Traws Pharma, Inc. (TRAW) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Onconova Therapeutics webinar. [Operator Instructions] As a reminder, this webcast is being recorded today, September 22, 2021. At this time, I would like to turn the call over to Avi Oler, Senior Vice President of Corporate Development and General Counsel.

Thank you, Tara. Good afternoon, everyone, and welcome to today's webinar. Earlier today, Onconova issued a press release announcing preliminary data from the Phase I/IIa investigator-initiated trial of oral rigosertib plus nivolumab in advanced KRAS-mutated non-small cell lung cancer, which is the topic of today's discussion. The data to be reviewed was presented at the RAS-Targeted Drug Development Summit earlier today. A copy of this press release as well as a replay of today's webinar can be found on the Investors and Media page of the Onconova website. Before we begin, I'd like to remind everyone that statements made in the press release and during the webinar will include forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties that can cause actual results to differ materially. Forward-looking statements speak only as of the date they are made as the underlying facts and circumstances may change. Except as required by law, Onconova disclaims any obligation to update these forward-looking statements to reflect future information, events or circumstances. For more information on forward-looking statements, please review the disclaimer in today's press release and the risk factors in the company's filings with the SEC. With that, it is now my pleasure to turn the call over to our President and CEO, Dr. Steve Fruchtman. Steve?

Thank you, Avi. Good afternoon, everyone, and thank you for joining this important meeting. During today's webinar, we will be highlighting the encouraging clinical data presented earlier today, which supports the potential anticancer activity of the rigosertib-nivolumab combination therapy in heavily pretreated patients with KRAS-mutated non-small cell lung cancer. An overview of lung cancer will be presented, including a multitude of KRAS mutations seen in lung cancer and the current treatment landscape. These data will be discussed with 2 important key opinion leaders: first, Dr. Raj Veluswamy, an Assistant Professor of Medicine, Hematology and Medical Oncology at Mount Sinai in New York's Icahn School of Medicine and the principal investigator of the trial. He will provide an overview of the treatment landscape and unmet medical need in KRAS-mutated non-small cell lung cancer. Following this overview, Dr. Veluswamy will present details on the Phase I/IIa study design and the clinical safety and efficacy data based on the current status of the trial. Afterwards, I'll provide additional context on the data and speak briefly about the broader development program being advanced at Onconova. We will then proceed into a question-and-answer session with Dr. Veluswamy and featuring our second key opinion leader, Dr. Scott Antonia, a Professor of Medicine at the Duke Cancer Institute and the Director of its cancer -- its Center for Cancer Immunotherapy. With that, I'll now hand over the call to our Chief Medical Officer, Dr. Mark Gelder, to introduce to you our key opinion leaders. Mark?

Thanks, Steve, and thanks to all of you who are listening as well. It really is my pleasure to introduce to you today our 2 key opinion leaders, who are both recognized experts in the field of thoracic oncology, particularly non-small cell lung cancer. Dr. Scott Antonia, as Steve mentioned, is from Duke Cancer Institute. Dr. Antonia is a Professor of Medicine at the Duke Cancer Institute and the Director of its Center for Cancer Immunotherapy. He is recognized as a world leader in the development of immunotherapy for lung cancer and served as a global principal investigator of the practice-changing Pacific Study. The study established anti-PD-101 as consolidated therapy for combined chemoradiation therapy as the global standard of care for locally advanced non-small cell lung cancer. As a clinician and translational researcher, the goal of Dr. Antonia's research program is to develop immunotherapeutic strategies for the treatment of cancer patients. We are thrilled to have the opportunity to hear his views on the available treatment approaches for non-small cell lung cancer and the importance of the data being presented here today. In addition to Dr. Antonia, we are also joined, as Steve mentioned, by the principal investigator of the Phase I/IIa study being discussed today, Dr. Raj Veluswamy. Raj, as previously mentioned, is from the Icahn School of Medicine at Mount Sinai. Dr. Veluswamy is an Assistant Professor of Medicine in the Department of Hematology and Medical Oncology and is a board-certified medical oncologist who specializes in the treatment of lung cancer and other thoracic malignancies. His research focused on understanding the factors responsible for clinical outcomes in lung cancer patients, from patterns of care to differences in therapeutic drug efficacy with a particular focus on individuals with KRAS-mutant non-small cell lung cancer. He has published extensively and received numerous merit awards such as the prestigious ASCO Young Investigator Award in recognition and support of his research. As a faculty member at Mount Sinai, he uses novel research methods to investigate complex mechanisms in cancer and its treatment, especially in molecular therapy and immunotherapy. We are indeed grateful that he is joining us here today. Dr. Veluswamy, please go ahead.

Hi, I'm very pleased to be here. I think we're going to start with an overview of the treatment landscape of non-small cell lung cancer with a focus on KRAS mutations on next slide. So I'm sure this group knows lung cancer is common. It has the second-highest incidence amongst all cancers, and it has the highest cancer-related mortality. Historically, we've always classified lung cancer according to histologic types. Non-small cell lung cancer makes up 85% of lung cancers, with the remaining 15% being small cell lung cancer. Within non-small cell lung cancer, we then focus really on the cell type, and adenocarcinoma some time ago has now become the most common type of non-small cell lung cancer, accounting for 40% of all cases. Next slide. Over the last 2 decades, it's become more clear that beyond histologic classification, the molecular classification specifically for adenocarcinomas where there's a predominance of molecular oncogenic driver mutations that are really driving these cancers really has come to light and has become increasingly more important as more targeted treatments have come to -- have been discovered and come to the clinical trials and now even in treatment. You can see a lot of these mutations on these tables such as EGFR, ALK, ROS1, and we've seen great success with targeting these treatments. KRAS, we've known about for 40 years and -- or so. And we really haven't made much progress until recently despite the fact that it's the most common molecular driver mutation in lung adenocarcinoma. Whenever we look at kind of what type of patients have these KRAS mutations, they're frequently associated with smokers. Interestingly, when you adjust for smoking, though, and other factors, females tend to have higher rates of KRAS mutations than males, and I don't think we really have a great answer for that yet. Next slide. So not all KRAS mutations are the same. So in general, RAS has 3 isoforms, and KRAS is most common in lung cancer. And so within KRAS, there -- these -- gain-of-function missense mutations that are in codons 12, 13 and 61. And with these mutations, it constitutively activates the RAS protein, which will lead to activation of several downstream pathways that eventually result in cell proliferation, differentiation and, ultimately, cancer. And so ultimately, when we talk about kind of these variants of KRAS, and you hear something like G12C, for example, which has come to light, that's simply on codon 12 where glycine residue is replaced by a cysteine residue. And so G12D and G12V, which are the other 2 common KRAS mutations, again, are the glycine amino acid is being replaced by another amino acid. And ultimately, this leads to the constitutive activation of this RAS protein. There's some data that shows that there are different phenotypes within these variants. And then as well, importantly, there's -- KRAS mutations are -- often have co-mutations with other genetic alterations, oftentimes with tumor suppressor genes like TP53 and STK11. And all of that said, what we've kind of learned about KRAS is that there's a lot of heterogeneity, clinical -- with clinical phenotypes with these mutations that they don't seem to all act the same, and really, the experience in the clinical trial data and different clinical data have kind of shown this. At the bottom right there, that's -- I believe that's some of the survival curves from the BATTLE I study, which really focused on molecular phenotypes, and it showed that different KRAS mutations had different clinical outcomes. And so next slide. And so -- and I think this is what it's all about because, ultimately, and this is a very busy slide, and we wouldn't have time to go through nearly, even start with it really. But the fact is that there are so many pathways that are impacted by KRAS. And so the idea here is that, potentially, the differences in these mutations and co-mutations might preferentially express certain pathways, and ultimately, it leads to the same kind of proliferation signal. But that's why it's really been so hard to target and treat. I mean prior attempts have looked at trying to inhibit some enzymatic steps in KRAS, which didn't work at all. And then there was -- some years ago, there was some excitement about trying to use MEK inhibition, which is one of the pathways in the KRAS signaling. And that, unfortunately, when it got to Phase III trials, didn't work. And so really, it has been a challenge to target these tumors. Next slide. That is until recently, there's been a lot of excitement about the ability to target KRAS G12C. And essentially, the structural analysis was done, and it revealed that the mutant cysteine residue had -- adjacent to a small pocket where you could actually fit in a drug, and this pocket was really -- is really only present in active form. So KRAS is a [indiscernible] switch as well that cycles from an on-state GTP-bound on-state to a GDP off-state. And in that off-state for G12C, leveraging this mutant cysteine residue there, it kind of appeared to be this pocket that these direct G12C inhibitors are able to fit into and block. That said, I'm sure everyone knows that the FDA granted accelerated approval for the Amgen compound sotorasib after seeing the overall response data of 36% for KRAS G12C locally advanced or metastatic non-small cell lung cancer progressed on at least one line of treatment. And, yes, as I said, this was based on the CodeBreaK 100 trial. And the overall response rate of 36%, when compared to other targeted treatments of molecular drivers isn't so exciting. But again, this is KRAS we're talking about, and this is really kind of some of the first data that we're seeing where we're able to target it. And so that's why it's generated some excitement. Next slide. So I'll just say that I think that there -- certainly, with the G12C, we're making some headway. It was part of, I think, the title is unmet needs. There's a lot of other KRAS variants that are important to target. And that was a lot of our interest in this trial right here. So I think at this point, I'll discuss the -- our current trial, this Phase I/IIa trial of rigosertib in combination with nivolumab for advanced KRAS non-small cell lung cancer patients. These patients progressed as well on one line of prior immunotherapy. Next slide. And so these are my disclosures. Next slide. So as we talked about KRAS, the -- kind of the overall story of KRAS. But where our interest really came for -- with rigosertib was over the last 5 years or so, several mechanisms of action of rigosertib have been proposed, and work from Prem Reddy at Mount Sinai's lab demonstrated that rigosertib was able to disrupt several RAS effectors and activating pathway. So it wasn't just one. And in their preclinical work, they were able to demonstrate that rigosertib impacted several of these pathways. And they proposed that rigosertib did this through competitive inhibition of the RAS-binding domain, which activated many of these effectors. There's -- and other groups have looked at the mechanism of action of rigosertib. The Morrison Lab found that rigosertib's ability to inhibit RAS signaling may be through its impact on the stress-activated JNK cascade. And then important to note the Weissman lab described really an alternative mechanism of action where they found that rigosertib's anticancer activity may be the result of a microtubule destabilization activity. There's some controversy here. Dr. Reddy's group kind of went back and did some of these experiments, and they felt that this microtubule destabilization activity, well, it wasn't from rigosertib, but instead, it was from a contaminating degradation product of rigosertib. That said, I think there's certainly some controversy here as for the exact mechanism of action. But the focus of this trial, the rationale that we used is really the data that's consistently shown that rigosertib is able to downregulate several of these RAS-signaling pathways. The other thing that we kind of further hypothesized was -- is that based on work from other groups that RAS signaling is additionally considered to be immunomodulatory, and that disruption of this RAS signaling might provide an opportunity to reinvigorate the antitumor immune response. And so that's why we really wanted to combine it with an immune checkpoint inhibitor. Rigosertib, as you might know, has been studied extensively before. Over 1,300 patients have been treated with rigosertib. And so it really gave us great safety data to inform our clinical trial design. And notably, there was no overlap, really, in toxicities with immune checkpoint inhibitors. Next slide. So briefly, here's some of the cell line work done by the Reddy lab to examine whether rigosertib inhibits that interaction between that activated GTP-bound RAS with downstream RAF or the MAPK pathway. And so they essentially took multiple KRAS-mutated cell lines, and they incubated them with DMSO, rigosertib and a BRAF inhibitor. And then they stimulated these cell lines to activate RAS, and they found that rigosertib does indeed downregulate -- looking at these codons, downregulates RAS, phospho-ERK and AKT signaling. And at the bottom right, you'll see that they did the same analysis with the mutated BRAF cell line, and they didn't find the same impact on MAPK signaling. And so this really kind of suggests that rigosertib is specific to KRAS mutations. Next slide. So here they essentially implanted cell lines in xenografts and treated with rigosertib. You can see here both models, there was inhibition of tumor growth with rigosertib treatment. And then again, on the top right-hand panel, we can see here the western blots that showed decreased expression of these RAS pathways. Next slide. These are just the references for those alternative mechanisms of the activated JNK cascade and the microtubule destabilizing properties proposed. Next slide. So Dr. Antonia can certainly speak to this in more detail, but immunotherapy is quite interesting in KRAS-mutated lung cancers. It's generally thought these tumors might be more immunogenic when you look at some of immunotherapy trial data in this post-hoc analysis, when you go back and look at the KRAS-mutated cancers, they seem to -- there's some suggestion that they might respond better, and this is supported by some real-world data as well. And so possible explanation is that KRAS is frequently associated, as we talked about, with smoking, which is immunogenic risk factor. And additionally, there's these concurrent co-mutations, so really affecting tumor suppressor genes. And so this could all lead to higher tumor mutation burden and, therefore, a higher -- which could be a proxy for neoantigen exposure and higher likelihood of response to immune checkpoint inhibition. Next slide. In addition, there's also [indiscernible] data that RAS signaling results in induction of several cytokines and chemokines that can alter the immune microenvironment, and without disruption, as I said, of the signaling [indiscernible] cancers to immune checkpoint inhibitors. So here's the data -- a recent publication from the Richmond lab, and they used an immunocompetent melanoma mouse model. And they found that rigosertib indeed does increase tumor infiltrating lymphocyte -- lymphocytes and results in immunogenic cell death, and this was strongly associated with CD40 expression. Next slide. This is another immunocompetent colorectal cancer model from Hanx, and they essentially treated with rigosertib and showed that it inhibited tumor growth as monotherapy. And then when they added their PD-1 inhibitor to the rigosertib, it appeared to synergistically work towards inhibiting tumor growth. Next slide. So this is our study design combining oral rigosertib with IV nivolumab. We included all patients with Stage IV lung adenocarcinomas that harbored KRAS mutation. All patients progressed on prior immune checkpoint inhibitor therapy either as a monotherapy or in combination with the platinum doublet chemotherapy. They had ECOG performance status of 0 to 2. The main exclusion criteria is we excluded patients that had EGFR-sensitizing mutations or ALK translocations. This normally is an issue because these mutations are all considered mutually exclusive. Additionally, we excluded patients that had conditions that might preclude them from immune checkpoint inhibitor treatment such as active autoimmune disease and those that were on high-dose steroids, and this is commonly done in trials, we excluded patients with untreated CNS metastases. So the trial had 2 phases. One was the dose -- first, the dose-escalation phase, followed by an expansion phase. So the dose-escalation phase, the nivolumab was given at the standard 240 milligrams on days 1 through -- day 1 and 15 in a 28-day cycle. The oral rigosertib was given on days 1 through 21 at 3 dose levels that were escalated. The first dose level, dose 1 was rigosertib at 280 milligrams twice a day; dose 2, rigosertib 560 milligrams in the morning and 280 milligrams in the afternoon; and dose 3 was 560 milligrams twice a day. And so as I mentioned, we had great safety data for rigosertib, and of course, we have great safety data for nivolumab. And so this really kind of gave us confidence to try to get to the highest dose as quickly as possible to provide therapeutic benefit for our patients. And so we employed an accelerated titration design. And so -- to start with. And this essentially puts -- uses single-patient cohorts at the lower dose levels to quickly accelerate. So -- and on the next slide, I'll be able to show you kind of that scheme. And so ultimately, when you reach the highest dose, or if you encounter a grade 2 toxicity, you transition to a conventional 3-plus-3 design. And so once we were at the highest dose of rigosertib, we went into a dose expansion phase with 12 additional patients for the combination. The primary objective was safety and tolerability, and the secondary objectives was preliminary evidence of efficacy, looking at overall response rate, progression-free survival and overall survival. And we did radiographic scans every 8 weeks. In addition, we got -- we're very interested in the correlative science. And so we got pre- and on-treatment tumor biopsies for most patients. And additionally, we also got serial blood collections. And this is really to really explore the genomic studies and immunophenotyping to really understand what's going on at the tissue level. Next slide. So the trial opened at Mount Sinai in June 2020 in the middle of the COVID pandemic. But I think we still accrued quite well. 12 patients are currently enrolled in the trial. And so on the bottom left, you can kind of see the progress. So there is one patient put on the 280-milligram twice-a-day dose 1 cohort, and they tolerated it well. The next patient was put at the dose 2 level and tolerated it well. And then 6 patients at the third and highest dose. And once that was designated as tolerable, then we moved into the expansion phase for 4 patients that have been put on that 560 milligrams twice daily. On the right, this table shows baseline characteristics of our study cohort. The median age is 60 years' old, with a range of 53 to 80. As you can see here, 92% of patients have non-G12C mutations with the most common being G12V and G12D. Most patients were smokers, current or former, as kind of expected. But what was a little bit unexpected was that 33% of our patients were never smokers, which -- I mean, usually, we wouldn't necessarily expect that with KRAS mutations. All patients had good performance status, and the cohort was heavily treated. 75% of patients had 2 or more systemic lines of treatment. The most -- 92% of these patients had immunotherapy in combination with chemotherapy. Next slide. This is our safety and tolerability data thus far. As you can see here, the treatment-related adverse events were mostly mild, mostly grade 1 and 2 side effects that were generally pretty well manageable. The most common side effects noted were the urinary toxicities, which have been well documented with rigosertib. We benefited from prior experience and several mitigation strategies. And so patients -- sometimes we were able to use -- some of them stayed on trial -- the drug the whole time. Other times, we had to do a temporary pause on the rigosertib and then restart. But for the most part, patients were able to stay on study drug. All the other toxicities were generally manageable or self-limiting. Importantly, there was no synergistic toxicities noted for either study drug. There was one dose-limiting toxicity at the 560-milligram twice daily dose, that's the third dose cohort, for grade 3 hyponatremia. And hyponatremia has previously been documented for with rigosertib. Next slide. This is our response data to date. So of the 12 patients, we have 7 evaluable patients. Evaluable is defined as having at least 1 scan on study drug. And of those 7 patients, 3 patients, that's 43%, have disease control with 2 partial responses and 1 stable disease. Of the 5 non-evaluable patients, 3 patients discontinued study drug prior to that first scan due to toxicity. Two of them did this voluntarily because of the GU toxicities, and the third patient had the dose-limiting toxicity, as previously mentioned. Currently, we have 2 patients on study drug in the evaluation window. So at the bottom, you can see the swimmers plot, and here you can see that the patients at the dose 1 level, the 280-milligram twice daily, had stable disease and had progression at 5 months. Patient 2, at the dose level -- the second dose level of 560 milligrams in the morning and 280 milligrams in the afternoon, had a partial response and was on trial for 8 months until disease progression. And then as well as patient 8 at the dose 3 level had a partial response and continues to respond after 6 months on trial. Next slide. So to dive into these partial responses a little bit more. This is the second patient at the second dose level. And so this was a Caucasian female, who is a current smoker, had excellent performance status. So she really had poor risk features of her cancer. She has mucinous adenocarcinoma. These are generally more aggressive histologic type. And additionally, I mean, she had a KRAS G12C mutation. Then these co-mutations are generally considered poor prognostic markers, STK11 and SMARCA4 mutation. She -- at the time of diagnosis, she had a PD-L1 of 99%. The sites of her disease were the lung and bone. At the time of diagnosis, she was thought to have an earlier-stage disease and was put on a neoadjuvant trial with immunotherapy and chemotherapy and received 2 cycles. But then on restaging, was found to have metastatic disease, for which she was put on standard first-line carboplatin, pemetrexed and pembrolizumab. But she quickly progressed after 3 months of treatment and then was enrolled in this trial. Next slide. So this is the RECIST of evaluation. You can see here on the top left, these are the 2 target lesions, and I'll point you towards the left upper low nodule, which, at 2 months, reduced in size, nearly 50%. And then on the upper right side, you can see the PET scan. This is an activity scan. And the baseline is on the left, and the 2-month scan's on the right. And you can see that left upper lobe lesion was quite active, and there was significant reduction in activity at 2 months. Also, interestingly, there is a [indiscernible] fusion on the left lung. [indiscernible] kind of at the bottom, which also disappeared. And then at the bottom is the target sum chart, which demonstrates the partial response. Next slide. This is patient 8 at the 560-milligram twice-daily dose who's had a partial response, and is currently still on trial. This is a Caucasian male, former smoker with good performance status, has a KRAS G12V lung adenocarcinoma with low PD-L1 expression at the time of diagnosis. The sites of disease are the lung and then previously treated brain metastases. And then this patient was put on standard first-line carboplatin, pemetrexed and pembrolizumab and then -- after progressed after 5 months of treatment and was thereafter put on this trial. Next slide. So this is the RECIST evaluation of this patient. Here are, on the top left, the 2 target lesions, which you can see a significant response at the 2-month mark. At the 4-month mark, the target lesions disappeared. This patient is considered partial response because the nontarget lesions are still present. And then at the bottom is the target sum chart. And so this is quite a nice response to treatment. Next slide. So as I mentioned, we really tried to get paired tissue biopsies pre- and on-treatment, and we did so for a good percentage of the patients. But sometimes these biopsies can be quite challenging. And so I have 2 paired -- 2 patients with paired biopsies that I can show you some data for. And so this was the first patient at the dose 1 level. And the first thing we were interested in doing is the pharmacodynamic studies to make sure that these drugs are hitting the target that we're interested in. And here, the top row is pretreatment, and on the left side of the top row is pretreatment course, and bottom is the on-treatment. And so we look for phospho-ERK staining. And so as you can see here on the top or the pretreatment, there was significantly high phospho-ERK staining. The second panel is essentially kind of showing the cells, at the cellular level, the phospho-ERK staining. And then we then applied a cell classifier to delineate what's tumor and what's stroma, and then we can really determine the percent of tumor cells that were positive for phospho-ERK. And so some 75% of these tumor cells were positive for phospho-ERK. But then on-treatment, we see, I think, a quite impressive complete, almost a near loss of phospho-ERK staining on study drug. And this patient did have a stable disease. So this -- clinically, this correlated with the stable disease that we saw at 2 months. Next slide. So on the other side, this is patient 10 who had disease progression on rigosertib, 560 milligrams twice a day. And again, here, the course from the pre- and on-treatment. And you see here, essentially no loss in phospho-ERK staining. And this really correlated with clinical disease progression. Next slide. So in conclusion, rigosertib is a novel agent that downregulates mutated KRAS pathways. It's mutation agnostic. And in combination with nivolumab. And this trial has been well tolerated with a low incidence of grade 3 or higher toxicities. We've only observed 1 dose-limiting toxicity so far, which was the hyponatremia. As far as response. Of the 7 evaluable patients, 3 patients, 43%, demonstrated clinical benefit with 2 partial responses and 1 stable disease. The responses were across different KRAS mutations. Going forward, we have 9 more patients to be enrolled in this 560-milligram, twice-daily expansion cohort. The molecular immune studies on the pre- and on-treatment biopsies in blood are currently ongoing, and we hope to really describe the pharmacodynamics and the impact of the immune microenvironment. And then we are also planning additional dose-escalation cohorts to determine the MTD and recommended Phase II dose. Okay. Thank you.

Thank you, Raj, for that very comprehensive presentation. So first of all, we're very pleased to have seen these responses, not just in the primary tumor, but metastatic sites as well. And as you may know, it's the metastatic sites that are the major cause of death for these patients. The results presented were from an extremely challenging population consisting exclusively of patients who previously failed therapy with an anti-PD-1 checkpoint inhibitor, which suggests that rigosertib, in combination, may augment the response to checkpoint inhibitors by blocking the RAS pathway. The responses were seen across multiple KRAS-mutated variants, and this is very intriguing and confirms the MOA that had been described previously. And this observation potentially differentiates rigosertib from other RAS pathway modulators that are in the clinic or under development that target particular KRAS mutations, such as G12C. Collectively, these results highlight rigosertib's potential to address an unmet medical need in patients who have very limited treatment options. The data today, together with prior clinical data, suggest that the combination of rigosertib with a checkpoint inhibitor may have applicability, not only to KRAS-mutated non-small cell lung cancer, but also to other indications such as melanoma, where PD-1 inhibitors have become the standard of care. If I can have the next slide, please. So looking forward, we will continue to support accrual in the Phase I/IIa trial that Raj just showed to you and the trial's expansion cohort to gather more patient data. And we will work with investigators to facilitate the clinical development of the rigosertib/nivolumab doublet. Additionally, an investigator-initiated study in advanced malignant melanoma evaluating rigosertib, in combination with a PD-1 checkpoint inhibitor is expected to be finalized and to start to accrue patients. Before we move on to the question-and-answer session, I'd like to emphasize that while we are very pleased with today's data and interested in the continued development of rigosertib in KRAS-mutated indications through investigator-initiated studies, we remain committed to preserving our primary focus and resources on our lead compound, ON 123300, a novel CDK 4/6 inhibitor that targets multiple tyrosine kinases as well. So I'm going to -- I really want to get to the question-and-answer session as soon as possible, so I'm going to go very rapidly through this. Narazaciclib is our novel ON 123300, and we are doing a trial both in the U.S. and China to establish the recommended Phase II dose. We will continue to study rigosertib in combination with nivolumab, interested in other novel combinations as well in KRAS-mutated non-small cell lung cancer and other KRAS-driven diseases. We continue to evaluate potential clinical and scientific in-licensing opportunities that we are aggressively pursuing. And we are well capitalized to continue these studies, as outlined today, with a greater than 18 months of cash runway. Next slide. If there are no next slide, which is good news, I'd like the operator to open up the question-and-answer session. So Tara, please.

[Operator Instructions]

And perhaps ideally, you can address your questions to Dr. Veluswamy or Dr. Antonia to answer your question. If not, I'll direct the question.

Great. Our first question comes from Charles Zhu at Guggenheim.

Maybe one for Dr. Veluswamy. Are you able to comment on any potential updates for patients 11 and 12 after date of cough. And whether or not they've been assessed yet with a post-baseline scan?

Yes. So for patients 11, 12, the ones that are currently in the evaluation window, we're expecting scans within the next week or 2.

Got it. And I'm also wondering, you had referenced something around not only expanding but also potential further dose escalation beyond 560 mg BID. And granted, you only have 1 DLT among 12 patients, but I'm kind of wondering, how much confidence do you have in being able to further escalate given you've also had 2 treatment discontinuations due to grade 2 on urinary toxicities?

Yes. I think that's something that we've definitely considered. As I said, the urinary toxicities, for the most part, have been manageable. A lot of it has to do with patients staying very well hydrated and really emptying their bladder at night. It's thought kind of as potentially a metabolite of rigosertib that kind of settles in the bladder that's causing this kind of irritation. And so these strategies have certainly helped. And so for the most part, I think that we're going to watch it closely as far as the urinary toxicities. And there's not entirely a clear signal as well that this is dose related either. I mean again, it's a small sample, but we're not entirely sure of that, so it's something we're going to watch closely. But the other -- beyond that, the other side effects really have been quite manageable with grade 1 and 2 side effects. So...

Got it. And one last question from me. I'm also under the impression from the existing literature that there are certain non-small cell lung cancer patients previously treated with checkpoint inhibitor that could potentially benefit from a further rechallenge or with another course of PD-1 inhibition. Along those lines, it's modest, but along those lines, I'm trying to understand to what extent the patients that you've enrolled into this trial could potentially fall into that bucket.

I wouldn't expect that because these patients have recently progressed on checkpoint inhibitors. The majority of them have recently progressed on checkpoint inhibitors. So just -- I mean to kind of be clear about your question, the thought that they have progressed previously on checkpoint inhibitors and for whatever reason, after a certain duration of time, rechallenge kind of reinvigorated, something kind of changed and reinvigorated kind of the antitumor immune response, is that the idea?

Yes. I guess the literature was probably just describing a few cases where either PD-1 was not tolerated or perhaps they had completed a course and then after some time that the tumors have come back.

No. That's not the case here. All patients progressed on PD-1 inhibitors. And so it wasn't a question of tolerability but all patients had previously progressed on PD-1 inhibitor.

If I may, maybe Scott can give his opinion about the expectation of responses if a PD-1 inhibitor or PD-L1 inhibitor switched, what would the expectation be, Scott?

I'll just reinforce what Raj just said. In my strong opinion, there's absolutely no chance that these patients were responding -- would have responded to nivolumab as a single agent.

Our next question comes from Joe Pantginis at H.C. Wainwright.

Great. Can you hear me?

Yes, Joe, we hear you.

Okay. Great. So a couple of questions, if you don't mind. First, obviously, rigosertib has had a bit of a long history. And I was hoping you or Dr. Veluswamy can discuss the potential of the drug as you assess its potential of hematological versus solid tumors overall because the mechanism of action, obviously, could impact each tumor type differently.

So I could add some color to that, and then I'll ask Raj and Scott to contribute their viewpoint, but they may not be as expert in the development and the history of rigosertib that we are. So rigosertib was being developed over a decade in high-risk mild dysplastic syndrome. I think that's what you're asking about, Joe. But when the study was first beginning, very little was known about the incidence of RAS mutations in MDS. And if you speak to hematologists about RAS, they actually know very little about it. It's mostly in the realm of solid tumors where RAS expertise lies. And what the INSPIRE trial, which was an overall survival trial of 370 randomized patients, showed, which will be presented, by the way, at a major medical meeting, less than -- I think it was about 12% or so, a small number, had mutations of RAS, and all of the patients with a mutation of RAS had other mutations as well in their bone marrow hematopoietic progenitor cells. So what's driving the MDS clone or the leukemic clone is really not well understood. And the rarity of RAS mutations in high-risk MDS suggested that, that was the wrong indication to study, and we hope now we are in a better path for better indications where rigosertib will have evidence of clinical efficacy. And I don't know if Raj or Scott wants to add to my words. Or that was...

You have to think about this as -- it's not completely known what the mechanism of action here is for the combination, right? The preclinical studies that Raj showed clearly showed that there was an induced accumulation of T cells and induction of CD40 expression, suggesting some impact on antigen-presenting cells and expansion of T cells by this agent. Of course, that could still be due to the impact on the tumor cells and influencing some sort of chemokine or cytokine release, but it doesn't rule out the possibility that there's some direct impact on the immune system as well. So it's most rational, of course, to continue to develop this along the path of KRAS-mutant tumors. But I wouldn't be surprised, and I would encourage the company to continue to think about that this may be, I think, certainly disease-agnostic. Really, all of our immunotherapies are disease agnostic, so I think it's applicable to other diseases where KRAS may be mutant. But I wouldn't be surprised if this had an impact in even KRAS mutation -- in KRAS mutation-agnostic fashion as well.

Got it. That's helpful detail. And you know what, I'm going to sort of combine my next 3 questions. The first one is you talked about some of the data implicating rigosertib with regard to TIL infiltration and the underlying mechanism of action of rigosertib, so I'm hoping you could discuss that a little bit. The second question is you talk about the -- obviously, you've addressed this a bit, obviously, with some of the earlier questions, but the combination of nivolumab and rigosertib and the combination safety profile and why you -- a little more color on why you feel the combination adds a safety benefit. And second, when you look at the overall -- I'm sorry, third, when you look at the overall viewpoint of combination studies right now in the investment field, an overarching question is what the contribution is of novel therapy -- novel therapies to the combination is. So here, you've talked about patients that have seen prior checkpoint inhibitors. So I think a basic question at this point is how can the investment community feel confident that rigosertib is adding additional benefit to these patients.

I think the clinical setting, the clinical trial design that Raj came up with answers that question, right? There's preexisting knowledge that this drug doesn't have much clinical activity as monotherapy in this patient population. Certainly selected patients had no chance of being responsive to anti-PD-1. So there's no question that this drug produced the response. And it's not surprising that you have to use -- so almost no immunotherapeutics have activity as monotherapy, right? When we first started developing immunotherapeutics for cancer in general or immunomodulatory antibodies targeting immune checkpoint proteins, nobody thought that any single agent would work, given the redundancy of the potentially immunosuppressive mechanisms. And so it's actually quite shocking that anti-PD-1 is something that gets lost, and people who have just come recently to the field -- it's actually quite shocking to us all in the field that anti-PD-1 had single-agent activity. And of course, early on, our hope was that there would be other pieces of the pie. So we labeled this as a driver immunosuppressive mechanism because, of course, anti-PD-1 produces tumor responses in those patients who do respond. And hope was that [indiscernible] would be the other pieces of the pie, and they would all add up, and we'd be able to treat a lot of patients. Of course, we're finding that, that is not the case. So I don't -- and there may be other driver immunosuppressive mechanisms that we can target and we may find. But I would say that, that would be the exception. And I think that the combination with anti-PD-1 remains extremely rational. So oftentimes, we get back, oh, just because we have anti-PD-1s, we combine it with the anti-PD-1. But there's an underlying biologic rationale underpinning that, right? The way that -- if anti-PD-1 works, of course, that produces a T cell response. And of course, a manifestation of a productive antitumor T cell response is the secretion of gamma interferon, which is a potent inducer of PD-L1. So even if your immunotherapeutic worked in the absence of PD-1 because, say, you had a tumor that didn't have any PD-L1 on surface, and you produced the response with your novel immunotherapeutic, you're certainly going to induce gamma interferon production in the tumor microenvironment and induce the expression of PD-L1. So the combination is actually rational and expected, right? We see this with ipilimumab and -- or tremelimumab anti-CTLA4 in combination with anti-PD-1. Anti-CTLA4 doesn't have any activity in lung cancer as a single agent. But the combination looks pretty -- more and more clear that the combination -- in combination with anti-PD-1. So I think that, that's still the model. So I think that there's no question Raj's trial design clearly demonstrated that this drug has -- is pivotal for the activity. It doesn't bother me at all. But in fact, it's quite expected that it needs to be given in combination with the anti-PD-1. And I'm sure that, that was the rationale that Raj was thinking about when he designed this trial.

Right. And then to extend from that, I think for non-small cell lung cancer, as Scott was saying, that immunotherapy, these PD-1 inhibitors are going to be backbones for many combinations going forward. And the advantage of these investigator-initiated trials, by the way, is the fact that we do get to do this correlative science that's going to help answer a lot of these questions. So I hope we can kind of shed light on some of these open questions soon, but I certainly think that -- I agree that the evidence is in these partial responses. Rigosertib is certainly what's causing these partial responses, and the checkpoint inhibitor potentially there is hopefully synergistically working with the rigosertib and to prove -- prevent future immune tolerance to the rigosertib. So the combination makes sense. Regarding the safety benefit, I don't necessarily know that there's a safety benefit. It's just that we didn't see increased synergistic toxicities. And so meaning that one compound, one drug did not potentiate toxicities of the other. And that was obviously something that we always consider with combination studies.

Got it. No, I really appreciate that color. And I just wanted to circle back on the purported underlying mechanism with regard to increases of TIL infiltration with regard to the underlying mechanism for rigosertib and its contribution. Any comments on that?

We saw an induced expression of CD40, right? So it may not be increasing infiltration but expansion within the tumor microenvironment. But you're absolutely right. It's still up in the air and understudied, and there's still a lot more to be learned about the mechanism of action. But the observation is there, right? There is an increase in the number of T cells in the tumor microenvironment with treatment with the drug.

Our next question comes from Robert LeBoyer at NOBLE.

First, I'd like to thank Dr. Veluswamy for the comprehensive presentation that was also very clear and understandable. And my question has to do with the trial going forward and the number of patients that you plan to continue enrolling as well as the time that you expect to continue this enrollment and treatment before going into Phase II. And also, the previous answer to the question suggested that the immune response hasn't really been quantified, and there's no data regarding the types of immune cells that we've seen. But if there was, if you could elaborate on that, great.

Okay. So to answer your first question regarding the future plans of this trial. So we have 9 -- now 8, actually, we just consented another patient, slots open for this expansion phase. I think we're -- we'll enroll fairly quickly and complete this expansion phase. I think there's still important things we can learn at the 560 BID, especially the fact that we are seeing a clinical signal. And so we plan to complete the expansion phase potentially in the next couple of months. And then at the same time, we'll put in the amendment for 3 extra cohorts is the plan. And here, we'll just continue it as a 3-plus-3 design. So it really depends on what we see from a tolerability signal and what the MTD is going to be. But potentially, once we do get a true MTD, I think that there, we've been discussing doing kind of a further expansion phase to get more information and more patients on study drug at these therapeutic doses. And so I hope that answers your question as far as at least what we know right now for the future plans.

Sure. Partially answers it. Is there any target number of cohorts or patients that you're looking at? Or any expectations for the length of timing before starting Phase II?

Yes. So I would imagine it will probably -- because we are enrolling a lot faster at this point. I mean we were a little slowed down because I think a lot of centers and their clinical trials program was impacted by COVID. But now I think things are very much open, and our [ lung ] volumes are higher, and referrals are higher. And so I don't want to overstate, but I think potentially, sometime in 2022, we would probably be able to have a true MTD is my guess, and hopefully, at that point, we'd be able to consider a Phase II -- a larger Phase II trial. I don't know if, Steve, you wanted to comment on...

No. We look -- thank you, Raj. We look forward to your continued accrual to this trial, and based on what we see regarding responses, safety, decisions regarding dose escalation because perhaps we'd see more responses, I think this is our best attempt to optimize the combination of rigosertib and nivolumab to make sure we have the best recommended Phase II dose. And that's what Dr. Veluswamy is trying to accomplish. So thank you.

This concludes our verbal portion of the Q&A. I'll now turn it back over to Steve for any questions that may have come over the web.

So I am looking at the questions, and thank you all for submitting them. I think, actually, all the questions have already been answered. So I think we're a bit over. I'd just like to thank all of you for your participation, but especially Dr. Veluswamy and Dr. Antonia for both their time and expertise in educating us about this field and indication. And we look forward to continuing to execute on our clinical development plan. And we'll keep you appraised of the progress. I wish you all a very happy and lovely evening, and thanks again for your participation, and I hope you found it informative. Have a wonderful night.