Good morning, everyone, and welcome to the Cullinan Oncology webinar to discuss updated clinical data for our lead program, CLN-081. Earlier this morning, we issued a press release providing an overview of the data which can be accessed on the investors section of our website at investors.cullinantherapeutics.com. During today's presentation, management will be making certain forward-looking statements as outlined on this slide. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve a number of risks and uncertainties which may cause actual results to differ materially from those contained in such forward-looking statements. These risks are described more fully in the company's filings made with the Securities and Exchange Commission, including our annual report on Form 10-K.
You are cautioned not to place any undue reliance on these forward-looking statements, and we disclaim any obligation to update such statements. In addition, this call contains time-sensitive information, accurate only as of the date of the live broadcast, December 16th, 2021. Cullinan Oncology undertakes no obligation to revise or update any forward-looking statement to reflect events or circumstances after the date of this live call. Joining me on the call today are Nadim Ahmed, Chief Executive Officer, Dr. Jon Wigginton, Senior Advisor and Chairman of the Scientific Advisory Board, Dr. Leigh Zawel, Chief Scientific Officer of Small Molecules, and Jeff Trigilio, Chief Financial Officer. Following management's prepared remarks, we'll be hosting a question-and-answer session. For those of you joining us on Zoom, you may enter the queue to ask a question by pressing the Raise Hand button.
Those of you joining via the web can ask a question via the chat function located below the video window on your screen. With that said, it's now my pleasure to turn the call over to Cullinan's Chief Executive Officer, Nadim Ahmed. Nadim?
Thank you, Leigh, and good morning, everyone. I'm very pleased with the positive momentum of our business here at Cullinan Oncology. We're making great progress in advancing our broad and deep pipeline of targeted therapies which have the potential to either be best in class and/or first in class. Today, we'll share with you the updated CLN-081 data. In terms of additional pipeline progress, the clinical studies for our FLT3 bispecific antibody and MICA/MICB antibody have now also started patient enrollment, supporting our evolution into a late-stage oncology company. You'll hear more about the promise of our pipeline in the coming weeks.
Turning to the subject of today's webinar, on behalf of my colleagues here at Cullinan Oncology, as well as our international partners, Taiho Pharmaceutical and Zai Lab, we're pleased to share with you updated data from our ongoing phase I/IIa trial evaluating CLN-081 in non-small cell lung cancer patients harboring EGFR exon 20 insertion mutations whose disease has progressed on or following prior therapy. Since our prior update at ASCO, we have made substantial progress with the CLN-081 program. Our dataset now includes a larger number of patients from which to assess efficacy and safety. Based on the totality of data across all dose cohorts, we have now selected a recommended phase II dose. In terms of efficacy data, we continue to see a high response rate at the 100 mg BID dose.
For the first time, we're able to share very encouraging response durability data from the initial phase I cohort of patients treated at the 100 mg BID dose. Combined with our favorable safety and tolerability data, we believe this clinical profile shows that CLN-081 has best-in-class potential. In terms of next steps, it's our goal to advance CLN-081 as rapidly as possible from both a clinical and regulatory perspective. I would now like to take the opportunity to thank the patients, their families, investigators, and the Exon 20 Foundation for their participation and support of our clinical trial program. I would now like to turn the call over to Leigh Zawel, our Chief Scientific Officer of Small Molecules, to provide more background on CLN-081 and the scientific rationale for developing the molecule. Leigh?
Thanks, Nadim. I'll just take a few minutes to provide some context for Jon's clinical update. EGFR is a well-validated oncogenic driver in non-small cell lung cancer, but the effectiveness of TKIs and other targeted agents in the exon 20 insertion mutant population has been limited by challenges in establishing a requisite mutant to wild-type selectivity index. It's critical in this space to have a drug that is potent against exon 20 insertion variants while also sparing wild-type EGFR. The failure to have that requisite selectivity index results in wild-type EGFR-associated toxicities like skin rash and diarrhea. These toxicities can lead to tolerability challenges which can limit the therapeutic benefit in terms of both response rate and durability. We believe that CLN-081 has the characteristics that allow it to thread this needle. The structure of CLN-081 is shown on the left.
Like many exon 20-targeted TKIs, it's a covalent inhibitor. However, the structure is differentiated. It's a unique compact pyrrolopyrimidine scaffold that is distinct from other exon 20-directed TKIs. It's also distinct in that it's not active against wild type HER2 or mutant HER2, which we suspect may provide a tolerability advantage.
CLN-081's preclinical package demonstrated to us that it had the potential to meet the target profile of a highly selective exon 20 insertion mutation inhibitor. In the upper right-hand corner, we've plotted some of the selectivity data that I told you was so important. The index shown on the vertical Y-axis comprises each agent, and here we're showing data for five different EGFR TKIs, some of them exon 20 insertion targeted. The Y-axis shows the wild-type EGFR IC50 divided by the mutant IC50 for several different exon 20 insertion variants, each one depicted by a different colored shape. The key takeaway is that regardless of what mutant cell line you focus on, 081 selectivity index is greater than one, indicating a favorable selectivity index. Also, regardless of the variant, 081's selectivity index compares favorably to a field of TKIs, including some exon 20 targeted agents.
081 also showed robust in vivo activity here in the bottom right, shown against a PDX model representing ASV exon 20 insertion mutation variants. Similar data was obtained with PDX and CDX models representing the major exon 20 insertion variants. Given this profile, we're very excited to test 081 in the clinic. With that, I will turn it back over to Jon to walk you through the trial architecture and the results to date. Jon?
Thanks, Leigh. As Leigh highlighted, the features of the molecule suggest that based on its selectivity, CLN-081 could have a more favorable risk-benefit profile in the clinic. As you'll see in the next few slides, we continue to be encouraged with the additional data that's accumulating that support that concept. This slide here highlights the architecture of the trial. As shown on the left side, this trial tested doses of CLN-081 ranging from 30-150 mg BID. The trial included two major components, including dose escalation and cohort expansion. Dose escalation began with a single-patient accelerated titration design and transitioned to 3+3 decision rules upon the first occurrence of a grade two or greater treatment-related AE, which occurred at the 100 mg BID dose level.
This trial had a very flexible, adaptive design that allowed for further expansion of any given cohort at the discretion of the sponsor, gated by acceptable safety and pre-specified efficacy criteria. Cohorts could be expanded to six, then 13, then 36 patients gated by these criteria. You'll note that we've expanded cohorts at the 65 mg, 100 mg, and 150 mg dose levels, including enrollment up to the maximum 36 patients at the 100 mg dose level. Enrollment of the 36 patients at the 100 mg dose has been completed and will be a key focus of the update regarding this ongoing trial. Although we expanded enrollment at 150 mg, this was subsequently discontinued after 11 patients based on assessment of the overall clinical profile at this dose.
Importantly, as Nadim noted, we've now nominated 100 mg BID as the recommended phase II dose. It should be noted as I go through these slides, as we get into the data, that they reflect data from a December 1 data cutoff, with one exception. Slide number 11 includes a more recent data cutoff of December 13 to capture an additional patient that had a confirmatory scan in the past couple weeks. This trial is being executed across a broad geographic footprint and includes sites in the U.S., EU, and Asia Pac. Along with our partner Zai Lab, we intend to initiate enrollment of the trial in China next year. Now let's turn to a review of the data, the next slide. Here you can see the updated baseline demographics of our patient population.
With expanded enrollment, there are now 73 safety evaluable and 70 response evaluable patients, a substantial increase since our ASCO update. We continue to enroll a heavily pretreated patient population, with approximately 2/3 of our patients having received two or more prior treatment regimens, i.e., third line or greater. More specifically, 37% of the patients received prior EGFR TKI, including four patients who enrolled early in dose escalation after treatment with other exon 20 EGFR TKI. We'll comment further on those patients later in the presentation. Lastly, over 50% of the patients were treated previously with a checkpoint inhibitor. Let's turn now to the next slide. Here we're looking at the key safety and tolerability characteristics of CLN-081, in particular at the recommended phase II dose of 100 mg BID.
As you can see, the table provides a high-level overview of the breakdown of rash and diarrhea, key toxicities related to the inhibition of wild-type EGFR, as well as laboratory abnormalities, including anemia and transaminase elevations across the 100 mg and 150 mg dose levels for comparison, as well as the overall safety population. We believe that the safety and tolerability profile is quite differentiated compared to other molecules in the class, and is particularly encouraging in the context of the observed efficacy of CLN-081, as I'll describe in a moment. Further, as we've mentioned, we believe that these data support nomination of 100 mg BID as the recommended phase II dose for CLN-081. Turning to 100 mg.
In the 39 safety evaluable patients that have been treated at this dose, 72% of patients have experienced treatment-related rash of any grade, and only 34% of patients have experienced diarrhea of any grade. Importantly, no patients have experienced grade three or greater rash or diarrhea at this dose, and the ratio of patients who've experienced grade one versus grade two events is approximately three to one for both rash and diarrhea. Events have been manageable with conventional supportive care, and no implementation of systemic GI prophylaxis has been required for diarrhea management. As has been seen with other EGFR TKI, a patient with grade three treatment-related pneumonitis has been observed at this dose.
Although the picture was also confounded, as annotated below on the slide, by recent treatment with a checkpoint inhibitor and a concurrent presence of a significant hydropneumothorax not related to treatment in the contralateral lung. Turning to 150 mg. Key observations in the 11 safety evaluable patients at the 150 mg dose included treatment-related grade three diarrhea in two patients, grade three rash in one, and two patients with transaminitis, grade three and four, respectively. In addition, one patient was reported as having grade three treatment-related pneumonitis. Again, as annotated below, this event was confounded by report of a concurrent pneumocystis infection, and the patient had been off drug for a few weeks at the time the event was reported. In addition, an increase in rates of dose reduction and dose continuation have been observed among patients treated at 150 mg compared to 100 mg.
These observations collectively informed our decision to discontinue further enrollment of patients at 150 mg after 11 patients. Collectively, the safety profile at 100 mg appears differentiated from other EGFR inhibitors, in particular, with respect to the incidence and severity of diarrhea. In addition, we believe strongly that this data supports nomination of 100 mg as the recommended phase II dose. I'll pause and now turn the call back to Leigh to provide additional insight on CLN-081's clinical pharmacokinetic profile before turning to our efficacy data. Leigh?
Thanks, Jon. The PK for CLN-081 has been well-behaved to date. Slide 10 plots the unbound plasma concentration from zero to eight hours for each of the cohorts from 30 mg on up to 150 mg. We've also put for context at the bottom two greenish colored lines that indicate GI50s for exon 20 insertion mutant cell lines, and at the top, a horizontal red line indicating the GI50 for a cell line with wild-type EGFR. So far we see dose-dependent exposure increases, limited interpatient heterogeneity, and sustained coverage above the greenish colored mutant GI50 lines throughout an 8-hour period supporting BID dosing. Below the 150 mg level, we see limited, if any, exposure over the GI50 for wild-type EGFR.
At 150 mg, we begin to see exposures above the wild-type EGFR IC50 range for nearly four hours. We think this data aligns with the safety that Jon told you about so far and with the efficacy that you'll hear about shortly, across the dose range from 30 mg- 150 mg. It specifically informs on the increase in toxicity events that we described at 150 mg and therefore underpins our decision to nominate 100 mg as the recommended phase II dose. Jon, back over to you for the rest of the clinical update.
Thank you, Leigh. Let's turn to the next slide. Here we see a summary of the breakdown of response characteristics for response evaluable patients treated at the 100 mg dose, 36 patients, the 150 mg dose, 11 patients, and the overall population across dose levels in aggregate, 70 patients. Again, with a December 13, 2021 data cutoff. In this now expanded data set of 36 response evaluable patients treated at the recommended phase II dose of 100 mg BID, 14 have achieved a confirmed response, yielding a very encouraging 39% confirmed objective response rate. Additionally, at the data cutoff, one patient had an unconfirmed response pending confirmation. Finally, three patients achieved unconfirmed partial responses which will remain unconfirmed. 17 patients had a best response to stable disease, and one patient had progressive disease.
In total, 35 out of 36 of the patients, or 97%, experienced a best response of stable disease or partial response, confirmed or unconfirmed, at the 100 mg dose. You'll also note that the confirmed objective response rate for the 11 patients treated at 150 mg was 27%, albeit in a small number of patients. If you can turn to the next slide. Shown here we have a swimmer's plot representing the time on study for each patient treated at 100 mg BID. To orient you, each bar represents an individual patient. Dark green bars indicate a best response of confirmed partial response. Light green bars indicate unconfirmed partial response. Blue is stable disease and red progressive disease.
What should be highlighted here is that a high proportion of patients have achieved an objective response or extended stable disease now in this larger data set of 36 response evaluable patients. Further, many patients remain on treatment, as indicated by arrows at the end of the bars, with building durability in patients who achieved an objective response. Also annotated on the left are the specific exon 20 mutational subtypes. Of note, we see objective responses and extended disease stabilization across the spectrum of exon 20 mutational subtypes. Let's turn to the next slide. Here we see a waterfall plot showing the best percent change in the sum of the dimensions of target lesions on the Y-axis. This gives us a lens on the extent of tumor regression, i.e., the depth of response among patients treated at 100 mg BID.
Each bar indicates an individual patient, and the color coding is the same as I described to you for the Swimmer's plot on the previous slide. This slide highlights that the vast majority of response evaluable patients treated at 100 mg BID, i.e., 33 of 36 patients, or 92%, experienced some degree of tumor regression, including patients who experienced an objective response and a large number of patients who have stable disease, but nonetheless experienced tumor regression. In addition, we see objective responses among patients who've been treated previously with other EGFR TKI or checkpoint inhibitor, as annotated on the slide with E and C respectively.
Although not included in this cohort, it's important to note that, you know, as we've described previously, there are also patients who have achieved an objective response in CLN-081 after progressing or recurring after prior treatment with other EGFR exon 20 TKI. Let's turn to the next slide. Here we see a spider plot, which gives you a sense of the kinetics of the tumor response to treatment. Shown on the Y-axis, we have the percent change in the sum of the dimensions of target lesions here over time, with each line representing an individual patient. Importantly, this spider plot shows that CLN-081 appears to work very rapidly, with 86% of the patients treated at 100 mg achieving some form of tumor regression at their initial six-week treatment assessment. If you can turn to the next slide.
Here, this next slide provides an initial assessment of the estimated median duration of response to progression-free survival from ongoing follow-up of the 13 phase I patients enrolled at the 100 mg dose level. These are estimated via Kaplan-Meier methods. From this analysis, the median duration of response has not been reached but is estimated at greater than 15 months, and the median progression-free survival is 12 months. These encouraging initial numbers reflect building response duration for the phase I population and will be complemented over time by maturation of data from the initial 23 patients that have enrolled in the phase II and been treated more recently at the 100 mg dose level.
In addition, we've seen, as shown here, a very encouraging disease control rate of 92%, among these 13 phase I patients, with disease control being defined as stable disease over six months or any PR. Let's turn to the next slide. This slide touches on the topic of CNS disease. As we all know, treatment of CNS disease is an important area of unmet need in patients with non-small cell lung cancer. A question that's arguably most meaningfully evaluated, not by non-clinical models, but by investigation in actual patients, particularly in the treatment of patients with active brain metastases. The current study does not allow for enrollment of patients with active untreated brain metastases.
Nonetheless, some interesting hypothesis-generating observations have emerged from the study, which does allow enrollment of patients with either a history of CNS lesions or clinically and radiographically stable treated brain mets. As you can see here, the disease control rate among these patients treated at the 100 mg dose level is similar to that observed for patients who lack CNS metastases, either historically or at baseline prior to treatment on this study. Further, we've received reports describing anecdotal examples of CNS lesions that have regressed in patients treated with CLN-081, although no objective responses have been observed to date. Collectively, these observations, we believe, provide supportive rationale for clinical testing in the future of CLN-081 in patients with active brain mets. I'll pause and turn things back now over to Nadim, who will summarize key takeaways from this update. Nadim?
Thanks, Jon. Thanks very much, Jon. The updated data today further affirm the potential for CLN-081 as a best-in-class molecule. From an efficacy perspective, CLN-081 has shown substantial antitumor activity with broad EGFR exon 20 variant coverage. We're encouraged by the high response rate in a larger data set. Furthermore, the responses are proving to be durable, and we are seeing impressive progression-free survival. From a safety standpoint, CLN-081 has a differentiated tolerability profile given the absence of grade three EGFR-associated events. Our goal now is to pursue a second-line registrational path as quickly as possible and then expand development into the frontline setting where even more patients can potentially benefit. We now have the appropriate clinical data set in-hand to have substantive discussions with health authorities, including the FDA, about next steps for the program, and we plan to provide a regulatory update in Q1 2022.
In closing, we're very encouraged by the updated data, which further support the potential for CLN-081 as an important and differentiated new treatment option for non-small cell lung cancer patients harboring EGFR exon 20 insertion mutations.
With that, we'll open up the line for Q&As. Leigh?
Thanks, Nadim. As a reminder, those of you listening via Zoom can press the Raise Hand button. For those of you joining us on the web, you can enter your question via the chat feature below the video window. Please bear with us while we pull for questions. Our first question comes from Jeff Hung at Morgan Stanley. Jeff, you can unmute.
Thanks for taking the questions. At ASCO, you had 13 response-evaluable patients. Can you talk about the baseline characteristics of those 13 patients compared to the additional 23 patients since then? You know, did the 23 patients have more severe disease or anything that you can point to for the lower response rate in those patients? I have a follow-up.
Thanks, Jeff. Jon, would you like to take that question, please?
Sure. Great question. You know, there are a couple of examples of some patients that had some bulkier disease in that, you know, some more significant disease in that set, but there's no obvious characteristics that we've discerned as being different. Obviously, importantly, you know, the 13 patients was a small number and, you know, now we have a much larger number, which is giving us a more precise estimate of the response rate now with 36 responsive patients.
Great. For the 150 mg dose, can you clarify how the best response of PR went from four patients in the April cutoff to the current three?
I'm sorry, could you restate that?
Yeah, sure. For the 150 mg dose, you know, can you clarify how the best response of PR went from four at the ASCO data to now being three. I was just curious, you know, the details there.
Jeff, I think you're referring to the total PRs and, you know, now what we're showing are three confirmed PRs.
Right.
Jon?
Can you hear me?
Can now, yes.
It's breaking up. I have to go back and check on that answer. I mean, I think we obviously have a larger number of. Are you asking why were there four confirmed PRs that took to-
Yeah. Just to answer your question. At ASCO, we had four total PRs, which include confirmed and unconfirmed.
Yeah.
We're showing five total PRs at the 150 mg, which includes three confirmed and two unconfirmed.
Okay. Thank you.
Does that address your question?
Yes. Thanks.
Okay.
Thank you, Jeff. Our next question comes from Ed White at H.C. Wainwright. Ed, you can unmute.
Good morning. Thanks for taking my question. I might have missed it at the beginning, but can you discuss were any of the patients subject to reduced dose or were there any dose interruptions? Also, I just wanted to get your comments on the current competitive environment and how you see it fitting in with the 39% ORR. Thank you.
Thanks, Ed. Jon, why don't you take the first part of the question around dose reductions, dose discontinuations at the various doses, and then I can pick up the competitive question.
If you look at the safety slide, there is a roll-up there, right, of the number of, and percent of patients at 100 mg and 150 mg, as well as the overall population that had treatment-related dose reductions and dose discontinuations. You can see that it's a pretty modest rate overall out of this data set. You will see that there's some step up there at 150 mg, as well. Where you can see at 150 mg, treatment-related discontinuations were a rate of 27%, and at 100 mg, but then the larger number of patients, 13%. The treatment-related discontinuations were 18% and 3% respectively.
Right. Thanks, John.
I'm sorry. I just wanted to get a little more in-depth on that. I should have been more clear. What were the doses reduced to and when there were interruptions, how long did the interruptions last?
Well, the duration of interruptions are gonna vary by patient. The typical response to someone who requires dose reduction would be to take them down to the next dose level. From 150 mg to 100 mg and at 100 mg would go to 65 mg.
Thanks, Jon. Let me address the second part of your question, Ed, and then perhaps let me just comment on the dosing. I think when you look at the safety profile, I think it's very clear that 100 mg is the dose to move forward, and that's why we're nominating it as the recommended phase II dose. So that would be number one. That feeds into the second question about competitive profile. One thing I would want to remind again is it's response rate and quality of response that's really important. I think we feel very good about the fact that we have a high response rate, and we're seeing very durable responses, impressive progression-free survival.
When we look at the combination of the efficacy of CLN-081, the differentiated safety profile of CLN-081, plus the oral route of administration, we feel very good about the competitive nature of the profile as a potential best-in-class molecule. Thanks for the question, Ed.
You're welcome. If I could just add one more question on the timing for submission. Have you already scheduled a meeting with the FDA, or is that going to be scheduled later for a meeting in the first quarter? Thanks.
Sure. Yeah, as I said in the presentation, we'll provide an update on the regulatory process in the first quarter of next year. Thanks.
Thank you.
Thanks. It looks like we have a question from Andrew Berens at SVB Leerink. Andrew, if you could unmute, please. It looks like you're still on mute.
Leigh, I think we have time for one more question.
Great. The next question comes from Bijan Mekoba at Stifel Financial. The question is, why was the 150 mg dose cohort discontinued?
Jon, would you like to take that question, please?
Yes. I mean, we think it's really clear from the overall clinical profile where we've shown you that we've had, you know, importantly, we've had grade three rash and diarrhea. We've had, you know, more from the perspective of significant grade three or greater events there. The safety profile. Higher rates of treatment-related dose reduction and discon relative to 100 mg. Obviously, as I showed you with the efficacy, the response rate was, albeit a small number of patients, lower as well.
Great. Thanks, Jon.
It looks like that's our last question for today. Thank you all for joining us. I apologize. We do have one additional question. Joseph Lee at Sender Company. Can you describe the pneumonitis case in more detail?
Jon?
Yeah. The patient at 100 mg that I mentioned had a grade three pneumonitis, and that's a patient that had prior checkpoint inhibitor therapy. The case was further compounded by presence of a concurrent, you know, pretty significant hydropneumothorax in the contralateral lung. You know, that's been reported as a-
If you did not anticipate asking your question via the phone, you can alternatively access-
I don't know if others got. I was getting huge feedback there. Again, it's a related, reported as a related event, but you know, some significant confounding features to it. Then the patient at 150 mg that had a case of treatment-related grade three pneumonitis as well had some pretty significant confounding variables, including the fact that there was demonstration of pneumocystis at the same time, and the patient had been off drug for some time, a few weeks, prior to the reporting of events as well.
Great. Thank you. I believe that's our last question. Thank you all for joining us today, and have a wonderful day.
Thanks, everybody.