Alkermes plc (ALKS) Earnings Call Transcript & Summary

Greetings. Welcome to the Alkermes Webcast with Expert Oncologist Panel to Discuss Nemvaleukin Alfa at ASCO 2022. My name is Rob, and I'll be your operator for today's call. [Operator Instructions] Please note, this conference is being recorded. I'll now turn the call over to Sandra Coombs, Senior Vice President of Investor Relations and Corporate Affairs. Sandy, you may begin.

Thank you so much. Good morning, and welcome to the Alkermes plc conference call and webcast to discuss clinical data from our ARTISTRY-1 trial that were included in an oral presentation at the 2022 American Society of Clinical Oncology Annual Meeting. Please note that during today's call, we will reference slides that are available on the webcast. If you've not already done so, please go to the Investors section of our site, alkermes.com, to access the webcast player. A PDF of the slides will also be available on our website following the conclusion of the call. During this presentation, we will make forward-looking statements based on our current expectations relating to, among other things, the clinical development of nemvaleukin, the potential therapeutic value of nemvaleukin and the anticipated safety profile of nemvaleukin. These forward-looking statements are neither promises nor guarantees and are subject to a high degree of uncertainty and risk. Please see Slide 2 of the investor presentation accompanying this webcast, our related press release issued last week and our most recent annual report filed with the SEC for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the statements provided on this call as a result of new information or future results or developments. With me today from the company are Richard Pops, our CEO; Jessicca Rege, Vice President, Oncology Clinical Research; and Elizabeth Dorn, Senior Medical Director at Alkermes. We're also delighted to have with us on the call, Dr. Ulka Vaishampayan, lead and presenting author of our ARTISTRY-1 data and Professor, Internal Medicine, Division of Hematology Oncology at the University of Michigan. Also joining us, Dr. Omid Hamid, Co-Director of Cutaneous Oncology; Director of Melanoma Therapeutics and Phase I Immuno-Oncology Program; and Chief of Translational Research and Immunotherapy at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate in Los Angeles. As well as Dr. Thomas Herzog, Professor of Obstetrics and Gynecology, Deputy Director at the University of Cincinnati Cancer Institute and Associate Director, GOG Partners. Today, Jessicca will discuss nemvaleukin differentiated molecular design and mechanism of action. Next, Elizabeth will read -- lead a roundtable discussion with our esteemed panel of clinician thought leaders focused on the ARTISTRY-1 clinical data presented at ASCO. Richard will then end with a brief overview of nemvaleukin's within the development landscape and the company's development strategy. We will open the call for Q&A. However, we will have a hard stop 50 minutes after the hour, and we'll get -- we'll be happy to follow up with any questions we don't get to during the session. I'll now turn the call over to Jess.

Thank you, Sandy. I'd like to start by expressing my appreciation for Dr. Vaishampayan, Dr. Hamid and Dr. Herzog for joining us today. And I look forward to hearing the perspectives related to the nemvaleukin ARTISTRY-1 clinical data set. During today's presentation, I'll highlight the therapeutic potential of the IL-2 pathway and the important differentiating features of nemvaleukin, molecular design and mechanism of action, followed by an overview of the ARTISTRY-1 trial design and the key objectives we set out to achieve with the study. Let's start with why the IL-2 pathway is an important target in the immuno-oncology field. IL-2 is a natural regulator of immune response. Expansion of cancer-killing cells can heighten the body's natural immunologic response to various tumor types and the efficacy of many cancer treatments depends on the robustness of this response. High-dose recombinant human IL-2 was one of the first immuno-oncology agents to be approved. It is an effective treatment, having demonstrated complete and durable responses in select tumors, but significant toxicities have limited its broader use. A long-standing challenge in the field has been to design a molecule that, when delivered at an optimal dose, can leverage the established antitumor effects of high-dose IL-2, while mitigating its hallmark toxicity. Such a molecule could be complementary to a wide range of therapeutic approaches that induce immunogenic cell death. Nemvaleukin is a unique cytokine, designed to capture and expand on the therapeutic benefits of high-dose IL-2 by selectively activating intermediate affinity receptor bearing antitumor effector cells, shown by the blue cells on the right; while mitigating IL-2-associated expansion of immunosuppressive regulatory T cells, or Tregs, shown on the left, as well as mitigating activation of vascular endothelial cells that express the high-affinity IL-2 receptor. Tregs have been associated with dampening of the immune response against cancer, and activation of vascular endothelial cells has been associated with severe toxicities, including vascular leak syndrome and hypotension. To achieve this selectivity for the intermediate affinity IL-2 receptor, we focus on the natural biology of IL-2 and its receptor, which we leveraged to confer differentiated properties to nemvaleukin. By combining the native IL-2 and IL-2 receptor alpha sequences, we engineered a stable fusion protein that is inherently active, does not require metabolic or proteolytic conversion and does not degrade into native IL-2. The IL-2 receptor alpha component sterically occludes nemvaleukin from binding to the high affinity receptor, as shown in the diagram. This unique approach allows nemvaleukin selective for the intermediate affinity IL-2 receptor. This design theory has been supported in practice by the clinical data from ARTISTRY-1. So expansion data from ARTISTRY-1 validates the differentiated pharmacodynamic profile of nemvaleukin resulting from its design. Nemvaleukin has been shown to activate cancer-fighting CD8 T cells and NK cells systemically. Activation and expansion of effector cells in the periphery may be key in driving antitumor efficacy against poorly immunogenic tumors that lack CD8 T cells and NK cells in the tumor microenvironment. Importantly, nemvaleukin selectivity for the intermediate affinity receptor has resulted in only minimal expansion of immunosuppressive Tregs and has also resulted in a differentiated safety and tolerability profile. We believe these features support nemvaleukin's therapeutic potential. ARTISTRY-1 provided an important data that revealed nemvaleukin's differentiated profile. The objectives for the study were clear. First, we aim to validate the molecular design features by demonstrating the dose-dependent and selective expansion of NK and CD8 T cells with negligible effects on the Treg cells. Secondly, we wanted to demonstrate that this immunologic response could translate into antitumor activity. Demonstration of monotherapy anti-tumor activity in tumor types where high-dose IL-2 has proven efficacious was essential to validating the potential therapeutic benefit of nemvaleukin and to support advancing our clinical program. In addition to single-agent antitumor activity, ARTISTRY-1 was designed to evaluate nemvaleukin's potential clinical benefit in combination with pembrolizumab. In a wide range of advanced solid tumors, including both PD-1 approved and unapproved tumors, as well as checkpoint inhibitor experienced patients. Finally, it's imperative for us to establish a differentiated safety and tolerability profile, both as a monotherapy and in combination with pemrbrolizumab, with a particular focus on mitigating the hallmark toxicities associated with high-dose IL-2. ARTISTRY-1 is the first in-human study of IV nemvaleukin. Part A of this global open-label Phase I/II study was the monotherapy dose escalation portion of the study, in which multiple doses of nemvaleukin were evaluated to assess their pharmacokinetic, pharmacodynamic and safety profile in order to determine the recommended Phase II dose. Today, we're going to focus our discussion on the data from the dose-expansion phase that followed Part A, evaluating nemvaleukin as monotherapy and in combination with pembrolizumab. The Part B monotherapy cohort was designed to assess IV nemvaleukin single-agent safety and potential efficacy in 2 tumor types where high-dose IL-2 has demonstrated efficacy: Melanoma and renal cell carcinoma. In contrast to the original studies evaluating high-dose IL-2, which were conducted over more than 20 years ago before the discovery of checkpoint inhibitors and other targeted agents, the majority of the patients in ARTISTRY-1 monotherapy cohort were checkpoint-experienced. These patients had a median of 2 to 3 prior lines of treatment, some patients having upward of 8 prior lines of therapy. Part C was a dose-expansion cohort that evaluated the efficacy and safety of IV nemvaleukin in combination with pembrolizumab across a variety of advanced solid tumors, including in patients with checkpoint-unapproved tumor types and in patients that had progressed or had received prior checkpoint therapy. The majority of patients in Part C were ECOG performance status 1, heavily pretreated with a median of 3 prior lines of therapy. The most common tumor types were non-small cell lung cancer, melanoma and ovarian cancer. All of these factors will be important to consider as we move into the discussion of the overall safety and efficacy for these populations in our roundtable session. With that, I'll now turn it over to our moderator of today's roundtable discussion, Elizabeth Dorn, Senior Medical Director at Alkermes. Elizabeth?

Thank you, Jess. First, I'd like to thank Dr. Vaishampayan, Dr. Hamid and Dr. Herzog for joining us today and sharing their perspectives on the ARTISTRY-1 data set presented here at ASCO. Dr. Vaishampayan is a lead investigator for the ARTISTRY-1 study and a key scientific adviser for Alkermes' cytokine development initiatives. Dr. Hamid is an investigator in our early nemvaleukin development studies and one of our lead PIs for the ARTISTRY-6 melanoma study and was also a key adviser on the design of that potential registration-enabling study. Dr. Herzog is a leading gynecologic oncology expert. And in partnership with Gynecologic Oncology Group, he is our lead PI for the ARTISTRY-7 study and contributed to the design of that study as well. Let's start by focusing on the monotherapy cohort, Part B, where we tested IV nemvaleukin single-agent safety and potential efficacy in 2 tumor types where high-dose IL-2 has demonstrated efficacy, melanoma and renal cell carcinoma. I'll start by focusing on the melanoma cohort, which included a variety of histologies, including cutaneous, mucosal, uveal and acral. My first question is for Dr. Hamid. Dr. Hamid, as a melanoma specialist and working with many early phase studies, what are your thoughts on the data overall, and particularly on the responses we have seen in mucosal melanoma?

Thank you. When I look at the data, it's important to note that mucosal melanomas are very hard to respond to immunotherapy. They have a response rate that's half that of cutaneous melanoma. Despite response with other agents, the duration of response for the majority of the mucosal melanoma patients is short. When I look at this data, the important points to make here is that there were single-agent responses in mucosal melanoma. Those responses have been durable and those responses are associated with minimal toxicity. That makes this a drug that's extremely worthwhile looking at single agent or combinatorial in mucosal melanoma.

Dr. Hamid, can you speak to the importance of the disease control rate in the post checkpoint population? And how you think about disease control rate within the context of treatment decisions that you are making for your patients?

Yes. For immunotherapy, the paradigm is different. It may not always be just response rate. It is the duration of control, the duration of response and the disease control that may indicate a significant survival advantage for early data. What we have seen with other combinatorials or single agents is that, despite the fact that they may have higher initial response rate, the duration of control and the ability to benefit patients has been short. The data we see here with nemvaleukin is extremely important and, associated with its safety, a wonderful data to take forward in this mucosal population.

Thank you so much. Would you please share your perspective on the time to response of those responses we have seen in patients in ARTISTRY-1?

Well, I think in artistry on the time to response for the majority of patients has been very early. When you're looking at imaging every 6 weeks or 9 weeks, and in the first imaging, you see response, that's in line with certain immunotherapies. But also -- and another point is not just early response, but the ability to take these patients to a more -- a deeper response and a more durable response. And we've also seen that with our experience with nemvaleukin.

Thank you, Dr. Hamid. That was very insightful. Moving on to the renal cell carcinoma cohort. Dr. Vaishampayan, as the lead and presenting author of the study and an expert in RCC, could you please comment on the responses we have seen?

Yes, of course. I think seeing the kind of responses we did in kidney cancer, post-immunotherapy is very critical. I mean, currently, immune checkpoint inhibitor is the backbone of treatment for advanced kidney cancer. And high dose IL-2, way in the past, had shown efficacy in advanced kidney cancer. Now to see this kind of response in kidney cancer post immune checkpoint failures, and 3 of the 4 patients had actually gotten combination of immunotherapy with both CTLA-4 antibody and PD-1 antibody. So I think it is a pretty promising response. And with the durability of the response, I think that makes it even more attractive for future development in kidney cancer, potentially as single agent or even as combination with the current toxicity profile that's been shown. In addition, I think compared to high-dose IL-2, this product is way more applicable to majority of our patients, which previously for high-dose IL-2, maybe 10% of my patients qualified in practice because you needed that robust performance status, and age-wise, they needed to be younger, healthier patients. And that does not appear to be a limitation for this product.

Thanks so much. In this cohort, we enrolled both the checkpoint-pretreated and untreated patients. However, all responders are checkpoint-pretreated. Can you speak about these results within the context of their prior therapies?

I think the numbers are too small, frankly, to comment on that. Median pretreatment number of therapies was about 2 and 3 in kidney cancer. So these were significantly pretreated patients. It's sort of in a way good that we are seeing responders in all immune checkpoint pretreated patients because as I said, majority of the patients going forward are going to get an immune checkpoint backbone of treatment, frontline. I think we should potentially build around that and plan for the pretreated setting to sort of -- it strengthens our hypothesis going forward, to plan. And of course the mechanism of action. Obviously, I think the good thing about this is that you can see that there isn't overlap on the -- between the mechanism of action of cytokine therapy like nemvaleukin and immune checkpoint inhibition. So the fact that resistant tumors, to immune checkpoint inhibitors, actually showed a response to nemvaleukin is very promising.

Taking a step back, Dr. Vaishampayan, you have been an investigator on a large number of Phase I oncology studies. In your opinion, how significant is this early demonstration of single-agent activity? And what are your thoughts on this activity within the context of, as you spoke about, the heavily pretreated patients that participated in the ARTISTRY-1 study?

Yes. I mean, I think it looks remarkably promising and it stands out, frankly, within all of our Phase I portfolio frequently. Because typically, even in the dose-escalation phase, we don't expect a whole lot of responses, we're still figuring out the dose, the toxicity, et cetera. But this compound sort of was fairly surprising in a pleasant hey, that not only did it show responses, but even the stable disease patients tended to have really longer remissions and durable remissions. So that, to me, is a big win for immunotherapy type of mechanism, where you're getting a tolerable agent that also showed quite a bit of durability of remission. So I think this kind of response and disease control rate were exceedingly promising. And the other issue is that these were fairly resistant tumors, I mean, GI tumors. And as you heard already, acral and mucosal melanoma, which are typically patients who don't have any other therapies, and that's why they are sort of disproportionately high in a Phase I team for -- they come in for Phase I trials, but we actually saw responses in those. So that, I think, is spelled for a very promising activity of this agent.

Thank you so much for sharing that perspective. Dr. Vaishampayan. We will now shift gears and focus on the data from Part C of ARTISTRY-1, evaluating nemvaleukin in combination with pembrolizumab. This slide shows a summary of all the responders we have seen in the cohort evaluating PD-1/L1 unapproved tumor types. In particular, we are encouraged by the durable responses seen in platinum-resistant ovarian cancer, or PROC, in this cohort. Dr. Herzog, as a leader in this space, what are your initial perceptions of nemvaleukin activity in this tumor type?

Well, thanks, Elizabeth. It's great to be with you this morning. I think that just looking at this table, you can certainly see the number of ovarian cancer patients there listed, which are 4 of them. And 2 of those patients had a complete response and 2 of them had a partial response, 1 of which was unconfirmed. So 4 out of 14 in the ovarian cohort total, which represents 28.6% response rate. So very impressive. Again, in a Phase I trial with all the caveats we just heard about, the difficulties with interpreting signals in Phase I trials. So very encouraging data.

Dr. Herzog, could you tell us a little bit about the unmet need in PROC? And can you talk about what duration of response means within the context of the unmet need?

Yes. So for platinum-resistant ovarian cancer, almost by definition, this is an area of unmet need because the activity that we see in this particular group is not very impressive. If we look at single-agent chemotherapy, we see response rates of 8% to 12%, and we see median progression-free survivals of 3 to 4 months with overall survivals of less than a year. So clearly, this is a group of patients who require novel therapies that are more effective than existing therapies that we currently can offer. So I think to your second question, in this cohort from ARTISTRY-1, in the ovarian cohort, we saw a duration of response of 53.4 weeks, which is really, really impressive. And so this is something that speaks to the tolerability of the regimen, but also the fact that there's clearly a strong signal from an efficacy standpoint that's present.

Thank you. And just building on those comments, how do you think about prolonged stable disease seen in some PROC patients in ARTISTRY-1?

Yes. If you look at the disease control rate, it was actually over 70%, I believe 71%, which is when you take your responders and add in your stable disease. Stable disease for many of these women is actually a reasonable goal in the sense that it likely provides an amelioration or continued amelioration of their symptoms and allows them to go on living their life. And this is in an area, again, where you don't have a lot of options. So there is benefit in terms of observing the stable disease and also fits nicely with the story that there's likely activity signal seen.

Thank you. And Dr. Herzog, one patient recently converted to a complete response after maintaining a partial response for over a year. Do you have any perspectives to share on this patient's time to response?

Yes. So there are 2 complete responders, and 1 of those confirmed was at cycle 6. And then went on to cycle 8 was the first CR. So it was a PR at cycle 6 and then became a complete responder at cycle 8. And then another patient converted at cycle 24 to a complete response. And then by protocol, at 35 cycles, the pembrolizumab was dropped, again, per protocol. And the patient from my understanding is now almost out -- almost 8 months later, still on monotherapy nemvaleukin. So really exciting to see that. And again, speaking, to me, to the tolerability of this. And again, a strong efficacy segment.

Thank you. And just lastly, can you provide your perspective -- actually, just moving on, thank you so much for that. I think, actually, we'd like to move on next to the PD-1/L1 approved tumor types. So here, we've seen responses observed across a range of tumor types, and many responders were heavily pretreated, including some previously treated with checkpoint inhibitors. Dr. Hamid, given our particular interest in melanoma, how do you think about these responses in combination with pembrolizumab, particularly the responses in the treatment-naive melanoma population? And how do these responses give further context to nemvalukin's monotherapy profile in mucosal melanoma?

I'd like to point out that some of these patients with melanoma were heavily pretreated. They had seen prior anti-CTLA-4 therapy. They had seen intratumoral therapy, they have seen anti-PD-1 therapy. And when you add on immunotherapeutics, the risk for toxicity is great. With a driver that targets interleukin-2, the concern for vascular leak or significant IL-2 toxicities leading to discontinuation and minimal dose density is significant. And we didn't see that with this. Repetitive dosing did not lead to significant toxicity, whereas you have a 3% to 4% treatment-related AEs leading to discontinuation. That's low when you look at combinatorial checkpoints giving high rates of grade 3, 4 toxicities in the 50%. That indicates a drug that is great combinatorial, that can be given prior to some of our more toxic regimen. And when you look at these patients that have been on for a significant amount of time, 54 weeks on or 28 weeks on, and having a response that is increasing as time goes on, what you found is an agent that's extremely promising, post-progression of approved therapies and deserves to be earlier in the therapeutic paradigm for melanoma.

Thank you, Dr. Hamid. Dr. Vaishampayan, can you speak to the RCC rollover responses in this data set?

Yes. I think there were some monotherapy responses as well as in the combination. There was one patient rolled over. And there continued to be remission. It's hard to make out what to -- it's hard to figure out what to make of it, it's small numbers. But there are some patients who had some prolonged stable disease and remissions with the combination rollover. But again, there need to be larger numbers to really be conclusive about this.

Thank you. Dr. Herzog. As you can see here, a number of other women's cancers have shown responses with the combination, including cervical and breast cancer. Could you please share your thoughts?

Yes. I'm not surprised in the sense that ovarian cancer has -- we've struggled in terms of seeing a checkpoint inhibitor activity that's been -- certainly that's been able to be carried forward for registration status. So I'm not surprised when you look at other cancers, like cervix, where you see -- where checkpoint inhibitors are already approved, that this combination has promise.

Thank you so much. Thank you all for sharing your insights on the antitumor activity we have seen in the ARTISTRY-1 study. We will continue to watch this data set mature as the majority of responding patients remained on therapy as of the October data cut. We'll now turn to the ARTISTRY-1 safety data. Starting with Dr. Vaishampayan. As an investigator with experience with high-dose IL-2 and many early stage compounds, as you spoke about, can you please share your thoughts on the overall safety profile observed for nemvaleukin?

Yes, of course. I think cytokine, especially high dose IL-2, had this definite concerns about capillary leak syndrome, and having tremendous toxicities with hypotension; nausea; severe fever, chills; and multiple lab abnormalities also, both transaminitis as well as increase in creatinine; at times renal failure, et cetera. So what we've seen and because of that, of course, to take every precaution, we admitted the patients in-patient, so for the first cycle, to see how they did. We monitored them very closely. And I think we were pleasantly surprised that, besides some fever, chills, which were very easy to control, we did not see any significant hypotension or any capillary leak syndrome. So because of that, I think this agent is extremely well tolerated. The half-life is relatively short, about 5 hours. So again, long-standing toxicities or continued ongoing toxicities have not been noted, unlike other immunotherapies, especially the immune checkpoint inhibitors for instance. Also due to this phenomenon of not having continued long-term toxicities, I think we've been able to continue patients on for prolonged periods of time. And as we saw, I think Dr. Herzog mentioned this also, we continue to get benefits. And a PR patient, after 2 months who was in PR, actually turned into a complete response about 18 months since starting treatment. So that, to me, is -- really speaks for the tolerance of this agent as well as the continued benefit.

And Dr. Vaishampayan, this is Jessicca. I just wanted to clarify one of the things. It was in the Part A portion of the trial when we were trying to determine the recommended Phase II dose. We did that inpatient setting. But all of the Part B and C was in an outpatient setting. I just wanted to make sure...

And even in the dose escalation, frankly, after they tolerated the first course, we were able to switch them to outpatient, depending on patient choices and physician choices, of course.

And Dr. Vaishampayan, if I can follow up with you on this slide, you see that neutropenia was a commonly observed adverse event. What do you believe is important to know about how this particular adverse event has manifested with nemvaleukin?

So a lot of neutropenia, as well as cytopenias actually, as well as potentially elevated liver enzymes, those are transient effects that are seen with IL-2 therapies. This neutropenia was -- lasted about 4 days. And there were no other repercussions like febrile neutropenia, no febrile neutropenia, no infections. So to me, this neutropenia was mainly seen because we were monitoring the patients so closely. Every day, they were getting labs, things like that, for a day 1 through day 5 therapy. So some of that is related to this, and it wasn't clinic -- it did not end up being clinically relevant.

Thank you. And Dr. Hamid, you talked about safety earlier. But specifically with your experience treating patients with nemvaleukin, can you discuss clinical management of the adverse events observed with nemvaleukin?

Yes. So my experience has been that these adverse events are manageable just with supportive care. Most are asymptomatic in our patients. They indicated the ability to continue to treat patients and get them the dose density that you need. When you look at the safety of this in comparison with high-dose IL-2, you realize that you've gotten the activity you want without the toxicity. Most of our patients were managed symptomatically. One point to make here is, although this is immunotherapy, this is not a checkpoint inhibition. Where toxicities, when they get to grade 3 or 4 with checkpoint inhibitors, can be durable and need high-dose steroids which may work contra to the immunotherapy. Historically, Interleukin-2 toxicity -- and this is a very important point because interleukin-2 has been out of the clinical armamentarium for so long. Historically, they're resolved it with time and supportive care and do not require steroids. The low incidence of this toxicity is important as we've seen the patients can be dosed and redosed. The durability of the response is inverse to the toxicity, which is a short duration and usually resolved on its own.

Thank you so much. Very insightful. To wrap up the discussion, Slide 19 summarizes all the responses we have seen in ARTISTRY-1. Nemvaleukin has demonstrated durable and deepening responses in a range of tumor types, both as a monotherapy and in combination with pembrolizumab in checkpoint-naive and checkpoint-experienced patients. I'd like to invite each of our thought leaders to share any additional thoughts on the diversity of responses we have seen so far as well as what tumor types or combinations they would consider for future development studies based on these data. Dr. Vaishampayan?

I think to summarize, nemvaleukin has shown remarkable efficacy even in the first-in-human, starting with the dose escalation as well as the expansion cohorts. Proof of principle has occurred with showing monotherapy efficacy data in both melanoma and kidney cancer. I think despite the pretreated patient population that went on, the tolerance was remarkable. I mean, 80-plus year old patients were able to get this therapy and continue on this therapy now 1 year, 2 years, plus rehab patients ongoing. So I think the remarkable tolerance and the promising efficacy really in a broad spectrum of malignancies, to me, is the extreme promise of this agent. It also stands alone. So it wasn't just the combination with immune checkpoint inhibitor therapy where we saw responses, we saw responses in monotherapy also. So that is another sort of big feature that stands out about this agent because it's always tough to separate out whether it was the immune checkpoint inhibitor or not. In addition, in multiple tumors that are sort of -- there's a huge unmet need, such as esophageal cancer -- I mean platinum-resistant ovarian cancer, of course, where the Phase III trial is ongoing; but also in the rarer varieties of melanoma, such as the mucosal and acral melanomas, where immune checkpoint inhibitor therapy does not deliver as much efficacy as cutaneous melanoma, and even in the pretreated cutaneous melanoma, to me, the efficacy was remarkable. I think going forward, besides the 2 tumor types where it's already undergoing clinical trials, there is tremendous potential to develop this agent, starting with kidney cancer, which would be a natural choice; and then of course a number of GI malignancies, pancreas esophageal, sort of -- and colorectal. I mean, there were responses across a broad range of tumors. So I think that might be -- those might be the next tumors to sort of start developing this agent in.

Thank you. Dr. Hamid?

I would say that what we've seen here is nemvaleukin bringing back our attention to Interleukin-2 as an effective therapeutic in melanoma and possibly other cutaneous malignancies. As we've seen, immunotherapeutics have a role with checkpoint inhibition in cutaneous and basal and Merkel. While at ASCO, we've also seen updated data in dual tolerable checkpoint inhibition. The next step is finding a third agent. That third agent needs to be low toxicity, durable response and single-agent activity. And I think drugs like nemvaleukin have stepped into the fore for the whole cutaneous malignancy realm.

Thank you so much. Dr. Herzog.

Well, Elizabeth, thank you again. I think for me, it's really about the depth, the degree and the duration of the response that you're seeing, and that's in conjunction with the really impressive tolerability. And so that really opens up a large spectrum of tumor types that one could look at. Certainly, in the GYN space, endometrial cancer, cervical cancer, all those would be promising with the activity that we see with checkpoint inhibitors already. And then I'm really excited about ovarian cancer because of the unmet need, particularly in platinum-resistant disease. And as the lead PI for ARTISTRY-7, I'm really excited for this Phase III [ GO-GN GOG ] study. So lots of opportunity ahead.

Thank you, Dr. Vaishampayan, Dr. Hamid and Dr. Herzog for your insightful comments and a great discussion here today. Our roundtable panel will be available for Q&A at the end of the call. But first, I will turn the call over to Richard Pops, our CEO. Richard?

Thanks, Elizabeth. I'll be brief. That was a really important conversation. I want to thank also each of Doctors Vaishampayan and Hamid and Herzog for joining us this morning. Even more importantly, I want to thank you for your support and participation in this development program. These are highly credentialed investigators with a range of options, so we're grateful that you're directing your work toward nemvaleukin. So ARTISTRY-1 had an ambitious design. Through it, we've learned a great deal about IV nemvaleukin's profile and its antitumor activity. As outlined on Slide 22, ARTISTRY-1 achieved the goals we set out to achieve. First, the data validated our design hypothesis and demonstrated nemvaleukin's differentiated pharmacokinetic and pharmacodynamic profile with selective expansion of CD8 and NK cells with minimal effect on regulatory T cells, or Tregs. Second, a revealed nemvaleukin's single-agent antitumor activity in tumor types where high-dose IL-2 has proven efficacy, which showed that nemvaleukin, like high-dose IL-2, is a potential cancer treatment in its own right. Also demonstrated activity in nemvaleukin in combination with pembro in multiple tumor types, underscoring the potential clinical benefit of nemvaleukin in combination with other cancer treatments in difficult-to-treat cancers. And as you've heard today repeatedly from the roundtable, duration of response is also an important therapeutic attribute, and it's one that can only be established in the clinic with the passage of time. Lastly, and not less importantly, ARTISTRY-1 showed nemvaleukin's differentiated safety profile, an attenuation of the hallmark toxicities associated with high-dose IL-2. These data provides a foundation for future clinical evaluation of nemvaleukin as we advance in our potential registration-enabling studies. So throughout the development of nemvaleukin, we've been cognizant of other IL-2 variants. We've been consistent in our belief in its differentiation. And now we have the opportunity to advance a potential first-in-class IL-2 variant immunotherapy. The IL-2 pathway remains an important target in oncology for a simple reason, high-dose IL-2 has proven monotherapy efficacy, and characterized by the durability of patient responses. And if its toxicity profile could be attenuated, its underlying mechanism has potential for broader use and could be complementary to a number of cancer treatment options. Nemvaleukin is now the most advanced IL-2-based immunotherapy in the clinic. It is distinguished by its unique molecular design, its resulting pharmacology, observed monotherapy and combination responses and the focused clinical development strategy that we are pursuing. So the progress we've made to date informs our clinical program for 2022 and beyond. Our clinical development strategy is tailored to address key unmet needs as we focus on difficult-to-treat tumor types. We remain focused on enrollment of our 2 potential registration-enabling studies: ARTISTRY-6, evaluating monotherapy in mucosal melanoma; and ARTISTRY-7, evaluating nemvaleukin in combination with pembro in platinum-resistant ovarian cancer. We'll also continue to enroll in ARTISTRY-2 and ARTISTRY-3 to evaluate various dosing regimens, including once weekly subcu dosing and less frequent IV dosing, respectively, in a range of tumor types. This is a focused program in our hands. But we believe that the full promise of an effective, well-tolerated IL-2 variant is its potential to be used in a range of combinations and tumor types. The ARTISTRY-1 data support further clinical evaluation and served as an important foundation as we pursue potential strategic collaborations to further expand the development program. So with that, I'll turn it back over to Sandy to manage the Q&A.

Thanks, Richard. And as I mentioned at the outset of the call, we do have a hard stop at 8:50 a.m. Eastern in order to get our thought leaders on to their next commitment. So we'll likely only have time for 1 or 2 questions. But with that, we'll go right to the queue. And we're happy to address any unanswered questions off-line following the call.

Our first question is from the line of Chris Shibutani with Goldman Sachs.

Appreciate the ARTISTRY-1 data and the comments from the KOLs. I wanted to ask about the ongoing Phase III program, specifically ARTISTRY-7 in the ovarian cancer population. If you go to clinicaltrials.gov, it appears as if the 6 mcg per kilo per day dose will be used. Can you share with us what data you have from the 6 mcg dose population in ARTISTRY-1? Perhaps, how many of those patients received those doses? And perhaps for the KOLs, without framing your response, maybe you could help us understand. You cited historical PFS in the 3- to 4-month range. What would be your expectations for response rates and PFS, what would be impactful? And then lastly, the PD-L1 expression levels. Do you expect to sub-stratify the patients? And will we see data based upon PD-L1 expression from ARTISTRY-7?

Jess, would you chime in first?

Yes, I definitely will start with regards to -- so with regards to specifically ovarian cancer in the 14 patients that we treated, those were treated with 3 micrograms per kg. And 6 micrograms is the recommended Phase II dose. The reason we are using 6 micrograms for ARTISTRY-7 is because that is where we have the established monotherapy activity within the drug. You asked how many patients have been treated with 6-microgram dosing. That was all of our patients in that monotherapy cohort, and many patients within the combination as well. Because as we were going through the dose-escalation portion of the trial, as we cleared the dose level, we allowed the combination to open up. And at the time of enrollment of those ovarian cancer patients, that's where we had 3. And when we looked at the both 3 and 6 data, we actually have seen the benefit does not outweigh the side effect profile. Side effect profile in 3 versus 6 were comparable. So we wanted to give the patients the best chance of success, and that's why we moved forward with the 6-microgram dosing in ARTISTRY-7. I'll hand it over to Tom to -- or Dr. Herzog to address your question on what's the expectation of what you would believe would be clinically meaningful for progression-free survival.

Yes, I'm pretty sure everybody on this call knows it's always a review issue with the FDA. But certainly, we'd be super excited about an extension of at least 3 months, would really be outstanding. But you don't look at just the PFS, which is the investigator-assessed PFS is the primary endpoint on the trial. But you also look at the duration of response, and you have to put that within the context of the toxicity that's seen. So I think all those numbers will come in on this, including the response rate and stable disease and everything else. And when you look at all that in totality, that's really what you need to look at when you take it to the FDA, as you know.

Did you want to comment PD-1 expression for ARTISTRY-7?

Yes, the ARTISTRY-7, I think you had asked about PD-L1 expression. So for ARTISTRY-7, it is one of the stratification factors associated with the trial. So we will have PD-L1 expression on all of the patients for ARTISTRY-7.

Great. And unfortunately, I believe we're at the end of our time. I regret that we didn't get to more of your questions. But want, again, express my appreciation to the -- to our guests today for the insightful discussion. And of course, we are available at the company to answer any follow-up questions. And next year, we will plan for more time. Thanks so much.

Thank you for having us.

Thank you, Dr. Vaishampayan.

Thank you. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.