKF, Krankenhaus Nordwest, to conduct a study with 12 patients in three cohorts, bintrafusp alfa plus eftilagimod, and the primary end point will be, of course, it's a phase I/IIa, safety, but also we will look, of course, at overall response rate, progression-free survival, so some activity parameters.

Now, the news flow in 2021 will continue to be very strong, as you can see here on slide 36. I think everyone was very excited by the recent validation of the LAG-3 MHC class II interaction. And it's great that we can work on a validated basis and that LAG-3 is in the spotlight. So, of course, we will continue to deliver in the future.

As you can see, we expect to report final overall survivor data from AIPAC. We hope for data updates from TACTI-002. We will continue to recruit patients into part A, into the extension, so the 74 patients. And I can say that we actually are recruiting better than originally anticipated, which is not so often in the clinical development, especially during COVID. And it's maybe a sign that our principal investigators are also very supportive of the treatment concept they have experienced.

We will also start recruitment for the first line head and neck cancer trial, TACTI-003. So, there might be a number of operational updates, also inside 005. In addition, and we should not forget about it, of course, this call is focused on eftilagimod, but also IMP761, our preclinical asset, the world's first agonist to LAG-3. There, we would like to provide also some updates and also from our partners.

So, it will be very busy for us in the second half of this year, and we feel obliged to speed up and to deliver as much as we can.

So, to summarise, I can keep it relatively short here, but, of course, I need to mention that we are the only LAG-3 pure play. We have more programs around LAG-3 than anyone else. We have multiple active clinical trials. We have good collaborations with different pharma partners, such as Novartis, Merck in the US, Merck in Germany, Pfizer, GlaxoSmithKline, LabCorp, and others. And, of course, we will aim to deliver data again. And, yes, this brings us to the end of the presentation, and I would like to thank, of course, Frédéric and Christian for their contributions, and will now pass back to Clive. Thank you.

Clive Tompkins: Thanks, Marc. Our first question today comes from Ahu Demir. I hope I've pronounced that correctly. Ahu, you're from Landenberg. Please go ahead with your question.

Ahu Demir: Thank you very much for taking my question. I would like to first congratulate the Immutep team for the progress and the data. My first question will be on the non-small cell lung cancer. Considering the recent approval of the triplet combination in the first line of non-small cell lung cancer and the favourable safety profile of LAG-3 targeting, are you planning to assess the triple combination of PD-1, chemo, and LAG-3, as it will be more compelling than CTLA4? And also when should we expect any data or any developmental activities on that front?

Marc Voigt: Thank you, Ahu. It's a very interesting question. A triple combination of anti-PD-1, eftilagimod and chemotherapy. And, actually, we have been receiving this question quite frequently, and some listeners have been providing that question also in advance. It's indeed something which we are actively internally discussing and evaluating different settings.

I have to say, though, that in first line non-small cell lung cancer, if you look already at the data from anti-PD-1 and efti in absence of chemotherapy, it looks actually pretty strong. So, to expand that by another combination partner with chemotherapy could make sense. It's not a must, given that we deliver it within the ballpark or better than what you can see with certain approved drugs. So, we can challenge approved first line settings, but again, you have to discuss that. We are doing that, and this is ongoing. We will certainly come at the right point in time to some conclusions, and then talk about that more publicly.

Ahu Demir: That sounds great, Marc. Thank you. I have one more question, then I'll pass it to the following participants. My second question is I think you have an advantage on perhaps assessing PD-1, PD-L1 combination synergies with efti that other companies do not have that advantage. So, I'm curious if you have seen any distinct synergies combining PD-1 versus PD-L1?

Marc Voigt: I think we have been delivering in both settings. Of course, to be fair, the combination with anti-PD-1, so pembrolizumab in this case, there we have much more data compared to avelumab. And, with all fairness, I think one has to say that the anti-PD-1 drugs like Keytruda, Opdivo are dominating the space.

Simply, the clinical data needs to tell. There seem to be similarities in the safety, so that eftilagimod in both settings is not adding a lot of toxicity. Nothing really severe, I would say. In terms of efficacy it's, of course, hard to compare with avelumab, between the 12 patients in different tumour types, while we have, of course, non-small cell lung cancer, head and neck cancer, and metastatic melanoma data from different clinical trials with anti-PD-1.

Ahu Demir: Thank you, Marc. I'll rejoin the queue. Thank you.

Marc Voigt: Thank you, Ahu.

Clive Tompkins: Thank you. Next question from Tanushree Jain at Bill Potter. Tanushree?

Tanushree Jain: Thanks, Clive, and congratulations to the Immutep team for really strong results coming out of TACTI-002. My first question is just on the non-small cell lung cancer. If you could perhaps talk to us about what's the current percentage of population who would receive the chemo plus Keytruda combination, versus just the Keytruda monotherapy. And, given the results that you've seen so far, what percentage of population do you think the efti plus Keytruda combo would be best suited to?

Marc Voigt: Thank you. Christian, would you like to take the question?

Christian Mueller: Thank you, Marc. That's a very good question. I think there are two different parts to it, so let's start with the first one. I think it depends from country to country and the reimbursement scheme you have. Typically, the approvals are for more than 1 per cent for pembrolizumab, but, typically used, pembrolizumab monotherapy is only for patients with a TPS score of 50 per cent or higher, which is about 30 per cent of the patient population.

In case the chemo plus pembro is approved and reimbursed, that will be used for the majority of the other patients. And it depends also on some other aspects, if it's a squamous or non-squamous tumour. In terms of the distribution, as I said, it's about one third, a little bit less than that, for high PD-L1 expressors, and about 70 per cent for patients with less than 50 per cent TPS expression.

Tanushree Jain: Great. And then, just the second question, in terms of the competitive landscape, we've got some data now coming out of the TIGIT compounds in combination with anti-PD-1. And I think -- correct me if I'm wrong -- but it looks like they've been shown to be more efficacious in the over 50 per cent population. Can you just comment on where you see those results versus what you've seen so far in your trial, in non-small cell lung cancer?

Christian Mueller: Yeah, I think there are two different aspects of that as well. It's a very good question. For the TIGIT data, you'll see there are two major TIGIT candidates which have reported results. Let's look for the one where you have randomised data. There you can clearly see that the increase in PFS and then response to it is solidly in the high PD-L1 expressors. So, that will probably, as Marc also mentioned earlier and Frédéric mentioned with the hot tumours, that would probably be the target for anti-TIGIT compounds, from my perspective.

How do we want to position efti is something we are discussing quite extensively internally, and was one of the reasons why we actually opened up the extension in part A, in order to have more patients. Basically, you have squamous, non-squamous and you have less than 1 per cent, 1 to 49, and above 50 per cent you have a couple of different cohorts, and you really want to know in which setting you have the best chance to move forward into registrational setting.

Tanushree Jain: And just between squamous and non-squamous, are you seeing a particular difference so far in the results?

Christian Mueller: I don't think it has been disclosed publicly, and nothing I would really like to comment on at this stage.

Marc Voigt: I think it's fair to say that we delivered in both settings, but of course, looking then at the subgroups, the numbers are of course smaller, and this is why we need to recruit more patients to have a very robust and solid basis to answer the question of specific tumour types like squamous, non-squamous. But we are at the point where we can't exclude the one or the other, let me phrase it this way.

Tanushree Jain: And just last question, just with the encouraging data coming out of the Relatlimab cohort, any thoughts around in melanoma to start with combining with an anti-LAG-3 like Relatlimab and efti and an anti-PD-1 or an anti-PD-L1?

Marc Voigt: To answer that, we have been asked quite a lot "What about melanoma?", as we have been delivering interesting data in our TACTI-mel clinical trial. It's published. It's an open question. We, of course, wouldn't give anti-LAG-3 and eftilagimod together, but in combination with anti-PD-1, as we had in TACTI-mel, could make sense. We have to make choices, and we decided to move forward in a head and neck cancer and the non-small cell lung cancer. The data justifies that. The good thing is that we have other options, which we just need to rule out based on resources and focus.

Tanushree Jain: Marc, is there anything which prevents you to combine an anti-LAG-3 with an efti?

Marc Voigt: Yes. That's the nature of efti and the nature of the anti-LAG-3, because efti are the four extra cellular domains of LAG-3. So, anti-LAG-3 would inhibit efti, so you would not give the two together. You would give it together with anti-PD-1, with chemotherapy. You can give it with radiation with all different options, but not with anti-LAG-3.

Tanushree Jain: OK, great. Thank you.

Clive Tompkins: Next question from Chris Redhead at Goetzpartners Securities. Chris?

Chris Redhead: Yeah. Great data, a couple of questions. Are you doing anything in terms of biomarkers, in terms of being able to stratify patients that respond or don't respond? I don't know whether there are biomarkers here. Just be interesting to know what you're doing in that regard.

Marc Voigt: Indeed. We are looking at a number of different panels and immune settings. Obviously, we would like to show that we can overcome some, let's say limitations, from anti-PD-1 therapies like low TPS or CPS score. And this is obviously related to anti-PD-1. We're obviously looking at that. If you would look, for instance, to try to measure in which patients eftilagimod would have imitations, these would be typically patients with monocytopenia. Maybe 1, 2, 3 per cent of the patients where you have nothing to activate of course eftilagimod could not work, but that's a very, very small patient population, so low single digit per cent. And you can't compare that to a PD-L1 biomarker or a LAG-3 biomarker, which is not relevant for eftilagimod, but for anti-LAG-3.

We are looking at different other things. We're looking at parameters like CD4, CD8 and K cell. Data has been published around that. And it's in general an ongoing debate, and also it's interesting, the biomarker debate. And I believe it will continue, based also on Relatlimab, because there was no strong, if any, biomarker correlation from Relatlimab. And this is something which needs to be further investigated in that setting. It took also a few years for PD-L1, which is less stable than, for instance, LAG-3, to come up to relatively robust tests and settings. So, we are looking at different things. There is very small limitation and we will continue to investigate that in the future.

Chris Redhead: Yeah, and just a follow-on. The one thing that seems to be very intriguing for me is the idea that the LAG-3 appears to have synergy with a number... potentially with chemotherapy. You can see that with some of the data from the AIPAC, particularly, when the chemo was being applied, you saw the shift in the curve. That's kind of something that's interesting, but also the new trial that you've got with German Merck. German Merck have a number of other… an interesting pipeline of various immuno-oncology products, particularly DNA repair. Is that something that, potentially, is there a fit there or not?

Marc Voigt: There could be a number of different fits. The beauty of eftilagimod is also the safety profile, and this follows also the rationale from the mode of action, so it's an MHC class II agonist. So, unlike, for instance, the blocking antibodies, where you need to have close to a hundred per cent receptor occupancy, meaning that you need to give possibly as much drug as you can, and then finetune. Here, we do not need to go to DLT or MTD. We simply go to the biologically effective dosage, and 1, 2, 3 per cent receptor occupancy in terms of MHC class II are good enough as we simply send, if you like, a positive push to the antigen presenting cells. And this opens from a safety point of view, which is for anti-CTLA4 limitation, a variety of different options. Will it work everywhere? Certainly not, but we could explore a number of different settings.

And, of course, the challenge for us is to identify the right settings, do the right robust clinical trial design. And, of course, there was interest in... external interest, I should say, in a variety of different areas. Yeah, we need to make choices. But, in general, it's most important that we move forward towards registration, and bring the product to the market as fast as we can, reasonably can.

Chris Redhead: Thanks.

Clive Tompkins: Next question from Matt Cross at Alliance Global Partners. Matt?

Matt Cross: Hi, all. Thanks for capping off ASCO this year with the webcast. Appreciate that. And congrats again on the data. Just a couple of questions from me, one on non-small cell and one about your solid tumour portfolio more generally.

I guess, as you know, it's been a common topic on the call about the potential positioning of efti within non-small cell. There was an interesting case-based panel discussion at ASCO this year exactly on this topic of checkpoint inhibitor use in frontline metastatic non-small cell. And I think it was interesting to see that, overwhelmingly, outside of cases where PD-L1 expression status was not only above 50 per cent, but somewhere in the order of 80 or 90 per cent, chemo plus pembro was still viewed widely by physicians as the preferred regimen where PD-1, PD-L1 monotherapy or something like Ipi/Nivo was only preferred in, again, those was very high PD-L1 expressors. So, I'm curious as we're thinking about the efti positioning, whether there's a similar situation where the approval standards are certainly one thing, but commercialisation, whether you think physicians are receptive to the use of an IO/IO combo with pembro-efti in patients that are not quite 80, 90, very high PD-L1 expressors, if maybe the tolerability, the really great tolerability, actually, that we've seen from efti plus pembro is persuasive enough to convince physicians to maybe give an IO/IO a shot compared to some of the others in the landscape.

And I know that's a lot, but the second question I had was on solid tumours generally. It seems like there's been kind of some controversy at this year's conference as well and for quite some time on the use of PFS or DFS end points as surrogates for overall survival. Curious as we're looking at the stage two aspects of TACTI-002 and possibly blinded randomised studies ahead, what your take is on the use of progression event-free survival type end points versus survival in terms of approval. Thanks.

Marc Voigt: Thank you, Matt. Frédéric, would you like to comment on PFS in different indications and relevance for OS?

Frédéric Triebel: Yes. In general, looking at what happened in the past with anti-3-4 and anti-P1 in melanoma, good PFS leads to even better OS. In carcinomas, the situation has been quite different. If you look at the survival in non-small cell lung cancer at three years, or even worse, at five years, few patients are still alive. And the problem is that when you add chemo to anti-PD-1, it has a detrimental effect and the very prolonged responses, clinical responses in use by the activated T cells are not seen anymore, and, therefore, the results in terms of OS are not very good.

Now, what are we going to do in terms of registration trials down the line is not decided yet. It's all about evidence-based medicine and a way we'll have the results from one of them and patients. And so we look at different subgroups, the three PD-L1 subgroups, the squamous, non-squamous, and decide where to go next. At the moment, it's too early to discuss this, I believe.

Matt Cross: Great. No, I appreciate that, Frédéric. Good to have your input and know there's plenty to be decided with the FDA. I guess, any thoughts on the use of pembro-efti and kind of the risk of needing to convince physicians that IO/IO combos do have use outside of very high PD-L1 expressors may be based on the tolerability data that you've shown relative to the pembro chemo mainstays.

Frédéric Triebel: It's not only about tolerability, it's mainly about efficacy as well. I mean, we have seen good responses in TACTI-002 in less than 1 per cent in 1 to 49 as well, so across the range of PD-L1 expression. And this you don't get with IO/IO combination in general.

Marc Voigt: I would like to add, Matt, that I think it's a good point regarding tolerability. If you look simply at our practical experience, and this means recruitment. If the current PIs in three different countries, actually, are supportive, and I think we can say, yes, the recruitment is better than we anticipated, which is always a good sign, and unfortunately rare in our industry. And, of course, it's also, for the investigators, a risk-benefit assessment. And looking at our safety data, I think it's quite a strong argument to test that. I think there was... when pembro chemo was approved, there was some hesitation around the toxicity. And if you have a good argument with as good or better efficacy, then I think it's a striking thing for regulators, for reimbursement, as you do not need to have maybe co-medications, and of course, most importantly, for the patients.

Matt Cross: Absolutely. Agreed. Thanks, Marc. I think that's why I, to some degree, stressed that the tolerability angle just... Given that, clearly, based on what we saw at ASCO from these surveys, physicians were seemingly willing to manage the tolerability challenges of pembro with chemo purely on the basis, I guess, of the level of response that they see. But if you're able to surpass, or at least, as you put it, be in the same ballpark with far better tolerability, I think that's really differentiating. So, congrats again on the very competitive data.

Marc Voigt: Great. Thank you, Matt.

Clive Tompkins: Next question. Dennis Hulme from Taylor Collison. Dennis?

Dennis Hulme: Thanks very much. My first questions, Marc, are about TACTI-003. Can you just update us on the status of the trial commencement, when you expect to recruit the first patients, how much do you expect the trial to cost and do you have targets about how many patients you'd recruit into cohorts A versus cohort B in that trial?

Marc Voigt: Yeah. Hi, Dennis. Thank you. First of all, how many patients should be recruited? In total, 154, and maybe in the cohort B, we have 20 or maximum 24 patients. So, the vast majority, let's say 130 or 134, will be in the first cohort. The study startup preparations are commencing. We are underway. We made very good progress. Country selection. All these things have been partly done already. And then you need to do the filing to the national regulatory authorities. This is underway, so that we can commence the study, start the study, mid of this year. So, the period we are already in or approaching. So, within the next very few months, we should see a good progress there.

In terms of cost of the study, this is, I would say, round about $10 million US, maybe a bit more. Depends also how you calculate, and at the end of the day, where you will recruit the patients. We should not forget that, in Australia, we get 43.5 per cent R&D tax incentive. In Europe, at least in certain European countries, you get 30 per cent tax incentive. And this is a scheme which, for instance, in the quite frankly speaking, most important market, in the United States, is not existing. So, it will depend also at the end of the day where we will recruit most patients.

Dennis Hulme: OK. Thank you. And, I guess, at ASCO, there was some mention of efti treatment related discontinuations. Can you give us a little bit of colour around that?

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

Christian Mueller: What we have reported at ASCO is the data as it has been reported by the investigator. So, what typically happens, the patient discontinues the treatment due to an adverse event, and then the investigator decides if he or she believes that this adverse event is possibly related to efti or to pembrolizumab. And there were a couple of occasions where the investigator decided that there is a chance of possibly likely related to efti. If I'm not mistaken, there were two patients who discontinued due to adverse reactions, but in general, what's important is not if the investigator decides that if it's related to efti or not. I think what's important is the total number of patients discontinuing the study treatment due to adverse events. And here, we see a similar percentage compared to pembrolizumab monotherapy, and not what you would expect with double IO or chemo plus pembrolizumab. I think that's what's important.

Dennis Hulme: Yeah. I take your point on the low discontinuation rate, but are you able to give any colour as the sort of events which the investigators thought might have been due to efti?

Christian Mueller: We could definitely provide that after the call.

Dennis Hulme: OK. Thanks very much. And, looking at the efti/avelumab combo, you had some very encouraging data there. Are you looking to do any further studies of efti combined with avelumab or with any other checkpoint inhibitors?

Marc Voigt: Yeah, this is also, of course, a good question. And we will evaluate this further, of course. The current data and the avelumab -- it's practically final data --and the avelumab combination would actually suggest, as this was the conclusion from Professor Goetze presenting at ASCO, to do the next clinical investigation there. Of course, it's not only clinical data, but multiple different other points which are coming into play if you want to move forward in terms of clinical development, like resources, partnerships, and focus, and also the active decision where you believe the drug would be positioned best and where you would allocate your resources, especially in the light of moving forward towards registration. And, of course, this is a decision-making process. We are not at the end, the same with melanoma and some other optionalities which we have been discussing, like triple combination, but at a given point in time, we will also make a decision there and then either move forward or not.

Dennis Hulme: OK. Thanks very much. So, my final question is, I know we're expecting additional clinical data from TACTI-002 in the second half of the year. Can you give any guidance as to when we might see the next update from TACTI-002?

Marc Voigt: Yeah. So, typically, as we continue to recruit, continue to generate data, I would rather believe more towards fourth quarter than in third quarter. No final decision there yet, but I think, in general, that would make sense to have a meaningful and a reasonable update rather in that quarter than the third one.

Dennis Hulme: Thanks very much. That's all from me.

Marc Voigt: Dennis, thank you.

Clive Tompkins: OK. And last question, Marc, perhaps from Naureen Quibria.

Naureen Quibria: I'll make this quick. And Marc and team, congratulations, especially to Dr Frédéric Triebel for his work on LAG-3 and his contributions and finally seeing that reward right now. Everybody's basically asked my question, all my questions, actually, but I was curious in terms of now that there is a pretty crowded LAG-3 competitive space, even though efti is unique in its MOA and so forth, are there other catalysts or are there any events outside of Immutep that we should be looking at in terms of paying attention to, just as we did with ASCO and BMS's Relatlimab?

Marc Voigt: Yeah. In terms of the LAG-3 space, we expect this to be much more vibrant and active. The reality is, if you look back the past five, six, seven years, the most active data contributor has been Immutep, actually, not BMS. And this was now, I would say, a splash they made with the phase III, very successful, which is good. We congratulate them. And they have been announcing, I believe, yesterday, in the post-ASCO discussion, that they look also at other settings in phase II, and also looking at a combination of anti-PD-1, anti-LAG-3 plus chemotherapy, if I'm not mistaken. The debate is ongoing in terms of the competitive positioning. I think, in melanoma, from our perspective, it's relatively clear, given the big safety advantage versus YERVOY plus OPDIVO. But I think we will see at the coming major conferences, meaning possibly at ESMO, at SITC, at some other conferences, more LAG-3 data than we have seen in the past, which was always very painful for us, as we believe it might be a similar pattern to PD-1, where there was limited data beforehand, and then, once it was a success, everyone tried to move forward and tried to push forward.

Naureen Quibria: Great. Thank you, Marc. That's it for me.

Marc Voigt: Naureen, thanks a lot.

Clive Tompkins: OK, and Marc, I think that is it for questions today, based on the time that we have. I'll hand back to you.

Marc Voigt: Yeah, thank you. And I apologise as we have been running over time, and I have to apologise also, we have been receiving other questions, for instance, from Boris Peaker from Cowen, from others, which we are not able to answer just given the time. I appreciate that every one of you took the time, and I simply say goodbye, thank you, and we will hear in the second half from Immutep as well, I'm sure. Bye-bye.

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