Cue Biopharma, Inc. (CUE) Earnings Call Transcript & Summary

Greetings, and welcome to the Cue Biopharma update call. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the conference over to Dan Passeri, Cue Biopharma's Chief Executive Officer. Thank you. You may begin.

Okay. Thank you, and good afternoon, everyone. We appreciate your time and interest in our update call regarding recent data and observations from our ongoing clinical trials of CUE-101, which is our first drug candidate representative of the IL-2-based CUE-100 series. Joining me on today's call is Dr. Anish Suri, our President and Chief Scientific Officer; Dr. Ken Pienta, our acting Chief Medical Officer; and Dr. Matteo Levisetti, our Senior Vice President of Clinical Development. So this conference is being recorded and will be available on our website for the next 30 days. As a reminder, and as shown here on Slide #2, this presentation and overview may contain some forward-looking statements. And any forward-looking statement made during this call represents the company's views only as of today, January 26, 2022. Okay. Our agenda for today's call is shown on the next slide, Slide #3. As an introduction, I'll be providing a brief overview of our observations to date before turning the call over to Anish, who will elaborate upon the underlying characteristics of our approach and more specifically the features of our IL-2-based CUE-100 series. As background context, it's important to remember that no matter what therapeutic modality is being developed and tested by the numerous companies within the immuno-oncology sector, whether that's a checkpoint inhibitor, cell-based therapeutics, bispecifics, cytokine therapies such as IL-2, et cetera, it's primarily the cancer-specific T cells that provide the therapeutic effect and clinical benefit. As Anish will elaborate upon momentarily, there are 2 critical components to achieving the desired therapeutic effect without the adverse side effects that often limit therapeutic activity. First, the patient must have the requisite cancer-specific T cells necessary to fight the tumor, albeit typically present at extremely low numbers. And these T cells are often exhausted, hence, the presence of cancer. Second, in order to avoid the adverse side effects from cytokines, such as IL-2, it's essential to provide selective and specific activation of only those cancer-specific T cells. We believe that the data generated to date for CUE-101 supports the premise that our IL-2 CUE-100 series possesses the required features and properties for effective and selective immune activation of cancer-killing T cells. After Anish's presentation, Matteo and Ken will provide an overview and status update of the emerging results from our ongoing Phase I trial of CUE-101. Ken and Matteo will show you that in our monotherapy trial, we currently have a clinical benefit rate of 50% in our combination study. We have 2 partial responses in the 4 patients that have been dosed to date between 2 milligrams per kg and 4 milligrams per kg. The data generated thus far supports our mechanistic premise that CUE-101 is stimulating the patient's immune system in a selective and cancer-relevant manner, resulting in what appears to be a very encouraging trend in overall median survival of the 46 patients in our monotherapy dose escalation and expansion cohorts. Ken and Matteo will further elaborate on these meaningful metrics momentarily. This emerging data is highly encouraging and, while still early, enhances our belief that CUE-101 enables mechanistic synergy with checkpoint blockade, further reinforced by emerging pharmacodynamic or PD data, demonstrating targeted CD8-positive T cell activation directly in the patient's body. Given this developing clinical data, we believe we are very well positioned to emerge as a highly differentiated solution provider, addressing the pressing needs of enhancing patient reach and therapeutic benefit derived from checkpoint inhibitors and other immunotherapy approaches. With that, I'll now turn the call over to Anish, who will briefly discuss the key foundational features of our Immuno-STAT platform. Anish?

Thanks, Dan, and good afternoon to all listening to this call. The next slide, Slide 4, exemplifies the obligatory need and challenges for selective T cell activation to drive successful outcomes of cancer immunotherapy. Appreciation of this need is of particular importance since an extremely small fraction of a patient's entire T cell repertoire, likely less than 0.1%, is tumor-specific. Hence, nonspecific modulation of all T cells without a bias towards the tumor-specific T cells, via modalities like checkpoint inhibitors of cytokines or bispecific T cell engagers, will continue to generate suboptimal outcomes for patients. We believe, and as Ken and Matteo will convey, that our IL-2-based CUE-100 series enables selective targeting, activation and proliferation of cancer-specific immune cells directly in the patient's body, achieving well-tolerated and effective therapeutic dose levels. With that background, let's move to the next slide, Slide 5, which briefly describes the Immuno-STAT platform that was designed to achieve specific modulation of cancer-specific T cells through rational and proprietary protein engineering. As shown here, the core framework of an Immuno-STAT molecule has a stabilized peptide HLA or pHLA component that selectively only engages those T cells that harbor T cell receptors for tumor-specific peptides. In addition, the Immuno-STAT molecule contains activating signals like cytokines, such as IL-2, that can be selectively delivered to tumor-specific T cells. This core protein framework is built upon an Fc backbone that provides significant structural stability. Modularity is a major strength of the Immuno-STAT framework that allows us to target diverse tumor antigens, along with safety, delivering a breadth of activating signals. This specific and selective modulation of cancer-relevant T cells, while circumventing global immune activation, allows us to achieve therapeutic dosing of highly immunoreactive signals, such as the cytokine IL-2. Furthermore, immunocyte molecules are manufactured with much ease and efficiency, using well-defined processes for antibody and execution proteins. We will comment more on manufacturability and stability towards the end of this presentation. Okay. So the next slide, Slide 6, exemplifies the challenges of IL-2 therapy, which are centered on lack of selectivity and indiscriminate activation, resulting in poor tolerability. As shown here, the primary challenge with wild type IL-2 or the different IL-2 variants in development is the fact that these molecules will still indiscriminately engage the vast majority of CD8-positive T cells with little relevance to the minor fraction of tumor-specific T cells. This lack of selectivity results in the broad activation of the immune compartment with no relevance to tumor specificity, hence creating a significant barrier for extracting the fullest benefit from IL-2 treatment. To maximize the fullest potential of IL-2 for cancer therapy, we designed the CUE-100 series Immuno-STAT, as shown in the next slide, Slide 7. The CUE-100 series Immuno-STAT selectively biased IL-2 to the tumor-specific T cells while avoiding the systemic activation of all T cells. As shown in the cartoon on the left and in the ribbon structure on the right, the CUE-100 series Immuno-STATs contains stabilized peptide HLA molecules, along with modified IL-2 molecules. The IL-2 variant is affinity-attenuated to selectively act upon tumor-specific T cells whose TCR is engaged to the peptide HLA component of the Immuno-STAT. If the TCR is not engaged, as would be the case with the vast majority of non-tumor-specific T cells shown in green, then the figure from the IL-2 variant on its own is relatively weak. Hence, the CUE-100 series is a molecular scaffold that exploits both TCR and IL-2 signals for biased activation of tumor-specific T cells. Importantly, the modularity of the CUE-100 series allows us to generate diverse therapeutic molecules containing different tumor antigens to target many cancers. The data emerging from the monotherapy and combination Phase I trials with our lead clinical candidate, CUE-101, support the premise that selective activation of the cancer-relevant T cell repertoire will not only expand patient reach but also enhance the therapeutic effect of checkpoint inhibition. Furthermore, the data from CUE-101 provides derisking and validation not only for CUE-101 per se, but for the CUE-100 series as an off-the-shelf, stable and easily-manufactured class of therapeutics. After Ken and Matteo present the clinical data for CUE-101, I will return to further elaborate upon our competitive positioning as well as addressing some of the ongoing challenges of cancer immunity pertaining to tumor heterogeneity and resistance mechanisms with our derivative programs. I will now turn the call over to Matteo to update you on CUE-101, our first Immuno-STAT as proof of principle of delivering an ideal therapeutic. Matteo?

Thanks, Anish. We're pleased to be presenting our updated data from the ongoing CUE-101 Phase I trial as both a single-agent monotherapy in third line and beyond as well as early data emerging from the combination study with pembrolizumab in first-line patients. As just conveyed by Anish, we believe that CUE-101's mechanism of action, as evidenced by the data sets generated to date, provides for effective and tolerated dose levels, enabling selective stimulation of the patient's immune system. I will begin this section by providing a synopsis and background to the ongoing trials, and then Ken will review the most recent data and discuss potential clinical implications supporting prospective paths towards registration. As seen on Slide 8, CUE-101, our first-in-human lead clinical candidate, is designed to selectively prime and expand HPV-E7-specific T cells. HPV-16 E7 protein is a primary driver of tumorigenesis and is a highly conserved T cell epitope, making it an ideal target for immunotherapy development. As we have previously reported, we have chosen to develop CUE-101 for the treatment of HPV positive head and neck cancer. We are utilizing CUE-101 as monotherapy in third line head and neck recurrent metastatic cancer and first line in combination with pembrolizumab. The molecular design of CUE-101 enables us to identify eligible patients based on HLA-A02 positivity and HPV-16 positivity for the tumor. As always, we would like to thank our principal investigators and the participating -- and the patients participating in our ongoing clinical trials. As we have noted on previous update calls, we have continued to successfully screen and enroll HPV-positive head and neck cancer patients to participate in our CUE-101 clinical trial throughout the COVID-19 pandemic, in large measure due to the commitment and convictions of our staff and our principal investigators to bring promising therapeutics to patients in need. The next slide, Slide 9, provides a high-level summary of the observations made over the course of the dose escalation part of the study. 38 patients were treated across 7 dose escalation cohorts without a maximal tolerated dose being identified. At SITC, we reported that we have robust PK with dose proportional exposure that is sustained across repeat dosing. Specifically, there is no evidence of drug clearing antibodies. We have previously reported the expansion of disease-relevant T cells in the blood of patients and evidence of tumor T cell infiltration on biopsies of tumors. On Slide 10, I want to emphasize the safety and tolerability of CUE-101 in patients, both as a monotherapy and an early combination with pembrolizumab. Our presumed recommended Phase II dose of 4 milligrams per kilogram appears to be well tolerated in the target population. Our first cohort of patients in the combination study at CUE-101 dosed at 1 milligram per kilogram and second cohort at 2 milligrams per kilogram did not experience any dose-limiting toxicities, and we are now enrolling the third cohort at 4 mgs per kilogram of CUE-101 with -- in combination with the approved dose of 200 milligrams of pembrolizumab given every 3 weeks. All of the SAEs and AEs observed to date are consistent with those that are observed with IL-2 administration or are typical of those observed with checkpoint inhibitors in the treatment of cancer patients. The most common AEs observed continued to be fatigue, anemia and decreased lymphocyte counts. Of note, no events of capillary leak syndrome or severe cytokine storm have been observed to date. I will now turn the call over to Ken to review some of our more recent and updated data. Ken?

Thank you, Matteo, and good afternoon, everyone. In our third-line monotherapy trial shown on Slide 11, 17 patients have been dosed at our presumed RP2D of 4 mgs per kg. We all recognize that PRs and CRs occur in a relatively low frequency in third line and beyond the HPV-positive head and neck squamous cell carcinoma patients. But in the 14 patients evaluable to date, we have observed one confirmed PR in 6 patients with confirmed stable disease lasting for more than 12 weeks, resulting in a clinical benefit rate of 50%. As shown at SITC in the next slide, Slide 12, the spider plot demonstrates the one patient with a PR as well as disease stabilization in other patients. Although the other stable disease patients have not crossed the threshold to a PR, these patients remain on study, and we are actively following them. We anticipate completing enrollment of the expansion cohort over the next few months. Additional data on the patient with the confirmed PR treated at the presumed RP2D of 4 mgs per kg is shown on Slide 13, demonstrating a very durable response now lasting for greater than 36 weeks, and the patient continues treatment in the trial. Increases in HPV-E7-specific CD8 T cells were observed in this patient on cycle 1, day 8, following treatment in the absence of increases in total CD4 and CD8 T cell populations measured in the peripheral blood. This finding is consistent with the high degree of selectivity that CUE-101 has for activating and expanding disease-relevant T cells and not inducing a general nonspecific state of immune activation. Consistent with the data we reported at SITC, sustained increases in NK cells were observed in this patient as well with only a modest and transient increase in Tregs. Increases in NK cell numbers are a consistent finding across patients dosed with CUE-101, and the effect increased in a dose-dependent manner from 1 mg per kg up to the RP2D of 4 mgs per kg. Of note, cell-free HPV DNA, a potential biomarker of emerging interest, was reduced by approximately 100% compared to baseline and coincided with the observed decrease in tumor measurements. On Slide 14, the next slide, examples of remarkable E7-specific T cell expansions from a baseline of less than 0.1% to approximately up to 3% in some subjects of the peripheral CD8 positive blood T cell population observed at different time points in patients treated at 4 mgs per kg are shown in the flow cytometry plots on the left. Representative data on NK cells and regulatory T cells observed in patients treated at the RP2D demonstrate increased -- demonstrate sustained increases in NK cells, accompanied by modest and transient increases in Tregs. The expansion of tumor-specific T cells demonstrates the highly selective pharmacodynamic effect of CUE-101 and the increase in NK cells is consistent with the anticipated effects of IL-2 on this population. These various data sets and biomarker metrics of selective activation of targeted T cells have bolstered our confidence that the drug's mechanism of action is providing a robust stimulation of the patient's immune system in a highly selective and tolerated manner. The punitive mechanism of action as evidenced by the supportive data emerging from the Phase I trials should, in theory, result in a demonstrative increase in overall survival. As such, as shown in Slide 15, we have been tracking patient survival data throughout the monotherapy dose escalation and expansion trial and have been very encouraged by observations to date. Slide 15 shows the cumulative survival data for 46 patients treated with CUE-101 monotherapy in the 2 phases of the study. The dotted red line at 8 months represents an estimate of the anticipated median overall survival for HPV-positive head and neck squamous cell carcinoma patients treated with checkpoint inhibitors in the second line setting based on published retrospective analysis. Although preliminary with 23 patients currently alive on treatment or in follow-up, the data are highly encouraging and appear to show a potential for meaningful enhancement of survival in patients treated with CUE-101 monotherapy. The data appears to support the premise that CUE-101 is stimulating the patient immune system even at the lowest dose ranges, resulting in what appears to be enhanced survival throughout the range of doses. It's expected at the higher doses, particularly at 2 mg per kg and 4 mg per kg, those doses may even have a greater effect on survival, and we continue to monitor these patients, including 12 out of 17 patients remaining alive from the -- at the RP2D dose of 4 mgs per kg. The underlying mechanism of action and supportive cumulative data from the monotherapy trial suggests that we should see additive or synergistic therapeutic effect in the combination trial with pembro. In the dose escalation part C of the trial, as shown on Slide 16, 7 patients have been treated to date with the combination of CUE-101 and 200 milligrams of pembrolizumab Q3 weeks. Dose escalation proceeded up to the Cohort 3 dose of 4 mgs per kg plus pembro without any DLTs being observed in 3 patients treated at both the 1 mg/kg dose and 3 patients at the 2 mg/kg combination dose. In Cohort 2, one patient has a confirmed PR at their 18-week scan with a 54% decrease in target lesions. The other 2 -- 2 other patients in Cohort 2 had target lesion reductions observed at their 6-week and 12-week scans. The patient treated in cohort 3 at 4 milligrams per kilogram CUE-101 plus 200 milligrams of pembrolizumab has an unconfirmed PR at week 6 with a 50% decrease in target lesions. The observation of these early responses in this patient population is highly encouraging, given the relatively low response rates observed historically with checkpoint inhibitor monotherapy. For example, pembro was approved in first-line patients with a 20% overall response rate and a median overall survival of approximately 12 months in patients with a CPS score greater equal to 1. At the 2 dose levels representing the therapeutic range for the monotherapy study, 2 milligrams and 4 milligrams, we have observed 2 PRs out of 4 with the remaining 2 patients having stable disease in their target lesions. While still early and representing very low numbers of patients, we are encouraged to have observed clinical benefit with these early patients. The emerging data enhances our conviction in the mechanism of action and supports the premise that the Immuno-STAT platform represents a potential breakthrough approach for targeted and selective effector T cell activation directly in the patient's body. Additional data on the Cohort 2 patient with a confirmed PR is shown on Slide 17. The scan images demonstrate the reductions in target lesions in 2, 3 and 4, all captured in the same slice of the CT scan observed at week 18 compared to baseline. As shown in the right upper panel, reductions were observed in 4 out of 4 target lesions. Also of note, cell-free HPV DNA as observed in the monotherapy patient with a confirmed PR was reduced again by approximately 100% compared to baseline and coincided with the observed decrease in tumor measurements. We believe that these clinical observations and the continued support of our PIs, who continue to accrue patients to the study, provide supporting evidence that CUE-101 is an active agent with promising potential for HPV-positive head and neck cancer patients, and our emerging data opens several potential options for our registration path shown on Slide 18. Notably, these include a third-line therapy for HPV-positive head and neck cancer and first-line HPV-positive head and neck cancer in combination with pembrolizumab. We have also initiated our neoadjuvant study with Washington University in St. Louis to demonstrate the value of CUE-101 treatment in patients prior to resection. I will now turn the call back over to Anish for concluding remarks before we open up the call to questions. Anish?

Thanks, Ken. As we continue to progress forward, demonstrating the specificity and selectivity enabled by our Immuno-STAT platform and as exemplified by emerging clinical data from our trials, we continue to differentiate and define our competitive advantages as a potential breakthrough in immuno-oncology. So as shown on the next slide, Slide 19, any therapeutic to be commercially attractive must have the following attributes. It must be effective, safe and tolerable, ideally being selective to optimize therapeutic potential while limiting unwanted side effects, and importantly, must also be scalable to manufacture and stable for storage with reasonable cost of goods. Cue Biopharma's Immuno-STAT platform addresses all of the above needs for multiple different cancers and diseases. In particular on Slide 20, I emphasize that we have further derisked the platform by demonstrating scalable manufacturing. The antibody like molecular scaffold generates a stable and symmetrical molecule that is built upon an Fc backbone. Like other antibodies and Fc-fusion protein drugs, Immuno-STATs are expressed in mammalian cell lines with scalable production from 50 liters to 2,000 liters to support clinical needs. GMP manufacturing follows upstream and downstream processes, similar to those defined for conventional monoclonal antibodies and Fc fusion proteins. And the titers and yields are in grams per liter range, which are in line with desirable commercial expectations. Importantly, the CUE-101 GMP batch demonstrates shelf stability of 3 years, hence supporting stable drug supply for current and future needs. Taken together, we anticipate that Immuno-STATs will demonstrate favorable cost of goods, in line with similar existing biologics. The representative clinical data for CUE-101 applies not only to CUE-101 per se, but also to the entire CUE-100 series and the Immuno-STAT platform. As shown on the next slide, Slide 21, our scientific and corporate development strategy has been to first derisk and validate our approach through CUE-101. The clinical data provides proof of concept for selective targeting of IL-2 to tumor-relevant T cells and NK cells. This approach is generally well tolerated at clinically-active doses with attractive PK/PD properties, and most importantly, demonstrates antitumor efficacy as monotherapy, thereby derisking CUE-101 as well as the entire IL-2-based CUE-100 series. Furthermore, as shown on Slide 22, we have expanded our pipeline and successfully demonstrated the platform's versatility and modularity through the progress made with CUE-102 and CUE-103 based upon the shared core framework of the IL-2-based CUE-100 series. We are on track for a CUE-1 IND filing for CUE-102, which is 99% similar to CUE-101, the primary difference being the replacement of the HPV-E7 epitope with the Wilms' Tumor 1 or WT1 antigen, demonstrating modularity of the Immuno-STAT platforms. We're targeting KRAS G12 mutant epitopes. We've also expanded HLA allele coverage to now include HLA-A11, A03 and B702 among others. Through the development of CUE-102 for WT1 and CUE-103 for KRAS, we can expand into major disease indications with significant patient reach exploiting the clinical derisking of IL-2-based CUE-100 series by CUE-101. And we have the experience with CUE-101, our expanding pipeline as a well-defined regulatory strategy and the potential for an expedited clinical development path. Due to the platform's versatility and flexibility, we've also made significant progress with derivatives of the core Immuno-STAT platform referred to as Neo-STAT and redirected Immuno-STATs or RDI-STATs as seen here in Slide 23. The Neo-STAT platform provides scale, enhanced efficiencies for production and greater flexibility to address tumor heterogeneity and targeting patient-specific neoantigens. The Neo-STAT scaffold is an off-the-shelf biologic to which any given tumor epitope can be conjugated as shown in the middle panel. In addition, RDI-STATs are a new class of bispecific T cell engagers that can harness the protective antiviral T cell repertoire to destroy cancer as shown here. We believe that RDI-STATs will offer potentially superior efficacy and avoid systemic activation of all T cells as has been noted with other bispecific engagers. And importantly, RDI-STATs address tumor resistance mechanisms linked to HLA loss or down regulation or loss of tumor antigen presentation. In closing, through the datasets emerging from the ongoing clinical trial of CUE-101, we believe we are well positioned to realize our vision of developing disruptive breakthrough immunotherapies, providing hope to patients by realizing the promise of harnessing the power of the immune system in a well-tolerated and effective and specific manner. With that update, we're happy to take any questions.

[Operator Instructions] Our first question comes from the line of Stephen Willey with Stifel.

Congrats on the update here. Do we know the proportion of stable disease -- durable, stable disease patients that are receiving monotherapy, 4 mg per kg, that are still on therapy? I guess when I look at the swimmers plot, maybe it appears that it's about 2/3 of those patients, but just wondering if you have that number available.

Yes, Ken?

Yes. Thanks for the question. So we have 6 patients on the monotherapy still on study right now.

Okay. So presumably, that's the partial responder, and then I'm getting 5 of 6 of the stable disease patients, of the durable?

So it's -- yes, one partial responder for stable disease and one patient too early.

Okay. And then also just curious if you also have the proportion of monotherapy for mg-per-kg patients that are also still alive.

Yes. We -- so we have 12 of 17 patients at the 4 mgs per kg that are still alive.

Okay. That's very helpful. And then just as you guys think about communicating a registrational strategy here at some point, the initial combo data looks really interesting. Presumably, you'll expand out a cohort at the go-forward combo dose. But are you going to want to have some of that data in hand before you try to articulate registrational plans? And I guess is there a chance that you guys look to move first into a frontline study in combination with pembro before looking at any kind of monotherapy salvage opportunity?

Yes. So actually, no. We think that the monotherapy data is very strong. And we expect that by midyear, we're going to have enough data to go forward to talk to the FDA to develop a strategy with them for a monotherapy registration salvage. We think that will be third line. We don't think we'll need the combo data to do that in support.

Our next question comes from the line of Mark Breidenbach with Oppenheimer.

Congrats on these data. First one kind of centers on the use of circulating HPV DNA as a surrogate of tumor burden. I'm seeing that for the responders in your monotherapy and combination cohorts, the target lesions are shrinking maybe by 50% or so, but there's nearly a 100% reduction in circulating HPV DNA. I'm just wondering how you can explain that discrepancy. And also, have you seen any HPV DNA reductions in the patients who only achieve disease stabilization?

So Anish, do you want to take that?

Sure. Mark, that is a very pointed observation that you made, which is the absolute flattening of the DNA while the tumor measurement. This actually leads to the aspect we've highlighted before, which is, is the scan measurement truly reflecting what's qualitatively present there at this point in time. I would remind you of the patient in -- at the 1 mg per kg cohort of monotherapy as a case report that we had discussed, where the tumor lesion was essentially flatlined as a stable disease. But when we had resected it, it was essentially a necrotic mass with massive infiltrate. So Mark, that's -- we've got to understand this better to understand what is actually the composition of the reduced lesion, and that's something that's very sort of acute and sort of foremost in our minds. And to the second point, have we seen perturbations of DNA in HPV DNA in other patients with stable disease? We have. We have seen fluctuations. We're continuing to build out that dataset to understand those relationships as well. And as we sort of longitudinally follow some of these patients, we'll hopefully have a much better understanding of that. And Ken, do you want to add something to that?

Yes. Mark, it's interesting because as you start to talk more and more of the investigators who work in this field, there is more and more belief that actually the cell-free HPV DNA is the most sensitive potential biomarker of disease activity. In fact, I was talking to one of our PIs today who said that they believe HPV DNA is much more sensitive. They actually believe that more than they do scan data at this point. So I think you're going to see a rapid evolution in the field, at least for HPV-positive cancers, to rely on that as an important biomarker of activity. And in fact, one of the things that we're planning on doing in the future is an adjuvant study, where we'll actually follow HPV DNA -- cell-free HPV DNA as the first marker of recurrence in patients who have been treated for cure, and the investigators believe that that's the most sensitive marker to follow. So really exciting times in the development of HPV-positive cancers.

Okay. That's interesting. And Ken, this one is maybe for you as well. Since we have some efficacy data for about 14 of 20 patients in the 4 mg per kg monotherapy cohort, are we getting close to a point where you can put limits around a median PFS? And you guys like to talk around sort of OS quite a bit. But in terms of PFS, what do you see as the bar to clear in a post pembrolizumab setting?

So great question. I think that we would certainly like to see a median PFS at least around 4 months, and that would probably correlate pretty well with the OS of greater than 8 months, and our target there is 12 months, actually. So we're -- I think the data -- we haven't parsed the data out that way just because we've been really focusing on OS as a registration path. As you know, the FDA doesn't really like PFS as a registration path. So we're certainly thinking at least 4 months, and I think that's going to bear out.

Okay. That's really helpful. And finally, maybe one last one for me. What can we expect in terms of the pacing of data readouts for the remainder of 2022? Or is the plan to kind of provide updates along the way with each new response? Or can we expect future updates to be presented in larger quanta at medical meetings? That would be helpful.

Yes. So why don't I take that and give a high level first? So thanks, Mark. Our intention is not to be releasing patient by patient, but larger quantums at this point. We're just highly encouraged by the data we're seeing to date. And we intend to be presenting, for instance, at ASCO, at conferences. And we have our quarterly earnings call, so we'll provide updates on those calls. But that's the sort of intent right now, is to make sure that going forward, the quantum of data are very substantive and meaningful.

Our next question comes from the line of Ren Benjamin with JMP Securities.

Of course, congrats on the ongoing data. Maybe just to start off with OS again. Can you talk -- are there any findings or learnings that you have regarding subsequent therapies that these patients might be getting and whether or not 101 might be having any sort of a priming effect or some sort of benefit for the subsequent therapies that might help you design a potential future study or combination study?

Yes. Thanks, Ren. Ken, do you want to take that?

Yes, Ren, we are gathering that data. We had to put in an amendment to get that data. Because initially, we were not collecting that, quite honestly. But what we've heard anecdotally from a couple of different investigators was that we weren't seeing retreatment with checkpoints, but we were seeing some retreatment with various chemotherapies as single agents and seeing what the PIs considered remarkable sort of responsive suggesting that there was some type of memory effect and some kind of priming effect. So we are collecting that data. What I can tell you is it looks -- there's no pattern yet. There's not enough data to say one therapy is better than another because all the PIs use a little bit of different approach. Generally, it's a single-agent chemotherapy, but not everybody is using the same chemo. Does that help?

Yes, that does. And then just switching gears, maybe briefly, to the selective T cell populations in the blood, you showed some very nice increases. I'm wondering if it's correlated at all with response. And wouldn't we -- I guess wouldn't we imagine that these T cells would actually decrease in the blood over time as they target tumor, right, and get caught up in the local tumor microenvironment? Am I thinking about that incorrectly? Or are we just looking at early data points and subsequent data points might actually show up?

Yes. Great question, Ren. Anish? Yes.

Yes. I think that's an excellent point. And in fact, we would agree with you. In fact, with the observations that if you see the examples that we've shown, these are from the recommended Phase II dose patients, these are at distinct unique time points. One example being an early cycle 1, day 8, I believe, and the others in later cycles. But I should qualify to the points you made, we don't always see them consistently because of the trafficking out of the blood. So this is a snapshot in time, Ren. Most likely, the vast majority of the T cells have actually extravasated into the tumor lesions and are likely resident there. We had examples of these in the few biopsies that we've analyzed, and we've shared that with these forums previously. It's one of the reasons why Ken and Matteo have sort of put the neoadjuvant study in place to have access to the tumor tissue. And most importantly, I'd like to just remind everyone of the preclinical study we published with the murine CUE-101 surrogate in 2020, where we saw about 2 orders of magnitude difference between what could be noted in blood versus what was present in the tumor. And the tumor in that situation with the mouse CUE-101 surrogate up to 20% to 50% of CD8 for tumor-specific as opposed to a fraction of a percent in circulation, again, agreeing with what you're saying, Ren. There's also a recent paper that just came out, I believe, in Journal for ImmunoTherapy of Cancer making the same point in melanoma patients who have certain specificities like mark 1 and NY-ESO, I believe that they were tracking. You see a loss of that in circulation in patients that tend to have robust responses and thinking there is again exactly what you said, of cells extravasating into the tumor tissue. So these are single snapshot time measurements, not indicative of a constitutive presence in the periphery.

Got it. And I guess just a final couple of questions. In terms of the ongoing combination study, when we get the next update, assuming it's ASCO or some time period there, about how many patients worth of data that you think we'll have? I think we're in the final RP2D combination cohort right now, correct me if I'm wrong. And maybe just related to that, the adjuvant study, which I know we're all eagerly awaiting as well given the biopsy data, can you just give us a status on that, status update?

Yes. Ken, do you want to take that? Or Matteo?

Yes, yes. Before we talk about that, I just wanted to follow-up on what Anish was saying about the peripheral T cells, Ren, in that as a clinician and a medical oncologist, I just have to stop and say that, that data is amazing. I mean when you see 3% antigen-specific T cells in the periphery, that is an amazing number. And it's well -- that correlates very well in many, many studies with T cell infiltration. I mean those T cells know how to go home. That is not a disconnect. So yes, we -- it's going to be something you capture somewhat randomly, but the fact that they're there, which almost always universally correlates with T cell infiltration and response. So we're really -- I'm just jazzed about that data. So on to your -- sorry, on to your question, the neoadjuvant study, they are actively looking for their first patient, quite frankly. They've been slowed down by Omicron. They have screened over 9 patients but are having trouble getting surgery scheduled and getting things on board. So we're very hopeful they're actively looking -- [ Wash U ] is very excited by that study. And we're all hoping that they get the first patient actually treated and through surgery soon. When you look at -- we are -- we have patients actively being screened for those last 2 slots in the third cohort. And assuming we don't see a DLT, we'll open immediately for expansion. We have to time those escalation patients to make sure we don't see a DLT. So we're expecting to have several more patients on by the time of ASCO, but I can't predict how many at this point.

Our next question comes from the line of Brian Skorney with Baird.

This is Luke Herrmann on for Brian. So just on the combinations, you have or expect to generate any data to help us parse out the relative degree of contribution from CUE-101 and KEYTRUDA. And then are there any differences in baseline characteristics that would explain differences in degrees of response so far?

So, Ken?

So to take your second question first, there's no different baseline characteristics that we can differentiate as of yet. These are -- so no. The -- and we really don't -- to say what -- how much CUE-101 versus pembro is helping here. We can only look at historical data where pembro in second -- in the first line has approximately a 20% PR rate in this setting. So we've always said that we need to at least double that to be -- have a to show meaningful additive or synergistic effect.

Great. And then -- but do you expect to give the T cell expansion data from the combo patients at any point?

Yes, we do. Yes.

Our next question comes from the line of Mike King with H.C. Wainwright.

Can you hear me all right?

Yes, we can hear you great.

Okay. I got to the slides a little bit late, so I'm kind of playing catch up here. But a couple of things that I wanted to ask about. I'm intrigued by the spider plot on Slide 12, where some of these patients are still trending down. So I guess this kind of relates to some of the other questions about when will we see follow-up data? But I think it's possible, conceivable that some of these durable, stable disease in the monotherapy could potentially convert to PRs. Is that a fair statement?

Yes. Thanks, Mike. So where -- these patients, as I said in -- as we were talking about it, neither of them has converted to a PR, but they do remain on study and are getting dosed. So we're actively following them, and we will give the updates as we get them. But full disclosure, they have not had a PR yet.

Right. Well, we can only hope. And then just with respect to the CD8 cells, you showed the one example of the patient who responded. But I wonder if you expect to provide a more fulsome disclosure of the additional patients in their CD8 T cell responses.

So all the tetramer positive patient examples that Ken spoke about, Mike, are from patients that are derived clinical benefit, including durable, stable diseases or the lesions trending down from the recommended Phase II direct cohort.

I see. Okay. This is 3 subjects, not one. I'm just looking at Slide 14. Okay.

That's right. Those are 3 separate examples. Yes. Yes.

Yes. Okay. Okay. Can you also remind us what the rationale for -- did you have a preconceived idea going into the study that 4 mg per kg was going to be the RP2D? And what should we -- why should we expect that more is better in this situation?

Sure. Why don't I -- go ahead.

And so Anish can also comment. But basically, what we saw there, Mike, was we were following not only the clinical data and monitoring safety and tolerability. But basically, following the PK and the PD, we basically saw a plateauing effect of how much the NK cells were going up with the CD8 cells, et cetera. Where we didn't get any more bang for the buck from going from 4 to 8, we had no idea where we were going to end up when we started, but we were very comfortable that 4 mgs per kg was giving us sort of a maximal PD benefit to be able to expand as well as really tolerable dose. And that's -- so we moved ahead with 4 mgs per kg rather than 2 or 8.

Got it. Okay. And then I'd be curious, at some point, if we could understand on the slide number, the swimmer plot, Slide 15, how those -- how the East Lane corresponds to dose? I assume at some point, you'll show us that. Is that correct?

Yes. So we would have to sort of regroup and review this, but we'll show that in the future. But for example, the very early patients up top were all at the lowest dose. So it's sort of time on study. So we didn't break it down by dose here. We have that data, but it's essentially -- by time, it's the earlier cohorts up top with the later cohorts on the bottom. But we can -- we'll clarify that in the future for you.

Okay. Super. And then finally, just on the one patient who progressed on the combo, the one-off study, the patient with durable, stable disease, the one-off study, can you -- do you understand what the reason was for going off study?

Yes. So the patient had -- and their target lesions had durable, stable disease but actually showed up with a couple of new nontarget lesions, so they came off for that reason.

Got it.

So mixed tumor response and...

Yes. And those were -- they were E67-positive as well? Did you biopsy that?

We don't have a biopsy of that patient.

Our next question comes from the line of Lou Basenese with Disruptive Tech Research.

Just had a quick follow-up on the monotherapy. I think Mike kind of unknowingly pointed out that the data that you're showing today on that slide is from SITC. But Ken made a comment about just following them. Can you give us some just other idea what's going on in terms of maybe other measurements that you're seeing since there's probably been 1 or 2 scans since that SITC data? Is there other measurements that give you just confirmation of the trends that you've already seen or what you're seeing that is giving you confidence there?

Yes. So why don't I take that generically, Lou, and then I'm going to turn it over to Ken to elaborate? So what we're most intrigued by, remember, these are third line and beyond patients that have been refractory to other therapies. And by essence of having cancers that are developing and progressing, they have compromised immune systems, low T cell numbers, et cetera. So what's really impressive about that spider plot is what is providing the therapeutic benefit is the patient's own immune system. So our drug is stimulating the immune system. So those measurements, one, they show that we're having an antitumor effect by stimulating the immune system. And as Anish pointed out, the scan itself, it tells us a certain metric that there's some activity. The tumor is stressed out in some cases where the immune system is attacking and having an effect on its size, but it's not a direct correlation. So we have to just monitor these patients over time. And what's most important is to see what effect it's having on their survival, and our objective with the neoadjuvant study is to get access to tissue, so we can really do a systematic survey of what's happening qualitatively. So we have some cancers that have trended down, and we haven't seen them cross the PR level yet. We just thought they still remain on study, and we're monitoring them. And again, we've had patients that have completely flatlined where they're complete stasis with the tumor over an extended time. And then where we were fortunate enough to get tissue sample, we saw those tumors were, in fact, filled with necrotic scar tissue. So we just have to keep learning as we get access to tissue and follow these patients out. So I think that's the most clarity we can provide.

Okay. And then just a quick follow-up there. That's super helpful. And I noticed on Slide 18, for the registration pathways, you've added a possibility as a third-line defense as a monotherapy. What additional data are you waiting for on that before speaking with the FDA? Is it more partial responses? Or are you more concerned with overall survival?

Yes. It's -- go ahead.

Yes. So we've always have actually been on the eye plan that if we had monotherapy activity, that we would be -- have a potential registration path. If you remember, we originally were second line after first-line failure. But pembro was approved in that time line, and we were functionally moved to third line and 97% -- all but one of our patients have received both chemotherapy plus/minus cetuximab and then a checkpoint and have failed both those therapies. So we are functionally in the third-line space, and we are -- so we believe with a clinical benefit rate of 50%, that that's going to -- will be overall survival data maturing that we expect that the -- we will have a monotherapy registration path to talk to the FDA about. That's always been part of our plan. We've previously presented that. So that's not new. We just have increased confidence we're going to be able to do it.

Okay. I appreciate it. Congrats and I'm really encouraged by all the amazing data, as you pointed out, Ken.

Our next question comes from the line of Robin Garner with Craig Hallum.

Congratulations on the data and thanks for taking the time to share with us. Two quick questions for you. The first is for the monotherapy patients on the 4 mg per kg, there are 2 to 3 that had progressive disease. Are there any markers that might indicate why these patients specifically didn't respond, for example, T cell response? Was that quite divergent from the other patients in this group? Or did they have a different rate of viral DNA changes?

Yes. I'll start off generically. And then Ken, if you -- or Matteo can elaborate. But Robin, just to remind you, these are third-line patients that are refractory metastatic. So some of these patients are extraordinarily in poor health when they come on to the study. So we just have a spectrum of conditions. And they are -- by essence of their state, they have compromised immune systems, very low T cell counts in the majority of cases. The T cells may be exhausted. So the fact that we're seeing the percentage of patients deriving benefit is what's so encouraging here. But I just want to remind that these patients are in poor state of medical condition coming in. Some of them are actually in a very poor condition. So it's a challenge. But on that, I'll hand it over to Ken, if you want to elaborate.

Yes. Thanks for the question, Robin. I think what we're seeing, in general, again, the data is constantly being -- maturing. But for those patients who are progressing or have progressed, we have not seen decreases in circulating free DNA for example, and we have not seen robust T cells -- antigen-specific T cells in the periphery. We're gathering all that data and we'll be reporting it at -- a lot of it at ASCO, I think. But yes, in general, the biomarkers are following our response data.

Okay. And then just switching to the combination study. Is there any more information you could provide about the patient with the unconfirmed PR? So Slide 17 was really nice for the confirmed PR -- for this unconfirmed patient. How many target lesions did that person have and that their circulating DNA also dropped -- the viral DNA also dropped from baseline to 100%?

So Ken and Anish, do you want to take that?

So I would actually -- the -- I don't believe we have the circulating free DNA from that patient. Do we, Anish?

We don't, yes.

No?

No, we don't. We haven't had a chance to look at that.

And I can add that there are 4 target lesions and reductions were observed in all 4 on the initial scan. So we're very encouraged by this as we clearly saw target lesion reduction in 4 out of 4 in the confirmed PR. So again, very encouraging to see, if you will, systemic response in all of the target lesions.

Ladies and gentlemen, we have reached the end of the question-and-answer session. I will now turn the call over to Dan Passeri for closing remarks.

Yes. Thank you. And look, we want to thank everyone for listening in. I appreciate your patience. We continue to generate data on an ongoing basis and want to basically thank the participating principal investigators as well as the patients and their family, without which we wouldn't be able to conduct these studies, and we look forward to providing you with updates as more data becomes available. And again, thank you for your time and attention, and stay safe. Thank you.

This concludes today's conference and you may disconnect your lines at this time. Thank you for your participation, and have a wonderful day.