Thank you for holding, and welcome everyone to the Agenus Fourth Quarter and Full-Y ear 2022 Financial Results Conference Call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question- and- answer session. If you'd like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you'd like to withdraw your question, again, press the star one. Thank you. I will now turn the call over to Zach, Head of Investor Relations. Zach, please go ahead.
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 timelines, as well as timelines 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. 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. 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. On top of that, to provide benefit beyond what is currently available with IO 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 advancing the ongoing botensilimab development program, including having dosed over 300 heavily pretreated patients with advanced solid tumors as part of our phase I-B trial. That's a very large trial by any account.
We've done this with as monotherapy and in combination with our PD-1 antibody balstilimab. Botensilimab has produced durable objective responses in nine cold and/or treatment-resistant cancers, including MSS colorectal cancer. MSS stands for microsatellite stable cancers that are particularly challenging to treat with immunotherapy. 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 have been treated and failed prior treatments.
Based on the unprecedented clinical responses in these patients, we have initiated three global randomized phase II trials 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 phase III study in MSS colorectal cancer later on this year in the hope that the cumulative data that we've generated between phase I, phase II randomized trials, and the initiation of phase III 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 from cancer, all kinds of cancers.
We remain committed to advancing our pipeline of innovative therapeutic and 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 code-named AGEN1571, and our CD137 program, otherwise also known as 4-1BB agonistic antibody, which is code named 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 communication means as well, again, throughout this year. Thank you for your attention. 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 benefit of the botensilimab/balstilimab combination compared to what has been reported with standard of care and other investigational therapies in patients with MSS-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%-2%. Other PD-1 or PD-L1 CTLA-4 combinations evaluated in this comparable patient population have reported response rates of only 1%-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%, 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 a 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 combinations in this second or third-line PD-1 refractory non-small cell lung cancer population have reported response rates of 6%-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 five 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%-10% in comparable patient populations. An update of this cohort will be presented at an oral plenary session at the Society of Gynecologic Oncology 2023 Annual Meeting in Women's Cancer on March 27th in just a couple weeks. At CTOS last November and presented by Dr. Breelyn 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 responses still ongoing at the time of the data cutoff. Other PD-1, PD-L1, CTLA-4 combinations have reported response rates of 12%-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, who have often described the results we have observed 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 II 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 components in this study. Finally, we have randomized to a fifth control arm that is a standard of care, either regorafenib or LONSURF at their approved doses and schedules.
We intend to submit for regulatory review of MS-stable colorectal cancer in 2024 a data package with this randomized phase II study along with data for more than 300 patients in the phase I-B study. This package will include overall response rate, duration of response, progression-free survival, and overall survival. We also expect to launch a phase III 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 I-B expansion, we reported responses with botensilimab monotherapy in patients who were refractory to PD-1 and as patients refractory to both PD-1 and CTLA-4.
This is an area of significant unmet need. We currently have an active phase II 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 second-line patients in a phase II 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 I-B 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's clinical activity in late-stage and 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 I 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 I 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. AGEN1571 is an ILT2 agonist antibody designed to modulate tumor-associated macrophages, T cells, NK cells, and NKT cells to overcome resistance to checkpoint blockade.
This clinical study was initiated based on preclinical 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. I'll turn the call back over to Garo to discuss our strategic partnerships.
Thank you, Steven. 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, coding presentations, plenary presentations, four of them within a six-month window at major conferences. 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. Progress was made with our truly differentiated R&D engine and strategic partnerships has been impressive by all accounts. 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. On top of that, royalties when these products are commercialized.
That's a 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. Of course, this is a testament to the strength of our pipeline and the innovative capabilities of our R&D platforms. 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, a TIGIT bispecific antibody now led by BMS.
We're also seeing very great progress with molecules targeting GITR, LAG-3, TIM-3, now led by Incyte. Looking ahead at 2023, that's this year, we have some major clinical milestones in sight. As Dr. O'Day mentioned, we're expecting to complete enrollment of our global randomized phase II studies of botensilimab in MSS colorectal cancer, melanoma, and pancreatic cancer. We expect to initiate a phase III study of botensilimab with balstilimab in MSS colorectal cancer, complete enrollment of our phase I-B study of botensilimab and AGEN2373, that's our CD137 molecule, in melanoma, and initiate botensilimab and balstilimab combination cohorts in a phase I study of AGEN1571, 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 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 of 2022. This includes non-cash 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. 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. 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. 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-resistant cancers, and added to that, improved benefit provided by other IO 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 of 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 justifiable. 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 wanna 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. 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.
Certainly. Again, if you'd like to ask a question, please press star one on your telephone keypad. Matt Phipps, William Blair, your line is open.
Good morning, guys. Congrats on the update in 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 II trial? You know, also, would you still need a botensilimab monotherapy arm, or could the kind of monotherapy data from colorectal and other indications kind of satisfy any contribution of components?
I answer the first question, if 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 III trial or a phase II trial, randomized phase II trial that would be expandable. In the interest of that, we made a decision to expand our cohort to at least 30 patients, perhaps more, but to at least 30 patients. We expect that that will be accomplished within the next several months. With that information, we will take it to the next steps.
If we can sustain 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. As you know, lung cancer is a very large indication. Even though there are some... and it's a hot cancer for the most part, but there are a number of patients that fail current therapies, including IO regimens in combination with other agents. That's the patient population that we've targeted in our phase I trial. That would be the patient population targeted in our expanded cohorts, and that's the patient population that we will go after in our registration strategy. Dr. O'Day, if you wanna answer the colorectal question.
Yeah. Thanks, Matt. For the colorectal question, I think the question was with the monotherapy arms in the colorectal trial as contribution of components. So our phase II 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. 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.
Okay, thanks. Just another kind of follow-up. Do you expect any milestones this year from your numerous collaborations? 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, they'll be significant milestones, not $5 million or $10 million.
Mayank Mamtani with B. Riley Securities, your line is open.
Good morning, team. Thanks for taking our questions and appreciate the level of detail. On the two phase III trials that you're, you know, 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, you know, how that differs from the ongoing randomized phase II data in terms of, you know, target patient population, study objectives. Then on the phase III lung cancer study that, you know, you just touched on, like what are sort of the key goals there? You know, is it late-line patients? Is it, you know, replacing IO chemo regimens in certain settings?
Specifically, are you looking to combine BOT with BAL in lung cancer, or you may consider using an external PD-L1? Then I have a couple of follow-ups.
Obviously the phase III CRC population that we're targeting is going to be along the same lines as our phase II 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 Dr. O'Day said, in the phase II randomized trial. Will we use BAL or approved PD-1 in non-small cell lung cancer? 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 I, I mean, with their own PD-1 or PD-L1 agents, and they're eager to become more competitive with something that will offer superior performance. 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. That remains to be determined.
Got it. 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, you know, things like BOR and OS? Then for the PROC data at SGO, would be great to hear what sort of incremental updates you may look to present later to SITC and you know, as you know, in ovarian, there's a few ways you segment your population, BRCA, FRα status. Is there sort of a biomarker-driven development in ovarian you're thinking as a next step?
Okay. Just to be sure that we are signaling the right kinds of information. For us, with an IO agent, like for example, CTLA-4 targeting antibody, our own CTLA-4 targeting antibody is not just the CTLA-4 binder, 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. The attributes of this molecule are responsible for a number of things beyond just achieving response rates, but durational responses driven by this molecule, the back end of the molecule, the Fc engineered portion that has imparted a number of other capacities, including recruiting immune cells and imparting, for example, downregulation 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, for example, like our AGEN2371. To cut to the chase, our ambition here is, number one, overall responses that are correlatable with overall survival that will translate potentially to cures for these patients. In fact, as you know, the using the word cure was a taboo in this field because it was not deemed that cancers or stage 4 cancers could be curable until Dr. O'Day injected the very first patient with CTLA-4, and that started a trend. Of course, with CTLA-4, Yervoy, we addressed a very narrow slice of otherwise incurable melanoma patients with curative outcomes.
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. Of course, having the other elements of our portfolio, gives us a high level of confidence that by combining these agents, we may be each able to achieve some remarkable outcomes for patients.
Great. Maybe just my final question, Garo, at that sort of high level about the portfolio. Are you able to comment your sort of perception of how, you know, big pharma strategics are evaluating next gen IO programs? As you know, PCV and ADCs are sort of the modalities gaining popularity. Curious if you take your pipeline in that direction and then, you know, as big companies trying to assess value at the program level, for example, for broad, y ou know, can you comment on if it happens at the indication level and if there's one or more tumor types that, you know, get more value, and how development stage and depth of data kind of play in that? Thanks again for taking our questions.
Okay. I mean, I don't want to really comment on behalf of what large pharma is doing because they've been very successful. Particularly since COVID, a number of large pharma companies have been printing money, basically. That's a great outcome for them. Now that money needs to be put to work. The way they're putting that money to work, rightfully, this is not a criticism, this is a very practical comment. The right way of doing that is to purchase immediate income. 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.
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. That's an immediate acquisition of company that has immediate sales and cash flow. That's their game plan. Now, we think highly of ADCs. 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, 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 rule out the possibility of, for example, immuno-oncology agents to be used along with targeted therapies, VEGF, and so on and so forth? No, including ADCs. We don't rule that out. We look at those agents as adjunctive agents to perhaps accentuate the immune response to achieve the kind of cures that we're looking for. That's our model.
Got it. Thanks for taking the question.
Emily Bodnar with H.C. Wainwright. Your line is open.
Hi. Good morning. Thanks for taking the questions. 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? Maybe if you could just comment, like, what level of response rate that you'd wanna see in the phase I-B in order to be confident to move into phase III?
Yes, thank you for the question. You know, 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, you know, how, you know, the big, you know, Taxotere in this setting and other molecules are really in the 10%-15% response rate, which is very short-lived, as you know. Obviously we need to have meaningful differentiation from that to move forward.
All right. Makes sense. Maybe also in your phase II 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 this setting, since, like, most of these studies have been more broadly evaluated? Thanks.
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 meds. Obviously, patients without active liver meds have higher response rates and better survival. This is the subgroup that we think is a significant subgroup in colorectal cancer and will drive our earliest path to registration. We're focusing the phase II and the phase III, as Garo just said, in that patient population for response, the duration of response, PFS, and most importantly, overall survival.
I think you asked that question about the control group and control group responses, Dr. O'day, are [audio distortion].
In this setting, in the second, third line setting in MS- stable colorectal cancer, the response rates to regorafenib or LONSURF have been in the single digits, very low- single digits. Their major impact, if you could call it that, is really in their, you know, PFS and OS, not their response rate, and that's even limited to several months.
All right. Thanks. Maybe, last question. Are you going to share any melanoma or pancreatic data, either from the phase I or phase II studies this year? Thanks.
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'll have a very good glimpse at how those trials are progressing by the end of this year. 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.
Great. Thank you.
Mike King with EF Hutton, your line is open.
Good morning, guys. Thanks for taking the question. 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. You know, what, I don't know, Christine, if you wanna say anything about how far the cash runway will take you, what cash use or what expenses R&D, SG&A might look like this year. I would imagine given the ramp up in trial activity that, R&D spend is gonna increase, but I don't know if you wanna quantify any of that.
Okay. Thank you, Mike. Notwithstanding the little excitement we had over the weekend, even though we didn't have a majority exposure, and all of that is resolved now, at least from our perspective. 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 to the second quarter of next year. Of course, realistically, given our track record, it's not to be expected that we're not gonna be able to bring in additional cash from sources that I outlined.
Do you, can you say how much 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 ATMs day in and day out. Some companies do that. We don't do that. We use ATMs opportunistically to manage our cash based on our spending patterns, the prospect of near-term cash infusion and so on and so forth. We do, I think, we have about 75 million shares remaining with ATM.
Okay. This is a question that comes up a lot with investors when I speak to them.
Yeah.
Okay.
Yeah.
And then—
By the way, I also wanna point out that a number of ATM executions for us have been not just going out and selling in market. We've also had a reasonable amount of ATMs come in as a result of inbound inquiries from institutions. Instead of waiting for a transaction, sometimes institutions will come to us, as they have as recently as the last few months, and said, "Would you consider, you know, 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. Thanks for the clarity. 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? 'Cause there's always that concern about, you know, whether patients are truly refractory or not. You know, the pseudo progression comes into play, et cetera. Steve, I don't know how much you can add to that.
Yeah. These are not pseudo progressions. These are refractory patients who have come off PD-1 chemo combinations and then were on PD-1 maintenance and progressed on that therapy. These are what we would consider refractory PD-1 patients.
Okay. They must have come off of maintenance?
Sorry, what was that?
I heard you, I thought I heard you say they must have come off of maintenance with PD-1.
Well, the standard first-line treatment is combination chemo and KEYTRUDA. That's one example of a triplet combination that's most commonly used. Those patients get a limited amount of chemotherapy over four to six months, and then they continue on PD-1. Obviously most of those patients respond upfront to the chemotherapy piece of that. They are refractory at some point, and it's usually during the maintenance phase.
Right. Okay. I assume by your traditional practice, these new responses are all confirmed responses, yes?
Out of the eight patients, we have four responses. Three are confirmed, and a fourth is waiting for confirmation with the next scan.
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.
Yes.
Not whether or not first is a real response or a not real response. We've confirmed that the first response is a bona fide response. By definition, you have to wait for the next scan to just put a check mark of it's confirmed.
None of the four patients have not confirmed with a second scan.
Understand. Okay. Great. Thanks very much.
David Dai with SMBC, your line is open.
Great. Thanks for taking my questions. First question just around the phase II active trial in MSS CRC. As soon as you would be looking at to submit a BLA in 2024, is it fair to assume that we'll see some top-line data in early 2024? I guess, you know, sort of similar to that, the question that we had earlier. Just to confirm that you could be rolling non-liver met patients in that trial. Is that correct?
That trial, the phase II trial is in patients who have not no active liver mets, meaning they could have never had liver mets or they would have had to have had treated liver mets, but not active at the time that the trial opens.
Got it. Just to confirm, we're gonna be seeing the top-line data early 2024. Would that be correct?
That is our expectation, but we'll have to follow the data and the accrual.
Got it. That's helpful, Steve. Another question just around the data expectations for the upcoming Society of Gynecologic Oncology Annual Meeting. How many patients should we be expecting, and what's the length of follow-up for these patients, the ovarian cancer patients?
We're not gonna give you the details, but stay tuned for the oral plenary presentation on the 27th. What I will say, though, is, you know, 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, the CTOS. This is our first opportunity to really present this data, the GYN data, the ovarian data, in front of a large GYN community. We're looking forward to that, and there will be additional data and follow-up presented.
Remember, we're producing follow-up that's mature too. The number of patients presented is less than what are currently enrolled. We feel that, this is very important data that will be presented in a couple weeks.
Got it. Just one last question, around the safety side of botensilimab/ balstilimab combo. We did see some instance of immune-related toxicity, including grade 3+ diarrhea and colitis in MSS CRC. What are the latest thinking around mitigation strategies around that? How has been the receptivity of the physician with respect to balancing the efficacy and safety side of the equation?
That's a great question. You know, toxicity immune-related toxicity correlates with clinical benefit. The important thing is early intervention, it's highly reversible with effective treatments. We've come a long way in the management of irAEs. In terms of the diarrhea/ colitis, you know, it's a spectrum. It's now, diarrhea and colitis are the same immune-related phenomenon in the gut. we have reported this toxicity in anywhere from 30%- 50% of patients at different doses and schedule. It's dose and schedule dependent. The important thing is that they're manageable with early interventions, with steroids and TNF inhibitors. we have a very targeted program in our phase II trials to early recognition of this toxicity and early intervention and subsequent prophylaxis with the combination of steroids and TNF inhibitors. it's been quite effective.
Most of the toxicity, it's sort of evenly split between grade 1- 2 versus grade 3- 4. 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. We think this is an important lessons learned from the first generation of IO therapy.
All right. Thank you so much.
Kelly Shi with Jefferies, your line is open.
Thank you for taking my questions. The first question is for the 23% ORR in microsatellite stable colorectal cancer you have reported. Is there a update on if all the responses are confirmed responses? Secondly, for the projected regulatory submission in this indication in 2024, you mentioned ORR, DOR, median PFS, all included as efficacy signals. I'm curious, have you discussed this regulatory path with the FDA? What has been the feedback on the accelerated path and what is the regulatory bar, if you can share some color? Thank you.
Let me ask you, Is the gist of your question, the continuation of what we have reported as response rates?
23% ORR.
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 disputes what we have reported as not continuing to be the trend in the range of, let's say, 20%-25% overall response rates in colon cancer. I mean, as you know, we started reporting this with ESMO GI last June, and then we reported again at SITC and again at ASCO. With the confirmed responses, the responses have been in the range of 20%-25%. As more data develops, of course, we're gonna report this at subsequent conferences.
Any other questions?
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 forewarned you because of the density of the data that Dr. O'Day was reviewing. The momentum continues. We're excited about engaging in expanded cohorts and additional announced trials that we're undertaking. 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 preemptively, and these are being done at leading institutions. Stay tuned, and we will, we'll keep you abreast of both clinical data and what is happening with our potential discussions with prospective partners. Thank you very much.
This concludes today's conference call. We thank you for your participation. You may now disconnect.