Hello, and welcome to the Incyte Data Highlights from SITC Teleconference and Webcast. At this time, all participants are in listen only mode. A question and answer session will follow the formal presentation. It's now my pleasure to turn the call over to Christine Chiou , Head of Investor Relations. Please go ahead.
Thank you, Kevin. Good evening, and welcome to Incyte's Oral PD-L1 Program Highlights Conference Call and webcast at SITC. The slides presented today are available for download on the investor section of our website. Joining me on the call today are Hervé and Steven, who will deliver our prepared remarks, and Jeff Jackson, our Vice President of Translational Sciences, who will join us for the Q&A. Before we begin, I'd like to remind you that some of the statements made during the call today are forward-looking statements and are subject to a number of risks and uncertainties that may cause our actual results to differ materially, including those described in our 10-Q for the period ended September 30, 2021, and from time to time in our other SEC documents. We will now begin the call with Hervé.
Thank you, Christine, and good evening, everyone. Today we are presenting data and perspective on our oral PD-L1 franchise, which consists of a portfolio of three oral PD-L1 inhibitors in clinical development. INCB086550, our most advanced candidate, is the first oral PD-L1 inhibitor to demonstrate clinical activity. We are conducting in parallel development of our two other oral PD-L1 inhibitor as we work to identify the best candidates for full development.
INCB086550 is undergoing dose schedule optimization and a phase II study is also underway, while both INCB099280 and INCB099318 are in dose escalation. An oral PD-L1 inhibitor would be important for safety reasons and for economic convenience and reimbursement reasons. As you will hear, we are making good progress, and 2022 will be the year when key decisions will be made on which product to move forward and potential registration path. Now I turn the call over to Steven.
Thank you, Hervé, and good evening, everyone. We have focused our development on oral small molecule inhibitors of the PD-1/PD-L1 axis. A potential advantage of an oral inhibitor includes better tissue penetration by a small molecule compared to an antibody, which may improve potency. Here on slide seven, using confocal microscopy, we're able to show you oral PD-L1 inhibitor-induced internalization of PD-L1. INCB086550 is able to bind to the PD-L1 receptor, leading to dimerization and internalization of the receptors from the cell surface.
Internalization starts within one hour and increases over time, as you can see towards the bottom of the slide. On slide eight, we are showing a set of pharmacodynamic biomarkers that demonstrate T-cell activation in patients treated with INCB086550. On the left-hand side, you can see the increase in plasma concentrations of the interferon-related cytokines, as exemplified by CXCL9 following INCB086550 treatment. In the middle, increases in the expression of multiple interferon-regulated genes in peripheral blood in a dose-dependent manner as measured by RNA-seq.
On the right, we are showing increases in proliferation of the circulating T-cell as measured by Ki-67, which we observed post-treatment for many patients. Moving on to the data for INCB086550 that was presented earlier today at SITC. Here on slide 9, the study design for the dose escalation and expansion study. The part 1 dose escalation evaluated 100 mg daily to 800 mg twice daily in a modified 3+3 design. There were three parts in the dose expansion phase. In the part 2 dose expansion phase, we looked at both IO-experienced and IO-naive patients.
In the part 3 dose expansion, we focused on a cohort of IO-naive patients whose tumors may be more likely to respond based on genetic status with microsatellite instability-high and mismatch repair-deficient solid tumors. In part 4, looking at human papillomavirus-positive tumors like squamous cell anal carcinoma or head and neck cancers, as we had seen early signals in HPV-positive tumors. Turning to slide 10. We had enrolled in the study at the cutoff of April 9 this year, a total of 79 patients, of whom 27 were in the dose escalation phase and 52 patients were in the dose expansion phase.
Specifically, part 2 A had 10 patients, part 2 B had 33 patients, and part 3 had nine patients. Over 60% of the 79 patients were heavily pretreated with two or more lines of prior therapy, and approximately 17% of patients had prior IO treatment. The study itself is ongoing with greater than 120 patients enrolled now. Here we see the breakdown of the number of patients treated per dose level, with the majority of patients being treated with either 200 mg twice daily or 400 mg twice daily. Moving on to safety and treatment-related adverse events.
Any grade treatment-related adverse event occurred in 58% of patients, with nausea and fatigue being the most common. Immune-related safety signals such as rash and pruritus indicate to us that we are achieving activity with regard to target modulation. Most treatment-related adverse events seen in this ongoing phase I study were consistent with what has been seen with PD-1/PD-L1 monoclonal antibodies, including immune-related adverse events. With the exception of an increased rate of primarily low-grade peripheral neuropathy.
Here you see on this slide, five patients experienced a peripheral sensory neuropathy. Moving to slide 13 and the occurrence of immune-related adverse events. We showed in the data that 15 patients or 19% experienced an immune-related adverse event. 10 patients in total or 13% experienced an immune-related adverse event of peripheral neuropathy. This includes both motor and sensory neuropathies, of which all were less than or equal to grade 3, and all grade 2 and 3 cases were resolved or improved.
In some cases, these patients required a dose reduction, some a dose interruption, and some required steroid treatment, as you can see on the slide. Only two patients had to discontinue therapy. Five of the 10 patients continued their treatment uninterrupted. Of the 79 patients enrolled, 68 were included in the efficacy evaluable population, which included all solid tumor participants enrolled in the study who had received at least one dose of INCB086550, completed a baseline scan, and met at least one of the following criteria:
At least one analysis. Among the efficacy evaluable population where we had assessed 100 mg daily to 800 mg twice daily, a response was seen in eight of the 68 evaluable patients, and disease control greater than 12 weeks was seen in a total of 13 patients. Looking at the IO treatment naive population as part of the 2B expansion cohort, there were three responses out of 14 patients treated with 400 mg twice daily. In part 3 , in the MSI-high deficient mismatch repair IO naive patients, we saw three responses out of five patients treated with 400 mg twice daily.
There were two additional responses at this cutoff, one at 800 mg twice daily in part one, and one at 400 mg twice daily in part 2A. Again, a very small n, but promising activity. This is the first oral PD-L1 inhibitor to demonstrate clinical responses. Of the eight overall responses, the majority were at the 400 mg twice daily dose level. Seven of the eight were in IO treatment naive and include human papillomavirus positive cancers, MSI high cancers, and deficient mismatch repair cancers. At the time of data cutoff, the majority of patients still had ongoing responses as designated with the plus sign on the right.
On slide 16, this is a swimmers plot of time to first response and the duration of response seen from the efficacy evaluable population, which was updated in the middle of this calendar year. As you can see, five of eight responses are still ongoing and there are responding patients who have been on therapy greater than 280 days. To summarize, INCB086550 is showing activity and its safety profile is consistent with monoclonal antibodies, with the exception of the peripheral neuropathy cases.
We are working to optimize the dose schedule for INCB086550 to attain the right therapeutic ratio, including evaluating intermittent dosing with a 400 mg BID dose. In parallel, we also have our two other oral PD-L1 inhibitors in dose escalation phase, and I'd like to spend some time talking about those developments as well. INCB086550 is the most advanced compound, while INCB099280 and INCB099318 are catching up quickly. We have enrolled more than 35 patients on INCB099280 already and more than 12 working as they should in terms of target modulation.
In terms of differences, one is more chemically distinct from the others. On slide 19, early preclinical data in the same mouse model shows that treatment with INCB099280 and INCB099318 induces comparable antitumor activity as was seen with INCB086550. Although still very early in this program, we are seeing tumor shrinkage in patients treated with INCB099280 and with INCB099318. To date, we have seen no evidence of peripheral neuropathy with either compound. In conclusion, we have three programs ongoing and the studies are enrolling well.
Over the next few months, we expect to have data available that will allow us to select our lead programs, and based on the clinical profile, we would be in a position to determine which indications we would move forward into full development. We look forward to continue updating you on this very exciting program. With that, I'd like to turn the call back to Hervé.
Thank you, Steven. On slide 22, this chart depicts the PD-1, PD-L1 antibody used across tumor types in the U.S. in 2021. PD-1, PD-L1 use is increasing worldwide, and it's driven by combination and monotherapy used in adjuvant and consolidation. On this chart, monotherapy use is depicted in dark blue. Use in combination with an oral agent is in light blue, and PD-1 or PD-L1 used in combination with an injectable is shown in light red or pink.
Clearly, an oral product could offer potential benefit for patients every time a PD-L1 therapy or PD-1 therapy is used, either as a monotherapy agent or when used in combination with an oral agent. Taking a quick look at lung cancer, for example. In 2021, 50% of treated non-small cell lung cancer patients received the PD-1, PD-L1 antibody, and 72% of the PD-1 or PD-L1 used is as a monotherapy regimen. For example, with durvalumab in stage III consolidation or in stage IV after the fourth cycle of chemo plus PD-1.
Taking another example, in renal cell carcinoma, around 50% of patients are treated with a PD-1 or PD-L1 therapy. 57% of those treated with the PD-1, PD-L1 are treated with a monotherapy regimen, while 41% are treated with an antibody in combination with an oral TKI. You know, the utility of an oral PD-L1 combination may, it may not offer a lot of value in combination with IV chemotherapy. If you look across the entirety of the U.S. PD-1, PD-L1 market, 80% of the current market would be amenable to an oral PD-L1 agent.
Turning to slide 23. Here we want to show where the potential benefits of an oral PD-L1 inhibitor would bring more value either to different geographic regions in combination or as a monotherapy agent. The oral route of administration could lead to ease of dosing and no office visit requirement, as well as no administration cost, which is more important in ex-U.S. regions where reimbursement systems favor oral administration. There is also an opportunity with oral combination, where the same economic and convenience argument applies, with the addition of the opportunity to create fixed dose combination products.
On the safety side, an oral small molecule inhibitor with a short half-life provides a switch off option if needed, while antibodies remain in circulation for long periods after the injection. This allows for easier titration and for better management of immune-related AEs. Lastly, there is a theoretical benefit for the potential of increased tumor penetration, and we will conduct additional studies to see if this could lead to increased efficacy. Overall, the opportunity for an oral PD-L1 is substantial, and we are very encouraged by the data coming from our oral PD-L1 franchise. With that, I'd like to turn the call over to Q&A.
Thank you. We'll now be conducting a question and answer session. If you'd like to be placed in the question queue, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing star one. One moment please while we poll for questions. Our first question today is coming from Salveen Richter from Goldman Sachs. Your line is now live.
Hi. Thanks. This is Matt on for Salveen. Congrats on the data. Could you just briefly discuss how we should view the 21% ORR in treatment naive patients in comparison to, say, Keytruda or other PD-L1s? And then also discuss maybe the safety results. Were you expecting to see the safety profile, or were you anticipating something perhaps better than the antibodies? And then finally, you recently initiated the treatment naive phase II in specific tumor types. Was that based on this data? Thanks a lot.
Yep. Matt, thank you for the questions. It's Steven. You know, firstly, obviously when you report out a study, you use the formal terms like overall response rate as it should be. You know, I think when you do early studies, you can see many patients either fall out early or as you saw, there were 11 patients who had no post baseline scan information. I wouldn't focus per se on the percent. I'm not saying that in any way as an excuse. It's just they can be a little tricky when you look at different numerators and denominators. What is really encouraging is that you know, we had eight real confirmed responses.
If you look at, you know, among 68, you get that response rate we determined overall of around 12%, or as you allude to in the more focused groups, it can go upwards of, you know, 20% plus. Again, the bottom line is, you know, with INCB086550, the first oral PD-L1 agent, we have an active immunotherapy and that the responses are durable. I think that's point number one. In terms of getting, you know, more precision around the response rate, it's. I'm gonna just answer your third question first before I come back to safety.
I think you have to look in more homogeneous, more likely IO responsive, less potentially beat up, you know, patients to get more precision on what we call benchmarking data, in particular tumor types, whether they be, you know, lung or renal or melanoma, et cetera. As you know, I alluded to in my presentation, we've already enrolled, you know, another 50 patients compared to when this data cut was. We'll have a good sense when we next present the data, what the true efficacy of the compound in those settings.
Again, very encouraged by these responses and the durability thereof. Just to quickly also say to you know, for the phase II, yes, it is built on the study. To be repetitive, it's just a cleaner, more homogeneous way of looking at it as opposed to a dose range in early study. In terms of safety, you never know when you take a new compound into the clinic, what you're gonna see 'cause they're all chemically distinct. You know, on the encouraging side, although not good for patients per se, is we're seeing immune-related adverse events.
That's what, you know, you wanna see that your drug is modulating the immune system, you know, and doing so in a fashion that causes what you would see with other immune modulators. Rash, pruritus, you know, potentially endocrinopathies that are immune-related, et cetera. Again, while not great for patients, it's you know that you're then doing the target modulation that you want. What was, you know, a little unusual and unexpected were these 10 cases of peripheral neuropathy, five of which were sensory.
It's a little higher than what's been reported for IO checkpoints, whether they're PD-1 or PD-L1, which is usually, you know, only a few percentage points. So that's on the straight sort of quantitative side. You know, in keeping with what we keep saying the 10-hour half-life of the drug, the moment it's held for an adverse event, you see pretty rapid resolution thereof. You can see, you know, only f our of the 10 actually required steroids on top of that to get to resolution. It just talks to the fact that when you switch off, as Hervé was saying, you get a, you know, the drug washes out and resolution occurs of the neuropathy.
Clearly it's not a side effect we want patients to experience, which is why, you know, we spend time and continue to spend time looking at dose and scheduling work to see if we can improve the therapeutic ratio a little bit better with INCB086550. We also took two other compounds into the clinic, INCB099280 and INCB099318. INCB099318 is chemically distinct from the other two. INCB099280 is a little ahead of INCB099318. As I said in the presentation, there are more than 30 patients treated with that and then about 12 patients treated with the last compound.
We've seen tumor reduction with both, which again, encouraging in terms of the mechanism of action and to date have not seen peripheral neuropathy. Obviously, that's caveated by the smaller numbers and the duration. The idea is to achieve the right therapeutic agent ratio with one or more of these agents that gives us the efficacy, a good safety profile that we can take forward, and that's what we're committing to doing, you know, hopefully sometime in 2022. I think I answered all your questions.
Yeah, that's great. Thank you very much.
Thank you. Next question today is coming from Yaron Werber from Cowen and Company. Your line is now live.
Hi. Thanks for taking my question. My question is actually about the neuropathy signal as well. Just wanted to get a few more details. Can you talk about the time of the onset and whether or not it appears to be cumulative and how reversible it is, and perhaps compare it to the course and severity seen with Taxanes?
Sure. Yaron, it's Steven again. It's in terms of time of onset, it was variable. You know, if I look across the 10 cases, I think the earliest onset was around day 38 with one of the patients, and then there was a later onset in another patient, for example, at day 108. There's some variability in time of onset, firstly. We don't see any cumulative nature thereof. Once recognized and managed either with reduction, interruption, steroids, or in two cases, discontinuation, there is no cumulative nature, and almost all had complete resolution.
Just to tell you that the grading of neuropathy is such that grade 1 is actually asymptomatic. It's only grade 2 onwards that's symptomatic. The grade 2s and 3s all resolved or dramatically improved, and there's no cumulative nature. It talks to reversibility clearly. In fact, five of the 10, again, not that we want patients to have this, but 5 of the 10 were able to continue dosing without interruption, and then had a resolution. You know, that's another interesting phenomenon. It's completely different from Taxane neuropathy, which involves a different process in terms of demyelination.
It tends to be more severe and tends to be reversible, so much so that it doesn't allow you to use the drugs in an ongoing basis or afterwards. You know, just to say, why we're really interested in the oral nature and the short half-life, particularly in adjuvant and maintenance settings where when you're trying to, you know, cure patients, in that setting, obviously, you really don't wanna run into severe toxicities with curative patients. If you have a drug that you can switch off quickly if you run into trouble, we view that as a potential huge advantage. Again, I think I've got all your questions.
Yes. Thank you so much.
Thank you. Our next question today is coming from Srikripa Devarakonda from Truist Securities. Your line is now live.
Hey, guys. Thank you so much for taking my question, and congrats on the progress. I had a question. You said INCB099318 is chemically and structurally different from INCB086550 and INCB099280. Can you tell us a little bit more about how INCB099280 differs from INCB086550 ? You know, it's small patient numbers, but you don't seem to see the peripheral neuropathy in these patients. Maybe provide some timeline for when we can see data from INCB099280, INCB099318, and also a data update from the additional patients you've enrolled for INCB086550.
One additional question is you now have a PD-1 antibody as well as an oral PD-L1 inhibitor, which seems to have activity. Based on all the data that you've seen so far, do you have a strategy for development, or would you rather wait to see the data from all three compounds before going ahead with the strategy? Thank you.
Yeah. Yeah, Kripa, it's Steven. I'll start off. I hope I got all your questions jotted down here, so I'll work through it methodically. So firstly, just again to say for INCB086550 , there were 79 patients in this cutoff in April. There are more than I think there are about 126 on now, and the study continues to enroll, and we will update that definitely in 2022. In terms of enrollment now, they're at, you know, doses that we know are pharmacologically active, and obviously we target in IO responsive tumors.
So we'll be able, as I said earlier, to give you a much better sense in a more homogeneous population at a more pharmacologically active dose of the INCB086550 activity. We are experimenting with scheduling changes like one week on, one week off or you know, other types of schedule modulations to see if we can ameliorate the neuropathy signal with INCB086550 . The other two compounds are enrolling incredibly well. As I said, you know, INCB099280 has more than three doz en patients on it and INCB099318 about doz en , and we'll continue to do that.
We commit again to show you data in 2022 for those compounds as well, 'cause they're enrolling well. Obviously we build on the learnings from INCB086550 . All of them next year should have substantive updates in terms of both efficacy and safety for those compounds. If you take that all together, we'll be in a position, as Hervé said right up front, to make development decisions, whether it may end up being with more than one compound, you know. We'll see.
There's potential optionality or and interest in some non-oncology indications as well for oral PD-L1s in terms of enhancing, for example, a virally directed therapy in things like hepatitis. In terms of your question, on, you know, PD-1 comparativeness, if I'm sort of paraphrasing what you said, I mean, that's obviously of interest, huge interest to us, to patients and to you guys. I think that'll come largely from the phase II for INCB086550, because, you know, we'll be again at active doses in homogeneous populations.
Also with INCB099318 and INCB099280 we can now because we know we have active compounds, people are, you know, much more likely to put IO responsive patients on it around the world, and we'll get a much quicker sense than we got from INCB086550 of comparative like activity compared to PD-1 in similar settings.
You know, on the IV oral complementarity in our own portfolio, I mean, obviously. As I said, I mean, chemo combination can be done with an IV product and except for the reversibility benefit that you get from the oral, potentially it has no other clear benefit. Sometimes some of the chemo based on cisplatin in lung cancer are not very easy to combine with oral product because of the side effect of the chemo. Where we see it, for example, in non-small cell lung cancer is that if you do a chemo plus IV antibody, you can then do the next 4 cycles.
I mean, that's the way it's used today. You can do the next 18 months of consolidation with an oral product. That could be a sort of IV for the chemo combination followed by oral for consolidation. That could be something that we are looking at.
Kripa, one other question you asked up front I didn't address, you know, differences. We haven't published the structures for INCB099280 and INCB099318, but we can say that INCB099280 is most similar to INCB086550 in terms of its structure. It also is most similar in terms of its PK behavior. Both have half-lives around 10 hours. Three-one-eight is most structurally distinct, compared to the other two. We'll have to wait till we publish it to give you more details, but the half-life thereof is about half, so about five hours compared to the other two.
Translationally, I can ask Jeff Jackson here to comment if he wants to. You know, MOA-wise, they all, at least in our hands, look like they do the same things in terms of what I outlined up front for INCB086550, in terms of the MOA.
Yeah, that's correct, Steven. They block PD-1, PD-L1 binding and have the same effects on T-cell activation and reinvigoration.
Great. Thank you so much. You got all my questions. Thanks, guys.
Thank you. Our next question today is coming from Luca Issi from RBC Capital Markets. Your line is now live.
Hi, this is Luca Issi on for Brian. Thanks for taking my question. I wanted to ask a little bit more about how your oral PD-1 is going to combine with some of the assets that you have in your portfolio. You know, are there any combinations that you're particularly excited about such as, you know, with adenosine or some of the bispecifics that you're working on in partnerships?
You know, sort of to follow up on the previous question, you guys also have retifanlimab, which, you know, originally you had as part of a maintenance strategy. I'm kind of curious how you're thinking about development of the oral PD-1 in combination with retifanlimab for maintenance. You know, maybe does the signal of peripheral neuropathy sort of interfere with this maintenance approach? Thanks.
Leonard, it's Steven Stein again. I'll start off, others may wanna add. You know, again, as Hervé was alluding to up front, you know, oral combinations have been of enormous interest to us from the beginning, whether they be with assets we have in our own pipeline or other assets, for example, directed at renal cell carcinoma. There's a lot of oral VEGF TKIs that are used there that would potentially combine well with an oral PD-L1. In our own pipeline, you know, the ones we may end up doing more work with once we have the dosing schedule we wanna use.
You alluded to one already that may be of interest. You know, for adenosine, we have an oral small molecule A2A/A2B inhibitor and an antibody CD73 inhibitor, so they hit the adenosine pathway from different angles and you get, you know, profound suppression of adenosine production and hopefully modulate the microenvironment in the right way. There you could again think about using an oral PD-L1 in that setting. But really, across our portfolio, all the oral combinations may be in play.
I didn't fully understand your PD-1 maintenance approach question, but no, I look at it 'cause for retifanlimab, currently we have programs in squamous cell anal carcinoma, MSI-high endometrial and Merkel cell plus a lung program. For an oral PD-L1, you know, Hervé used the example of durvalumab in the PACIFIC Study in stage III lung cancer, for example, where after chemoradiation you have upwards of 18 months of IV PD-L1 inhibition used there. If you think about using an oral in that setting, it would lend itself perfectly.
Then just to be repetitive, obviously the efficacy is paramount, but on the safety side, if you ran into trouble, the ability to switch off we think would be a powerful differentiator there. We think these oral PD-L1 may lend themselves to all sorts of adjuvant and maintenance use. Obviously there are places where the IO checkpoints are established, but there's still, you know, many areas in addition that haven't been addressed yet in terms of either maintenance or adjuvant settings. Across the board there. Thanks.
Great. Thanks.
Thank you. Next question is coming from Jay Olson from Oppenheimer. Your line is now live.
Oh, hey, thanks for the update, and thanks for taking the questions. Can you comment on whether or not you found any correlation between response to INCB086550 and PD-L1 expression levels? Can you talk about what sort of oral-oral combinations you may have looked at preclinically? If you could comment on any potential synergies you may have seen with TKIs or KRAS G12C inhibitors or any other oral combos you may have looked at preclinically. Thank you.
Jay Olson, hi, it's Steven Stein. Jeff may will likely add to what I say. It's early. We didn't only select patients by PD-L1 positive or negative in the early part of the study until we did the later cohorts I alluded to, which were enriched either for IO-sensitive tumors or MSI-high or mismatch repair-deficient or HPV-positive. Even in those settings, we took all comers, and we'll do more correlative work afterwards, which Jeff may wanna speak to.
To date, to my knowledge, just to get to the exactness of your question, we haven't seen, you know, amongst the eight responders at least, a strict correlation with PD-L1 expression level and INCB086550 activity, but we probably need more data and more experience to get to that. In terms of preclinical synergies, I'm not sure we've published any work in that regard yet. I'll see if Jeff wants to add anything to what I said.
Yeah, I would just echo, Steven, what you said. I mean, while we're assessing PD-L1 expression and other, you know, potential biomarkers, tumor mutational burden and gene signatures, the numbers of patients that we have that are in IO sensitive indications don't really allow us to establish any kind of correlation with those biomarkers at this point.
Okay, great. Thank you.
Thank you. Our next question is coming from Reni Benjamin from JMP Securities. Your line is now live.
Hey, good evening, guys. Thanks for taking the questions. Steven, you had, you know, one patient who had prior IO treatment and still got a response. I'm kind of curious, you know, are there any learnings here, especially in regards to potential post IO use of these oral PD-L1s? I have a follow-up.
Reni, hi. Thanks. It's Steven. Yeah, I mean, obviously, you know, that remains in the broader context, a massive unmet medical need, right? You know, patients with prior IO treatment, who either primary refractory or end up being resistant, you know, people have tried, you know, different combinations, et cetera, there. To date, you know, nobody really had a big pop in terms of efficacy. I don't know yet what to make of the one case.
It was a colon adenocarcinoma that had prior IO treatment that ended up response. It's probably a little too early to tell. We will have a greater collective experience, you know, in 2022 to present for you. Whether we'll address that unmet need or not, you know, remains, I think, to be seen. While interesting, it isn't n of one at the moment. I'll just say that, you know.
Got it. As we think about future development, you know, and how registrational studies might ultimately be done, should we be, you know, thinking about it in terms of, you know, larger IV, you know, IO and oral targeted therapy versus, you know, oral plus oral targeted therapy as a superiority study, a non-inferiority study? Do you think there might be a faster path, you know, to market where, you know, it's a little bit more of either, you know, biomarker driven or comparability studies driven?
Yeah. Reni and Steven, I'll start. Hervé likely will add something. Obviously, we haven't yet made the decisions which we said, you know, we will, we'll make next year. You know, in my mind, you know, obviously, you know, one way to go and many are doing this, including ourselves in some settings, is a smaller niche tumor setting. But I think, yeah, and I'm you know, this is just hypothesis like at the moment, we'll have to do our development plan next year.
But in you know, our maintenance adjuvant settings, you could either go to areas where there's no established care standard yet and go against placebo in those settings, because there's no care standard, just like Hervé did in PACIFIC in stage III lung. You know, potentially, which I think what you're alluding to is go head to head against those in you know, some type of non-inferiority setting or more like replication studies as well. All of those have potentially been entertained.
I think once we get more comfort on which of the compounds is the correct one, which has the right therapeutic ratio, then we'll be able to tell you know, perhaps in 2022, which way we'll go. We haven't yet decided, so all of the above. My own feeling is, you know, again, these oral maintenance settings are of huge interest.
Got it. Then I guess just one trying to understand the unmet need. You guys make a very good argument regarding the differentiation, right, of an oral PD-1 and the ease of dosing and the like. Is the unmet need, you know, I wouldn't think it's compliance, but is it compliance? Is it mainly convenience? Are physicians, you know, kind of through your either sales force feedback or just through your key opinion leader panels, telling you that this is something that they're looking for? Or is it a situation more where, you know, you guys see an opportunity where you can bring something to market and then kind of, you know, even though doctors aren't necessarily looking for it, once they see it, will start using it more?
Yeah. There's a bit of everything. You know, one thing I'll say is, there's the whole globe out there, not the U.S. alone. There are parts of the world where, you know, oral use of checkpoints may be particularly helpful in terms of freeing up chair time in chemotherapy suites, etc. But also, you said it correctly, you know, currently when all you have is to go away on a maintenance regimen but keep coming back for injections is what you have. Once you have an alternative, which is oral only, you know, I think it would be enticing from a convenience point of view as well.
What I was trying to say, maybe clumsily in my presentation, was in the adjuvant setting, your aim is to increase cure. You know, that's what you're trying to do, is to improve cure rates. When you do that, you know, efficacy is obviously paramount, and I'll say that again. Occasionally you'll run into, unfortunately with any therapy, but even with checkpoints, you know, really severe toxicity that could be life-threatening. That's not a great outcome in an adjuvant curative setting.
We think a potential differentiator there, as long as you have the efficacy piece, is the ability to avert that by switching off the immune stimulation that you give in really quickly and avoiding, you know, a dramatic life-threatening toxicity. That's the one way I thought about it. I don't know, Hervé, do you want to add anything to that?
No, I think it's relatively clear. On the clinical profile, there is a hypothesis of better efficacy that we have absolutely no data to speak about today, but that we will be checking because there is a different penetration. It's not the same mechanism. That's something we need to work on to identify that if it is there. There is something that we know already, and we know it for the patient we have treated, is that on the safety side, the switch off aspect of it can become very important. Now, who are the patients who benefit most from the ability to switch off?
They are early stage curable patients. That's certainly one category. Now there is another one that is emerging, is IO/IO combination, where we know that the. Sometimes very, very problematic, where being able to switch off one of the two components of the combination could be very useful. That's the safety efficacy kind of profile, if you want to think about it that way. Then you have the convenience aspect, which is what it is. On top of convenience and the cost of infusion and the fact that it is freeing up chairs in a hospital, which sometimes is very important.
There are, in many parts of the world, a reimbursement aspect to this, where in fact the IV product injected in the hospital are part of the hospital budget, right? Prescription product, like an oral product, would be outside of that budget. If we are able to show that we have some sort of similar, you know, profile clinically with the switch of opportunity and that it's something that goes through a different reimbursement system, I think it could be used very widely. That's sort of the way we are thinking about it now.
Great. Thank you guys very much for taking the questions.
Thank you. As a reminder, that's star one to be placed into question queue. Our next question is coming from Matt Phipps from William Blair. Your line is now live.
Good evening, guys. This is Rob Andrew here on for Matt Phipps. Thanks for taking our question. A bit of a follow-up from some of the earlier questions on development here. You know, you've mentioned you're now up to 120 patients for eight fifty here, giving us a bit of insight into where you're at with enrollment for two eighteen and three eighteen. Maybe first, you could just kinda provide some perspective on what you think you need to get to in terms of patient enrollment for these other two assets to reach the decision on what goes forward.
Second, you know, is the phase I plan for two eighteen and three eighteen gonna look similar in structure to the phase I here for eight fifty in terms of dose expansions and such like? Lastly, Steven, you've just mentioned a couple of times building on some of the learnings from this phase I with INCB086550. Maybe you could just elaborate a little bit more on what you think those learnings are and whether you think they can kind of expedite the kind of early development for INCB099280 and INCB099318 here. Thank you.
Yeah. Rob, Steven, thank you for the question. I. You know, so the reason that we're now doing more schedule modification is largely to try and prove the therapeutic ratio as regards to peripheral neuropathy. You know, extremely encouraged by the activity. The rest of the profile is very similar to IV checkpoints. If for INCB099280 and INCB099318, we don't run into that, you know, for reasons, you know, related to their chemical structure or something else, then we won't have to do that scheduling work.
So as soon as we're in a pharmacologically active range, and we're already seeing tumor reduction, we can go a whole lot faster and just expand out that way. So that would be the chief learning thereof. The other thing is a little bit more an operational thing. You know, the way studies work is, you know, physicians will put their patients on obviously with equipoise, but once there's an expectation of benefit, right? In the beginning, we didn't know these things worked at all, right? You have heavily beaten up phase I patients coming in who are very unlikely to respond.
Now that we've demonstrated and published efficacy, and we've already seen this with our program because we share with investigators what's going on, you know, they enroll patients. That part will help us operationally in a very strong way. In terms of numbers, you know, it's gonna be hard for me to commit now exactly. You have, you know, 3,000 patients on INCB099280, 1,000 on INCB099318. If it continues enrolling this way and we get, you know, appreciable numbers of between 80 and 100 patients on both programs in an early part of next year, then we'll be sitting on a very good data set to make decisions. We may not even need that many patients. That's my sort of reaction to your question.
Thank you.
Thank you. Our next question is coming from Vikram Purohit from Morgan Stanley. Your line is now live.
Great. Thanks for taking my question. You just spoke a bit about the volume of data you might have by 2022 from three different molecules, but I was wondering if you could speak in a bit more detail about how you plan to compare and contrast the data sets you might have at that point in order to prioritize the one or two molecules that you think are the best. Secondly, a point of clarification. You mentioned that six of the eight responses were in the 400 mg BID dose, and I wanted to see if you could clarify how many of the 68 efficacy-evaluable patients had received the 800 mg dose in either BID or QD. Thanks.
Yeah. Steven, I'm gonna come back to the second part of your question in a moment. What we'll do is, you know, it's a little tricky to answer your first question in terms of compare and contrast, because it'll be driven by, as is always the case, both efficacy and safety. If we end up with, for example, either INCB099280 or INCB099318, having a similar degree of efficacy but no peripheral neuropathy, you know, then the decision's easy, right? From that regard. Efficacy in general in oncology always trumps safety. You know, if you end up with a even greater efficacy signal in one of the other compounds, you know, that's one you'd likely take forward.
It's a little hard to say, you know, on its own the drivers, 'cause it comes in both those columns. What you want is, you know, appreciable numbers of patients, which we're pretty confident we're getting now, and an ability to have some durability of follow-up to see, you know, responses, duration of responses and the safety profile. In terms of how many patients received the 800 dose in, that was largely, I think, in the Part 1 phase of the study. I think it was, of the 79, one patient at 800 daily and another six patients at 800 BID. A total of seven patients at the 800 dose, and then we went back down again.
Okay. Understood. Thank you.
Just to tell you, maybe this will help. At 200 milligrams, from a translational perspective and above, you start seeing the chemokine and T-cell changes you want. From a PD point of view, you're getting, you know, the receptor occupancy you want, saturation above 200 and definitely at 400, and all the PD things you want. You're in that pharmacologically active range already. And 800 was just going above that to see if anything else happened there.
Thanks.
Thank you. We've reached the end of our question and answer session. I'd like to turn the floor back over to Christine for any further closing comments.
Thank you all for joining us tonight for our SITC update and for all of your questions. We look forward to speaking with you at upcoming conferences. Thank you and goodbye.
Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time and have a wonderful day. We thank you for your participation today.