AGEN - NASDAQ

Thank you for holding and welcome, everyone, to the Agenus Fourth Quarter and Full Year 2022 Financial Results Conference Call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. [Operator Instructions] Thank you. I will now turn the call over to

Thank you, Jack, and thank you all for joining us today. Today's call is being webcast and will be available on our website for replay. I'd like to remind you that this call will include forward-looking statements, including statements regarding our clinical development, regulatory and commercial plans and time lines as well as time lines for data release and partnership opportunities. These statements are subject to risks and uncertainties, and we refer you to our SEC filings for more details on these risks. Joining me today are Dr. Garo Armen, Chairman and Chief Executive Officer; Dr. Steven O'Day, Chief Medical Officer; and Christine Klaskin, Vice President of Finance. Now, I'd like to turn the call over to Garo to highlight our progress and speak to our outlook for the remainder of the year. Garo?

Good morning, everyone, and thank you for joining us this morning. We are absolutely thrilled to share the progress we've made at Agenus in advancing our deep immuno-oncology pipeline. Our portfolio is designed to address areas of high patient need and to unlock the large untapped market opportunity in cold and treatment-resistant cancers. And on top of that, to provide benefit beyond what is currently available with I-O treatments in other tumors, including hot tumors. At the forefront of our pipeline is botensilimab a clinical stage multifunctional Fc-enhanced CTLA-4 antibody with potentially blockbuster capabilities. Over the last 12 months, we've made substantive progress addressing the ongoing botensilimab development program, including having dosed over 300 heavily pretreated patients with advanced solid tumors as part of our Phase 1b trial. That's a very large trial in account. And we've done this with as monotherapy and in combination with our PD-L1 -- I'm sorry, PD-1 antibody balstilimab. Botensilimab has produced durable objective responses in nine cold and/or treatment resistant cancers, including MSS colorectal cancer and MSS stands for microsatellite stable cancers that are particularly challenging to treat with immunotherapy. So, we've seen results in MSS colorectal cancer, MSS endometrial cancer, platinum-resistant refractory ovarian cancer, PD-1 resistant refractory non-small cell lung cancer, PD-1 and CTLA-4 resistant refractory melanoma, a particularly challenging patient population. PD-1 resistant refractory hepatocellular carcinoma, PD-1 resistant refractory cervical cancer, angiosarcoma and liposarcoma, this is a very extensive list of difficult-to-treat cancers that had been treated and failed prior treatments. Based on the unprecedented clinical responses in these patients, we have initiated three global randomized Phase 2 trial, evaluating the efficacy and safety of botensilimab monotherapy or combination therapy with balstilimab in MSS colorectal cancer, melanoma, and pancreatic cancer. We aim to initiate a Phase 3 study in MSS colorectal cancer later on this year in the hope that the cumulative data that we've generated between Phase 1, the Phase 2 randomized trials and the initiation of our Phase 3 trials will lead to a rapid approval path for the benefit of the patients. We are thrilled by the clinical results we have seen with botensilimab and are excited about its potential to positively impact the treatment landscape for patients obviously suffering for cancer, all kinds of cancers. We remain committed to advancing our pipeline of innovative therapeutic therapeutics and believe that our portfolio of programs in the immuno-oncology space is robust with multiple programs in development, including, very importantly, our ILT2 program, which is codenamed AGEN1571 and our CD137 program, otherwise also known as 41BB agonist antibody, which is codenamed AGEN2373. Both of these molecules are progressing in the clinic. We look forward to sharing more updates on our progress during various conferences throughout this year and our other communications means as well again throughout this year. Thank you for your attention. And now I will turn the call over to Steven O'Day to highlight the recent clinical data presented on botensilimab. Dr. O'Day has a very extensive section today because there's a lot to talk about. And so we'll ask him to go through it very, very orderly, slowly because I think the content is something that is not to be rushed, Dr. O'Day.

Thank you, Garo. Together with our investigators, we were pleased to have had the opportunity to present data updates from the botensilimab and balstilimab development program at five medical meetings over a nine-month period, including plenary sessions at ESMO World Congress on Gastrointestinal Cancer, the Society for Immunotherapy of Cancer, otherwise known as SITC, the Connective Tissue Oncology Society, known as CTOS along with a late-breaking oral session at the American Society of Clinical Oncology Gastrointestinal Cancer Symposium this past January, and finally, an oral plenary session at the upcoming Society of Gynecologic Oncology Annual Meeting. These presentations highlighted the durable responses and meaningful clinical benefits of the botensilimab, balstilimab combination compared to what has been reported with standard of care and other investigational therapies in patients with MS stable colorectal cancer, non-small cell lung cancer, ovarian cancer and sarcoma. I'll now briefly describe these data updates, beginning with our MS stable colorectal cancer program. In metastatic MS stable colorectal cancer after failure of first and second line therapies, the current standard of care is a 12-month overall survival rate of approximately 25% and an overall response rate of only 1% to 2%. Other PD-1 or PD-L1 CTLA-4 combinations evaluated in this comparable patient population supported response rates of only 1% to 5%. Our latest update of botensilimab program in metastatic MS-stable colorectal cancer was from an expanded cohort of 70 evaluable patients presented at ASCO GI by Dr. Anthony El-Khoueiry, Associate Director for Clinical Research at USC Norris Comprehensive Cancer Center and the Keck School of Medicine at USC. This presentation showed that treatment with botensilimab, balstilimab combination resulted in a 12-month survival rate of 63% and including a 12-month survival rate of 81% in patients with no active liver metastasis and a 40% 12-month survival rate in patients with active liver metastasis, suggesting a favorable overall survival in each of these patient subpopulations. Median overall survival in the overall population and the subset without active liver met disease has not yet been reached. The overall response rate of the 70 evaluable patients was 23%, and 69% of these objective responses were still ongoing at the time of the data cut. The disease control rate, which is inclusive of complete responses partial responses and stable disease was 76%. These patients had a median number of four prior lines of therapy. Turning to anti-PD-1, PD-L1 relapsed refractory non-small cell lung cancer. At SITC, we reported our first four evaluable patients with two objective responses or 50% response rate and three out of the four responses with disease control for a 75% disease control rate. Since SITC, we have four responders out of a total of eight patients now with four additional patients treated, confirming the response rate reported at SITC in a larger patient population. Other PD-1 or PD-1 CTLA-4 combination in the second or third-line PD-1 refractory non-small cell lung cancer population have reported response rates of 6% to 13%. Based on these early clinical signals, we are aggressively expanding enrollment in this non-small cell lung cancer cohort and plan additional non-small cell lung cancer studies. In 19 evaluable patients with platinum relapsed refractory ovarian cancer, we observed high responses for an overall response rate of 26% and a disease control rate of 63%. Other PD-1 or PD-L1 CTLA-4 combinations have reported response rates of 3% to 10% in comparable patient populations. An update of this cohort will be presented at an oral plenary session at Society of Gynecologic Oncology 2023 Annual Meeting in Women's Cancer on March 27 in just a couple of weeks. At CTOS, last November and presented by Dr. Bree Wilky at the University of Colorado, data was presented on a cohort of heavily pretreated metastatic sarcoma patients of mixed histology. Of the 13 evaluable patients, the 12-month overall survival rate was 77%, and the median overall survival had not yet been reached. The overall response rate was 46% with 67% of the objective response is still ongoing at the time of the data cutoff. Other PD-1, PD-L1 CTLA-4 combinations have reported response rates of 12% to 16% in comparable patient populations. Reflecting the high unmet patient need in each of these cancer types, we have been encouraged by the consistently positive feedback we have received on these data from key opinion leaders in the field across diseases, what often describes the results we have reserved in these cold or PD-1 refractory settings as unprecedented. Now I'll summarize our plans for ongoing clinical activities, starting with MS stable colorectal cancer. We have launched a randomized Phase 2 trial of botensilimab and the botensilimab, balstilimab combination therapy in patients without active liver metastasis who have received one or two prior lines of standard of care therapy. This study is actively enrolling at sites around the world. Importantly, we have designed this study to satisfy key regulatory requirements, including exploration of two known active fixed doses of botensilimab. In addition, we are evaluating both botensilimab as monotherapy and as combination with balstilimab and to establish the contribution of respective component of the study. Finally, we have randomized to fifth control arm that is a standard of care, either regorafenib or long serve at their approved doses and schedules. We intend to submit a regulatory review of MS stable colorectal cancer in 2024, a data package with this randomized Phase 2 study, along with data for more than 300 patients in the Phase 1b study. This package will include overall response rate, duration of response, progression-free survival and overall survival. We also expect to launch a Phase 3 confirmatory study in MS stable colorectal cancer in 2023 that will be powered to demonstrate statistically significant and clinically meaningful overall survival. We expect this study to be considerably or fully enrolled by the time of our potential regulatory submission in 2024. Now, let's turn to melanoma. In melanoma, as part of the Phase 1b expansion, we reported responses with botensilimab monotherapy in patients who are refractory to PD-1 and patients refractory to both PD-1 and CTLA-4. This is an area of significant unmet need. We currently have an active -- a Phase 2 study evaluating botensilimab monotherapy in these cohorts of PD-1 refractory and PD-1 CTLA-4 refractory disease and plan to explore a rapid registration path, if the observed signal remains robust. In metastatic pancreas cancer, we are evaluating a second line patients in a Phase 2 randomized study comparing standard of care gem-abraxane to gem-abraxane in combination with botensilimab therapy. We continue to enroll patients in our ongoing Phase 1b expansion cohorts with a focus on PD-1 or PD-L1 refractory non-small cell lung cancer patients. Like our approach with melanoma, we plan to explore a rapid registration path in non-small cell lung cancer, if the observed signal continues to remain robust. Botensilimab clinical activity in late-stage refractory cancers has generated substantial interest from leaders in the field worldwide, including requests for cooperative and investigator-sponsored trials. As we progress trials to support potential registration in colorectal cancer, melanoma and lung cancer, we plan to leverage these important partnerships to expand development in indications such as sarcoma and ovarian cancer as well as other areas where botensilimab has already demonstrated promising potential clinical benefit. While advancing the clinical development of botensilimab and balstilimab remains our top priority, we also continue, as Garo said, to progress a focused number of additional programs combining botensilimab with other agents in our pipeline to further expand the therapeutic potential of botensilimab and unlock the full potential of our portfolio. Let me tell you a little bit about those programs. We expect to complete enrollment of our Phase 1 study of botensilimab in combination with AGEN2373, a CD137 agonist in PD-1 relapsed refractory melanoma in the first half of 2023. AGEN2373 is a conditionally active CD137 agonist designed to stimulate the activation of cytotoxic T and NK cells while mitigating the liver toxicities common to this target class. The advancement of this study triggered a $5 million payment from our partner Gilead last year. We also dosed the first patient in the Phase 1 study of AGEN1571 at the end of last year as a monotherapy and continued dose escalation of monotherapy this year. In addition, we will be combining our AGEN1571 in combination with botensilimab and balstilimab in advanced solid tumors this year. AGEN-1571 is an ILT2 agonist antibody designed to modulate tumor-associated macrophages, T cells NK cells and NK T cells to overcome resistance to checkpoint blockade. This clinical study was initiated based on pre-clinical data we reported at the 2022 American Association for Cancer Research Annual Meeting which showed superior potency and functional activity of AGEN1571 compared to the only otherwise known clinical stage asset as well as enhanced immune cell activation when combined with botensilimab or balstilimab. Now, I'll turn the call back over to Garo to discuss our strategic partnerships.

Thank you, Stephen. As you can see, it has been a very, very busy year with a lot of impressive data that has been generated and the validation that we have received in making presentations, podium presentations, plenary presentations four of them within a six-month window at major conferences, and a substantial number of KOLs that have been engaged in discussions about the data and about our next steps with the data for expansion of our trials and a potential registrational pathway. So progress with me with our truly differentiated R&D engine and strategic partnerships has been impressive by all accounts. And as you know, we have generated $825 million in cash already received through our partnerships with the potential to deliver an additional $2.7 billion in future milestone payments, and on top of that, royalties when these products are commercialized. So that's the side of our business, which doesn't drain any resources, including cash resources from the Company. This is in addition to us advancing our own portfolio which may result in a significant upside, a financial upside for the Company. And of course, this is a testament to the strength of our pipeline and the innovative capabilities of our R&D platforms. And thank you for that team, Agenus Research. In 2022 alone, our partnership with Merck, BMS, Incyte, UroGen have resulted in the launch of nine new additional clinical trials of our partnered assets. What's even more impressive is that these trials are all evaluating molecules discovered here by Agenus, including some exciting ones like MK-4830, an ILT4 antagonist now led by Merck and BMS-986442, antigen bispecific antibody now with by BMS. We're also seeing very great progress with molecules targeting GITR, LAG-3, TIM-3 now led by Incyte. Looking ahead at 2020 -- I'm sorry, 2023 is this year, we have some major clinical milestones inside, as Dr. O'Day mentioned. We're expecting to complete enrollment of our global randomized Phase 2 activate studies of botensilimab in MSS colorectal cancer, melanoma and pancreatic cancer plus we expect to initiate a Phase 3 study of botensilimab with balstilimab in MSS colorectal cancer complete enrollment of our Phase 1b study of botensilimab and AGEN2373. That's our CD137 molecule. In melanoma, and initiate botensilimab and balstilimab combination cohorts in a Phase 1 study of AGN1571, a very exciting molecule that targets the myeloid arm of the immune system. We're also advancing seven clinical collaborations evaluating combinations of external agents with our PD-1 and CTLA-4 antibodies, sponsored and executed by our partners. All in all, we are incredibly excited about the future potential of our pipeline and our partnerships. We're thrilled, of course, to share these updates with you all. With that, I'll turn the call over to Christine for a financial update, and I'll come back for closing remarks. Christine?

Thank you, Garo. As we head into 2023, we remain financially strong and well positioned for continued growth and success. We ended the year with a cash, cash equivalent and short-term investment balance of $193 million, demonstrating our ability to manage our resources effectively and efficiently. In the fourth quarter of 2022, we recognized revenue of $28 million, bringing our total revenue for the year to $98 million. We incurred a net loss of $74 million in the fourth quarter and $231 million for the full year 2022. This includes noncash expenses of $33 million and $96 million, respectively. It is important to note that we have made significant investments in our pipeline, which we believe will drive our future success. We remain committed to our mission of discovering and developing innovative therapies for patients, and we are confident that our investments will yield great benefits for patients in the long run. Overall, we are pleased with our financial position and remain optimistic about the future. As we continue to make progress across our pipeline and with our strategic partnerships, we look forward to the continued progress towards our goal of improving patient outcomes. I'll now turn the call back to Garo.

Thank you very much, Christine and Dr. O'Day for that wonderful summary. And of course, it's been quite a year for us. The clinical data generated in 2022 has been robust, and the results of botensilimab, balstilimab combination therapy have shown superior benefit compared to what's been reported so far for standard of care and other investigational therapies. This demonstrates the potential of this combination and it's a proxy potentially for our future combinations to provide significant benefit to patients and address the large medical need that exists in cold and treatment resistances and added to that improved benefit provided by other I-O therapies in hot tumors. Looking ahead, to 2023, we anticipate achieving important clinical milestones. On top of a year that has already demonstrated very impressive outcomes. That will set the foundation for a potential regulatory filing or potential botensilimab plus balstilimab within a period of time that will be in the best interest of patients based on robust data that can be justified. So this is the promising next steps for our combination therapies. Of course, none of these progress would be possible without the hard work and dedication of Agenus team members as well as the support of our physicians, caregivers, participants in our clinical development program as well as our partners. We're committed to our mission of bringing curative and I want to underline curative therapies to cancer patients and are excited to continue our dedication to this mission with our partners and stakeholders. Curative is very important and Agenus is well positioned, we believe, to be able to accomplish this because we have a very unique, strong armamentarium of compounds that we have the flexibility to combine for the best outcome for patients with a curative therapy. So let's open up the call for questions and continue the conversation. Please feel free to come up with any questions you'd like. Yes, Jack back to you.

[Operator Instructions] Matt Phillips with William Blair. Your line is open.

Congrats on the update on the non-small cell lung cancer cohort. I was wondering how many patients do you want to enroll in that cohort before deciding on a Phase 2 trial? And also, would you still need both from the monotherapy arm or could the kind of monotherapy data from colorectal and other indications to kind of satisfy any contribution of components?

So, I'll answered the first question is that's okay and then turn it over to Dr. O'Day. With regard to non-small cell lung cancer, when we observe the kind of sustainable, robust patient outcomes in the form of response rates. We made a decision just about a month ago. to expand that cohort significantly so that we can justify starting perhaps a very large even a Phase 3 trial or a Phase 2 trial, randomized Phase 2 trial that will be expandable. So in the interest of that, we made a decision to expand our cohort to at least 30 patients, perhaps more, to at least 30 patients. And we expect that, that will be accomplished within the next several months. And with that information, we will take it to the next step. If we can the kind of impressive results we've seen in a very small patient population, if that could be sustainable, then it will justify our next steps for an expanded trial. And as you know, lung cancer is a very large indication. And even though there are some and it had cancer for the most part, but there are a number of patients that fail current therapies, including I-O regimens in combination with other agents and that's the patient population that we've targeted in our Phase 1 trial that would be the patient population targeted in our expanded cohorts, and that's the patent population that we will go after in our registration strategy. But Dr. O'Day, if you want to answer the colorectal question.

Yes. Thanks, Matt. For the colorectal question, I think the question was that the monotherapy arms in the colorectal trial contribution of components. So, our Phase 2 trial is designed to look at contribution of components with botensilimab in addition to the combination. We don't feel that PD-1 monotherapy is required for contribution given its lack of essentially zero response rate in this setting and so, we will be looking at the contribution of botensilimab. It wouldn't be ethical to treat with a PD-1-only arm in that disease setting.

Just another kind of follow-up. Do you expect any milestones this year from your numerous collaborations? And just how much of a priority is additional business development for you this year?

Yes. There is the potential of several milestones this year. I don't want to quantify them or identify the source of them. But these will be -- when they come through, there will be significant milestones, not $5 million or $10 million.

Mayank Mamtani with B. Riley. Your line is open.

I appreciate the level of detail. So on the phase -- on the two Phase 3 trials that you're talking about initiating in 2023, can you just talk a little bit about like the differences in kind of what you're trying to achieve? Like for example, for the CRC confirmatory study, how that differs from the ongoing randomized safety data in terms of target patient population, so your objectives? And then on the Phase 3 lung cancer study that you just touched on -- like what are sort of the key goals there? Is it late line patients? Is it replacing I-O chemo regimens in certain settings and specifically are you looking to combine bot with bal in lung cancer? Or are you -- you may consider using an external PD-1, L1? And then I have a couple of follow-ups.

So obviously, the Phase 3 CRC population that we're targeting is going to be along the same lines as our Phase 2 population, so that we can show the kind of robust responses that we've seen already so far, which will be repeated in a randomized setting as backed in the Phase 2 randomized trial. And will we use bal or approve PD-1 in non-small cell lung cancer. Well, right now, the plan is to use bal, right now. But it's also a function of potential partnerships that we may engage in because as you know, there are companies out there with their own Phase 1-- I mean, with their own PD-1 or PD-L1 agents and very eager to become more competitive with something that will offer superior performance. And so with those partnerships, we may engage in some creative structures that allows them to also have a head start with their own PD-1 that may have had exposure in lung cancer. So that remains to be determined.

Got it. And then just specifically to the data that is sort of coming up on the lung cancer cohort, did you say how you might be tracking on things like DOR and OS? And then for the PROC data at SGO, it would be great to hear what sort of incremental updates you may look to present relative to SITC. And as you know, in ovarian, there's a few ways you segment your population, BRCA, FR alpha status. So is there sort of a biomarker-driven development where in your thinking of the next step?

Okay. So just to be sure that we are signaling the right kinds of information. So for us, with an I-O agent, like, for example, CTLA-4 targeting anybody our own CTLA-4 for targeting antibody is not just the CTLA-4 binders, but it does four additional things. And that's why we call it a multifunctional CTLA-4. It is not an improved CTLA-4. It really is a multifunctional CTLA-4, and the attributes of this molecule are responsible for a number of things beyond just achieving response rates but duration of responses driven by this molecule, the back end of the molecule, the Fc engineered portion has impacted a number of other capacities, including recruiting immune cells and impacting, for example, down regulation of regulatory T cells, stimulation of memory T cells. These are all very important elements, as you know, Mayank, for the extension of responses or even achieving curative treatments in combination with an agent or example, like our 2371. So -- but to cut to the chase, our ambition here is, number one, overall responses that are collateral with overall survival that will translate potentially to cures for these patients. In fact, as you know, using the word cure was a taboo in this field because it was not deemed that cancers or stage four cancers could be cured until Dr. O'Day injected the very first patient with CTLA-4. And that's started a trend of course with CTLA-4 Yervoy, we interested a very narrow slice of otherwise incurable melanoma patients with curative outcomes. And because of the attributes of our molecule botensilimab, we hope that, that narrow slice effect will be broadened and not just be in melanoma, but much -- many more cancers than melanoma. That is our ambition. And of course, having the other elements of our portfolio gives us a high level of confidence that by combining these agents, we may be able to achieve some remarkable outcomes for patients.

Great. And maybe just my final question, Garo, that sort of high level about the portfolio. Are you able to comment your sort of perception of how big pharma strategy, start evaluating next-gen NIO programs. As you know, PCB and ADCs are sort of the modalities gaining popularity. Curious if you take your pipeline in that direction? And then as big companies trying to assess value at a program level, for example, for bot -- can you comment on what happened at the indication level, and if there's one or more tumor types that get more value and then how development stage and depth of data kind of play in that.

Okay. So I mean -- I don't want to really comment on behalf of what large pharma is doing because they've been very successful. And particularly, since covered a number of large pharma companies have been printing money basically. And that's a great outcome for them. And now that money needs to be put to work and the way they're putting that money to work, quite fully, this is not a criticism is a very practical comment. The right way of doing that is to purchase immediate income. And so the transaction, for example, that you heard yesterday was a major step that is driven by a concern about a patent cliff, which is a real issue with big pharma today, not just one company, but across many companies. So they have the challenge of a major patent cliff and how do they address that by putting that cash that they've generated with COVID and other means to work. And that's an immediate acquisition of a company that has immediate sales and cash flow. And so that's that their game plan. Now, we think highly of ADCs, but that's not our business model. Our business model is use the body's immune system, the power within the body to be able to overcome this miserable disease, that's our business model. And that's what we've been doing for the last 29 years and unwaveringly pursuing this, and that's what we will continue to do. Now do we think -- do we rule out the possibility of, for example, immuno-oncology agents to be used along with targeted therapies VEGF and so on and so forth. Now including ADCs, we don't rule that out. But we look at those agents as adjunctive agent to perhaps to accentuate the response to achieve the kind of cures that we're looking for. So that's our model.

Emily Bodnar with H.C. Wainwright. Your line is open.

Is there anything that you can share about the two new patients who responded in the lung cancer cohort in terms of like background characteristics? And maybe if you could just comment like what level of response rate that you'd want to see in the Phase 1b in order to be confident in move into Phase 3?

Yes. Thank you for the question. All four of the responses have been in a PD-1 refractory resistant setting. And I think that's what's very important. In terms of the response rate, how -- the [indiscernible] here in this setting and other molecules are really in the 10% to 15% response rate, which is very short lived as you know. So obviously, we need to have meaningful differentiation from that to move forward.

Makes sense. Maybe also in your Phase 2 study for MSS CRC since you're focusing on patients without liver mets, could you kind of comment on how you expect the control arm to perform in the setting since like most of these studies have been more broadly evaluated?

So right now, we've reported, obviously, all patients with a 23% response rate, and we've also shown survival data in the non-active liver mets. And so obviously, patients without active liver mets have higher response rates and better survival. This is a subgroup that we think is a significant subgroup in colorectal cancer and will drive our earliest path to registration. So, we're focusing the Phase 2 and the Phase 3, as Garo just said, in that patient population for response, the duration of response, PFS and most importantly, overall survival.

And I think you asked the question about the control group and control group responses, Dr. O'Day.

So in this setting, in the second, third line setting in a stable colorectal cancer, the response rates to regulator long serve have been in the single digits, very low single digits. Their major impact, if you could call it that, is really in their PFS and OS, not their response rate. And that's even limited to several months.

All right. And maybe last question. Are you planning to share any melanoma or pancreatic data, either from the Phase 1 or Phase 2 studies this year?

So, I think the -- I think it's premature to really declare when we will be able to share that data, but we're hoping that at least internally, we have a very good glimpse at how those trials are progressing by the end of this year. And depending on the nature of the data, meaning how many patients we've seen respond and how many patients had reportable outcomes, we may be able to report that in the first quarter at a major conference, first quarter of next year at a major conference.

Mike King with EF Hutton. Your line is open.

Congrats on the updated non-small cell lung cancer data. I wanted just to see if we could get any -- just maybe a housekeeping question first on financial guidance. What -- I don't know, Christine, if you want to say anything about how far the cash runway would take you, what cash use on what expenses R&D and G&A might look like this year? I would imagine given the ramp-up in trial activity that the R&D spend is going to increase, but I don't know if you want to quantify any of that?

Okay. Thank you, Mike. Notwithstanding the little excitement we had over the weekend, of course, even though we didn't have a majority. And all of that has resolved now at least from our perspective. And so without any additional milestones, which is unlikely and without any additional cash infusion into the Company, partnerships and other means. We believe our cash runway will take us through the second quarter of next year. And of course, realistically, given our track record is not to we expect that we're not going to be able to bring in additional cash from sources that I outlined.

Do you -- can you say how much do you have left on the ATM?

We have -- I mean, as you know, Mike, we have a very comfort zone with the ATM. I mean, as I've said publicly, we don't use ATM day in and day out. Some companies do that. We don't do that. We've used ATMs opportunistically to manage our cash based on our spending pattern is the prospect of near-term cash infusion and so on and so forth. But we do -- I think we have about 75 million shares remaining with ATM.

This is a question that comes up a lot with investors. Can I speak to that? Okay. And then...

And by the way, I also want to point out that a number of ATM executions for us have been not just going out and selling in the market. We've also had a reasonable amount of ATMs coming as a result of inbound inquiries from institutions. So instead of waiting for a transaction, sometimes institutions will come to us. As they have as recently in the last few months and said, would you consider giving us x amount of shares through the ATM, sometimes we comply and sometimes we don't, depending on the price of the stock and the timing of things.

Okay. Great. Just again, to come back to the lung cancer data, the question we get a lot, obviously, is what defines refractory, what definition do you guys use? Because there's always that concern about whether patients are truly refractory or not, the pseudoprogression comes into play, et cetera. Steve, I don't know what -- how much you can add to that?

Yes. These are not pseudoprogression. These are refractory patients who have come off PD-1 chemo combinations and then we're on PD-1 maintenance and progress our met therapy. So these are what we would consider refractory PD-1 patients.

Okay. So they come off of maintenance.

Sorry, what was that?

I thought I heard you say it must have come off of maintenance with PD-1.

Well, so the standard first-line treatment is combination chemo and KEYTRUDA as one example of a triplet combination is most commonly used. Those patients get a limited amount of chemotherapy over four to six months and then they continue on PD-1. So obviously, most of those nations respond upfront to the chemotherapy piece of that. And then during the refractory at some point, and it's usually during the maintenance phase.

Right. Okay. And I assume by your traditional practice, these new responses are all confirmed responses, yes.

So, out of the eight patients, we have four responses, three are confirmed, and a fourth is waiting for confirmation with the next scale.

So just to clarify, by the way, the way it works with our reports, the definition of a confirmed response is the outcome of the second scan, not -- whether or not first is a real response or not real response. And we've confirmed that the first response is a bonafide response. But by definition, you have to wait for the next scan to just give a check mark of it's confirmed. So, none of the four patients have not confirmed with a second scan.

David Dai with SMBC. Your line is open.

So first question is just around the first active trial MSS CRC. Since you will be looking at to submit BLA in 2024, if you assume that we'll see some top line data in 2024. And then I guess sort of similar to the question that we had earlier, do you -- just to confirm that you could be rolling down liver mets patients in that trial. Is that correct?

That trial -- the Phase 2 trial is in patients who have no active liver mets, meaning they could have never had liver mets or they would have had treated liver mets, but not active at the time of the trial opens.

Got it. And so just to confirm, are you going to be -- we're going be seeing the top line data in 2024 -- early 2024. Was that correct?

That is our expectation, but we'll have to follow the data and the accrual.

Got it. That's helpful, Steve. So another question just around the expectations for the upcoming Society of Gynecology Oncology annual meeting. So how many should we be expecting? And what's the length that follow-up for these patients with the ovarian cancer patients?

So we're not going to give you the details, but stay tuned for the oral plenary presentation on the 27. What I will say, though, is we've obviously had multiple conferences in front of GI community with our MS stable colorectal. The real only opportunity for expanded other diseases was at SITC last year where we highlighted lung and ovarian and sarcoma. We did have the opportunity to present the sarcoma data, as I said, at a disease-specific sarcoma meeting last year with CTOS. And this is our first opportunity to really present this data, the GYN data, the ovarian data in front of a large GYN community. So, we're looking forward to that and there will be additional data and follow-up presented. And remember, we're producing follow-up that's mature, too. So the number of patients presented is less than what we are currently enrolled. So, we feel that this is very important data that will be presented in a couple of weeks.

Got it. And then just one last question around the safety side of botensilimab, balstilimab combo. So we do see some incidence of unit-related Grade 3 plus diarrhea and colitis in CRC. So what are the latest thinking around mitigation strategies around that. And then how has been the receptivity of the physicians with respect to balancing the efficacy and safety side of equation?

So that's a great question. Toxicity-related -- immune-related toxicity correlates with clinical benefit. The important thing is early intervention, and it's highly reversible with effective treatments. We've come a long way in the management of RAEs. In terms of the diarrhea colitis, it's a spectrum. It's now -- diarrhea and colitis are the same immune-related phenomenon in the gut. And we have reported this toxicity and anywhere from 30% to 50% of patients at different doses and schedule. It's dose schedule dependent. The important thing is that it's are manageable with early intervention with steroids and TMS inhibitors, and we have a very targeted program in our Phase 2 trials, the early recognition of this toxicity and early intervention and subsequent prophylaxis with the combination of steroids and TNF inhibitors. And it's been quite effective. And most of the toxicity is sort of evenly split between Grade 1, 2 versus Grade 3, 4. And we expect that to improve substantially in terms of Grade 3, 4 with our mitigation strategy. When physicians and patients understand that toxicity can be associated with clinical benefit they will report the symptoms earlier, and they can be managed more quickly. And we think this is an important lesson learned from the first generation of I-O therapy.

Kelly Shi with Jefferies. Your line is open.

The first question is for the 23% ORR microsatellite stable colorectal cancer you have reported. Is there an update on if all the responses are confirmed the responses? And secondly, for the projected regulatory submission, in syndication in 2024, you mentioned ORR, DOR median PFS all included as efficacy signals. I'm curious have you discussed this regulator passed with FDA would have been the feedback on accelerated path? And what is the regulatory bar in different shares in color.

Let me ask you, is that gist of your question, the continuation of what we have reported as response rates.

23% ORR.

Okay. So we have reported in colon cancer as of the ASCO GI meeting, 23% ORR and that hasn't changed. In other words, we don't have additional information that dispute what we have reported is not continuing to be the trend in the range, let's say, 20% to 25% overall response rates in coal. I mean, as you know, we're reporting this with ESMO GI last June, and then we reported again at SITC and again at ASCO. And with the top confirmed responses, the responses have been in the range of 20% to 25%. And as more data develops, of course, we're going to report this at subsequent conferences.

There are no further questions at this time. I would now like to turn the call back over to our presenters for final comments.

Thank you very much, everyone. It's been a long conference call as we forward because of the density of the data that Dr. O'Day was reviewing and the momentum continues. So, we're excited about engaging in expanded cohorts and additional announced trial that we're undertaking. And there may be some additional surprise trials that will be announced both in the form of investigator-sponsored trials that may be the focus of attention here, including, for example, trials that will address the toxicity issue pre-emptively, and these are being done at leading institutions. So stay tuned and we will keep you restart clinical data and what is happening with our potential discussions with prospective partners. Thank you very much.