Sutro Biopharma, Inc. (STRO) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Sutro Biopharma KOL Conference Call to discuss Phase I interim dose expansion clinical data for STRO-002 for treatment of advanced ovarian cancer. [Operator Instructions] Please be advised that the call is being recorded at the company's request and will be available on the company's website for at least 30 days. Now at this time, I would like to turn the call over to Ed Albini, Chief Financial Officer at Sutro Biopharma. Sir, please go ahead.

Thank you, operator. Good afternoon, everyone, and thank you for joining us. With me on the call are Bill Newell, Chief Executive Officer; Dr. Arturo Molina, Chief Medical Officer; Dr. Trevor Hallam, President of Research and Chief Scientific Officer; and we also welcome on the line Dr. R. Wendel Naumann of the Levine Cancer Institute at Atrium Health. This afternoon, we issued a news release that you can find on our website at www.sutrobio.com, which includes interim data from our ongoing Phase I dose expansion study of STRO-002 in ovarian cancer. Before we start, I would like to remind you that today's call will include forward-looking statements. These forward-looking statements are based on Sutro's expectations and assumptions as of the date of this call. Each of these forward-looking statements involve risks and uncertainties that could cause Sutro's clinical development programs, future results or performance to differ significantly from those expressed or implied by the forward-looking statements. Please refer to Sutro's filings with the SEC, including our 2020 Form 10-K for information concerning factors that could cause Sutro's actual results to differ from those expressed or implied in the forward-looking statements discussed on this call. Except as required by law, Sutro assumes no obligation to update any forward-looking statements discussed on this call to reflect any change in expectations, even as new information becomes available. The agenda for today is as follows: Bill Newell will open up the discussion. Dr. Wendel Naumann will then present the interim dose expansion data for STRO-002. Arturo Molina will next give a few summary remarks. Bill Newell will have brief closing remarks, and we will then close with a Q&A period featuring Dr. Naumann, along with the Sutro team, including Bill, Arturo, Trevor and myself. With that, I would now like to turn the call over to Bill Newell for a welcome and introduction.

Welcome to our conference call discussion of our interim data update of the STRO-002 Phase I dose expansion study in advanced ovarian cancer. Despite recent advances in the treatment of ovarian cancer, there remains a significant high unmet need for more and better treatment options for advanced patients with progressive disease. Previously, we presented the near final results for our Phase I dose escalation study at ASCO in June 2021, showing encouraging efficacy and safety for STRO-002 in an all-comers patient population with very advanced ovarian cancer who had experienced a median of 6 prior lines of therapy. Today, we will focus our attention on our dose expansion study. The data cutoff for today's presentation was November 8, 2021, at which time, we had dosed 43 of the 44 patients who are ultimately enrolled in this study. All patients had advanced progressive ovarian cancer, having received up to 3 prior lines of therapy. We did not restrict enrollment based on folate receptor alpha expression levels and therefore, all-comers, who met the enrollment criteria, were enrolled. With both Phase I dose escalation and expansion studies, we have now treated a total of 83 ovarian cancer patients with STRO-002. As of the November 8 interim data cutoff for our dose expansion study, 33 of the 44 patients on the study were evaluable under RECIST criteria. Meaning that they had received at least 1 post-treatment scan. Of those 33 patients, 7 patients had achieved partial responses, which had been established with 2 post-baseline scans. In order to get a more complete picture of our RECIST responses for this interim update, we additionally reviewed subsequently scheduled scans for RECIST responses only on those patients who had an unconfirmed partial response with only 1 scan as of November 8. As our news release states, we had 5 patients who had unconfirmed partial responses with only 1 scan as of November 8. Based on the follow-up with these 5 individual patients, 4 of those 5 patients were confirmed partial responses at their next scheduled scan. This resulted in a total of 11 confirmed partial responses and a corresponding interim 33% overall response rate in this unenriched patient population. As an exploratory analysis, we performed an enrichment cutoff of patients with fully receptor alpha expression levels above 25% using a tumor proportion scoring algorithm or TPS algorithm, which selected for 25 of the 33 RECIST evaluable patients. In this exploratory analysis, we see an even higher 40% overall response rate for this enriched patient population. In this study, we are looking to determine whether future trials should commence dosing at 5.2 or 4.3 milligrams per kilogram as well as an appropriate enrichment strategy with an eye towards identifying patients most likely to benefit from STRO-002 and maximizing the probability of success in our clinical trials. Although the dose expansion study is still ongoing, and we have not yet determined a final dosing regimen or enrichment strategy for our future trials, our interim data suggests that commencing patients at a dose of 5.2 milligrams per kilogram may result in better patient outcomes and that fully receptor alpha expression levels of above 25% may best identify the patients most likely to benefit from STRO-002. Based on the patient population we've been studying, which includes primarily platinum-resistant ovarian cancer patients, we believe there may -- this may be an appropriate therapy for approximately 70% of these patients. Based on this interim data in this unenriched patient population of 33 RECIST evaluable patients, we have begun to see a meaningful dose response differentiation of approximately 28%, favoring the 5.2 milligram per kilogram over the 4.3 milligram per kilogram starting dose. Specifically, the 5.2 milligram per kilogram cohort had 17 patients who were RECIST evaluable as of November 8 and were associated with a 47% overall response rate. In contrast, the 16 patients in the 4.3 milligram per kilogram cohort were associated with a 19% overall response rate. As we will discuss further on today's call, STRO-002's tolerability profile so far looks generally consistent with what we've seen previously, clinically and preclinically. Since we have today treated a total of 83 ovarian cancer patients in our dose escalation and dose expansion studies, we believe we have a good understanding of the safety profile of STRO-002. We believe that the side effects that have been seen are manageable by treating physicians and, importantly, do not include blurred vision or other significant ocular toxicities, which may require an additional clinician on the patient's physician team. With that, I would now like to introduce Dr. Wendel Naumann. He is a co-principal investigator in the STRO-002 dose expansion study and currently Professor and Director of Gynecologic Oncology Research and Associate Medical Director of Clinical Trials at the Levine Cancer Institute of Atrium Health. He served as a Board member of the Executive Council of the Society of Gynecologic Oncology and the Chair of the Education Committee and Co-Director of the SGO Winter Meeting. His clinical experience includes targeted therapies and immunotherapies, and he runs the Phase I trials in gynecologic oncology at the Levine Cancer Institute. Dr. Naumann, over to you.

Bill, thank you for that introduction. It's my pleasure to present this data. The dose expansion cohort randomized patients to dose levels of STRO-002. The data cutoff for this report was November 8, 2021. As you can see from the CONSORT diagram on the right, a total of 44 patients were enrolled. 1 patient had not received a dose by the data cutoff, leaving 43 patients randomized and dosed as of this report. Of these 43 patients, 2 discontinued prior to dosing and 8 patients did not have a post-treatment scan prior to the data cutoff, leaving 33 evaluable patients. TPS score showed greater than 25% in 25 patients and less than 25% in 8 patients. Dosing was based on ideal body weight. 23 patients were randomized to the 4.3 milligram per kilogram cohort and 20 patients to the 5.2 milligram per kilogram cohort. Median age of this patient cohort was 60. Median time from diagnosis to enrollment was 2.8 years and was slightly less in the 4.3 milligram per kilogram cohort. Patients could have received up to 3 prior lines of therapy prior to enrollment in the trial. Median number of prior lines of treatment was 3 in the 4.3 milligram per kilogram cohort and 2 in the 5.2 milligram per kilogram cohort. 63% of the patients had prior therapy with bevacizumab, and 65% had prior therapy with PARP inhibitor. Next slide. This is the waterfall plot of best response to therapy. The teal bars represent patients treated with the 4.3 milligram per kilogram dose and the dark blue bars represent patients treated with the 5.2 milligram per kilogram dose. Yellow triangles denote ongoing treatment as of November 8. 70% of the 33 patients had some reduction in tumor volume. 12 of 33% or 36% achieved greater than a 30% reduction in tumor volume. Overall, there were 7 confirmed PRs at the time of the data cutoff, and there were 5 additional patients who achieved greater than 30% response that was unconfirmed at the time of the data lock, with 4 of these having a subsequent confirmed PR in the next assessment scan after the data cutoff that are counted in the response rates. One of the unconfirmed responses was later classified as having stable disease and is not counted in the response rates. This is the investigator-assessed objective response by RECIST version 1.1, broken down by the 2 dose cohorts. It's important to remember that these cohorts are not enriched for folate alpha receptor expression. Of the 33 patients, there were 7 patients with a confirmed PR and 4 patients with an unconfirmed PR that was confirmed at the next assessment scan after the data cutoff for an overall response rate of 33%. In the 4.3 milligram per kilogram dose, there are 3 PRs in the 16 evaluable patients for partial response rate of 19%. In the 5.2 milligram per kilogram cohort, there are 4 PRs and 4 unconfirmed PRs that was subsequently confirmed on the next assessment scan for an overall response rate of 47%. 14 patients or 42% had stable disease as their best response. Interim data would suggest that 5.2 milligrams per kilogram starting dose may have a higher response rate. Next slide. This spider plot shows the RECIST response broken down by treatment cohort. Responses were generally rapid and many were durable, as you can see at the 16 and 24-week landmarks, even for patients with stable disease. Next slide. This [ squirmers ] plot shows both the dosing and the time from treatment to a greater than 30% response. Dark blue represents treatment at 5.2 milligrams per kilogram and teal represents treatment at 4.3 milligrams per kilogram and the light blue at 3.5 milligrams per kilogram. Most patients who achieved a PR did so at their first assessment scan. Despite the dose reductions after starting at the 5.2 milligram per kilogram dose, responses were durable with many patients remaining on study more than 16 weeks and some more than 24 weeks. 23 of the 43 patients remained on study at the time of the data cutoff. This data will be used to inform the recommended Phase II dose pending data maturity. Next slide. These are CT scans of a patient of mine that was enrolled in the dose expansion cohort. She was originally diagnosed with ovarian cancer in January of 2020 and is treated with 6 cycles of taxane and carboplatinum. Unfortunately, she recurred less than 6 months from initial treatment. At this point, conventional single-agent chemotherapy would be predicted to have less than a 10% RECIST-defined response rate. And not surprisingly, she progressed through both liposomal doxorubicin and gemcitabine. She was subsequently treated with STRO-002 at 4.3 milligram per kilogram dose in May of 2021 and at that time had a large disease burden, which is a disease in anterior bowel wall, pelvic, aortic and axillary lymph nodes. As you can see from these scans, she had an excellent response to treatment with dramatic and ongoing tumor reduction after 5 cycles of chemotherapy. The lesions in the abdominal wall have almost resolved, right axillary node, paraaortic node and the pelvic nodes, all backed to CT scan to find normal size. This is the tumor proportion score analyzing the expression of folate alpha in the expansion cohort. The tumor proportion score is a calculation of the percentage of cells that stained for folate alpha expression by IHC regardless of staining intensity. This is commonly used in clinical practice in calculating the expression of PD-L1 and is reproducible between pathologists. When the tumor stained at 25% or less, the response rate was only 12.5%. For levels higher than 25%, the response rate ranged from 40% to 43.8%, with a little difference between the TPS cutoffs of 25%, 50% or 75%. TPS greater than 25% expands the eligible patient population that might benefit from STRO-002 to approximately 70% of patients with platinum-resistant ovarian cancer. Next slide. This is the safety data on the 43 patients who have been dosed in the expansion cohort for treatment emergent adverse events that were greater or equal to Grade 3 and noted in more than 1 patient. Overall, STRO-002 was well tolerated and no new safety events were observed. The most common treatment-emergent adverse event that was Grade 3 [ averse ] with neutropenia. This was observed in 61% of the 4.3 milligram per kilogram cohort and 75% of the 5.2 milligrams per kilogram cohort. However, Grade 3 for greater febrile neutropenia is rare and was seen in only 2% of the 4.2 milligram per kilogram cohort and 5% of the 5.2 milligram per kilogram cohort. Most neutropenia was managed with dose delays of 1 week or with the use of growth factors because the half-life of this drug is longer than traditional chemotherapy and is recommended that growth factors are not started before post chemo day 8. There was one case of Grade 5 neutropenia. This patient had been treated with growth factors and had prior Grade 4 neutropenia. After this event, the protocol was amended to require dose reduction for Grade 4 neutropenia. Except for febrile neutropenia, the Grade 3 or greater toxicity was less than 10% for other side effects. Of note, there was no significant ocular toxicity noted in the expansion cohort, including keratopathy. I'm going to turn this now back over to Dr. Molina to discuss the ongoing strategies with STRO-002 going forward.

Thank you, Dr. Naumann, for presenting the STRO-002 expansion cohort interim efficacy and safety data update. In summary, the dose expansion data provide initial insights on a go-forward clinical development and registration enabling strategy. The overall efficacy outcomes reported today showed a 33% overall response rate in a nonenriched population across all folate receptor alpha expression levels at both 4.3 mg per kg and 5.2 mg per kg dose levels. The interim data demonstrates evidence of dose response. Specifically, an overall response rate of 47% or 8 out of 17 patients was observed in the unenriched patient population who started treatment at the 5.2 mg per kg dose level. This initial data suggested responses in patients starting at 5.2 mg per kg are maintained even when a subsequent dose adjustment is implemented. Using tumor proportion score, or TPS, the interim data suggests that a cutoff of greater than 25% folate receptor alpha expression levels are correlated with higher clinically meaningful responses. With this TPS cutoff of greater than 25%, we observed an overall response rate of 40% or 10 out of 25 patients representing approximately 70% of patients enrolled in this study, which is predominantly platinum-resistant ovarian cancer. To date, we have treated 83 women with advanced ovarian cancer in dose escalation and dose expansion. As we get more experienced with STRO-002, we have not observed new safety signals. The keratopathy signal has not been observed and prophylactic corticosteroid eye drops are not needed. Neutropenia was the leading treatment-emergent adverse event, resulting in treatment delay or dose reduction. We saw this in dose escalation and have implemented a protocol amendment for dose adjustment if a patient develops Grade 4 neutropenia. With this approach, we have seen amelioration of neutropenia in subsequent cycles. As we look forward to the expansion of the STRO-002 franchise, we are pleased to provide an update on additional clinical studies in ovarian and endometrial cancer and nonclinical work on other tumor types. As you heard earlier, we completed enrollment of the 44 patients in the dose expansion cohort in less than a year. We have initiated a study of STRO-002 in combination with bevacizumab. This trial is open and enrolling patients. We are planning to meet with the FDA in the first half of 2022 to discuss a potential pathway for accelerated registration with a single-arm nonrandomized study in patients with advanced ovarian cancer. We're also actively exploring the role of STRO-002 in other solid tumors. To that end, last year, we began enrolling patients in the endometrial cancer expansion cohort. Our initial preclinical work provides a strong rationale for testing STRO-002 in non-gynecologic malignancies such as non-small cell lung cancer and anticipate starting a pilot study in the second half of 2022. With these ongoing and planned clinical studies, we're optimistic about developing the full potential of STRO-002 to address important unmet medical need across multiple tumor types. I would like to hand it over to our CEO, Bill Newell, for closing remarks.

Thank you, Dr. Naumann and Dr. Molina, for taking us through this interim data review of STRO-002. We are very encouraged by this interim data. We started the clinical development of STRO-002 in the first quarter of 2019. Based on the data we've seen in the dose escalation phase and this interim data from the dose expansion phase, we are very encouraged about the potential and differentiated efficacy and safety profile for STRO-002 to bring new hope to more patients with advanced ovarian cancer. We will continue to pursue the accelerated approval pathway for STRO-002, leveraging Fast Track designation, which we received last year, and we plan to discuss the full data set with FDA later this year. We will also continue to invest in STRO-002 more broadly, including in endometrial and non-gynecologic cancers. We look forward to having more complete data from our dose expansion cohort later this year and to engaging in regulatory conversation about our path forward towards registration. All of us at Sutro would like to thank the 83 women who have participated in our ovarian cancer studies as well as their families as well as the investigators and their teams who are treating these women. You are paving the way for other women with advanced ovarian cancer to have a new treatment option. I'd also like to thank our entire Sutro team, who brought STRO-002 from concept through manufacturing and now to patients. With that, operator, you may open up the lines for our question-and-answer period.

[Operator Instructions] Our first question comes from Roger Song with Jefferies.

So first of all, congrats for the great data. I think this is definitely something we are looking for. A couple from us. So the first one is, I know you have done this kind of analysis for the high dose versus low dose and high expression level versus low expression level for the folate receptor alpha. So any kind of insights around the matrix. For example, for the high-dose cohort, how many of them are actually -- have the high folate receptor alpha expression level, so we can know basically that's the kind of a key population we should go going forward?

Roger, this is Bill. Sorry, my throat is a little scratchy. So I'll try to be as clear on this as I can be and then hand it over to Arturo. As you know, in this dose escalation study involving all-comers, one of our key objectives is to understand what an appropriate enrichment strategy might be for STRO-002 for purposes of future clinical development activities. We have to remember that an enrichment strategy for 1 therapeutic use in a pivotal trial might not be the right enrichment strategy for a different therapeutic being studied in a broader patient population. Based on what we observed in the dose escalation portion of the study and now these observations are being confirmed by the interim dose expansion data, we had a view that the PS2+ scoring algorithm likely would not be appropriate for STRO-002 as we saw responses and durability across medium and low expression levels not seen by others. I'd like to ask Arturo to continue to comment on this -- on your question.

Yes. Can you hear me?

Yes. I can hear.

Yes. So Roger, Sutro and ImmunoGen are using the same Ventana assay to determine the expression of folate receptor alpha in tumor cell membrane by IHC. ImmunoGen scoring algorithm, which is referred to as PS2+, requires at least 75% of tumor cells showing moderate or strong intensity of folate receptor alpha, and this is referred to as 2 plus or 3 plus. Now Sutro's tumor proportion score, or TPS scoring algorithm, requires at least 25% of tumor cells showing any intensity expression of folate receptor alpha, which includes 1 plus, 2 plus and 3 plus. Based on this interim data and mindful of what we saw in dose escalation, we decided to focus on the TPS scoring algorithm and not PS2+ and use it as a basis for understanding what patient population might benefit most from STRO-002. Now we've looked at several folate receptor alpha expression cutoffs, TPS greater than 25%, TPS greater than 50%, and TPS greater than 75%. Clearly, the interim data suggests an obvious enrichment cutoff at TPS greater than 25%. And the difference between at a 12.5% overall response rate at TPS less than 25% and 40% overall response rate in patients with TPS greater than 25% is quite striking. So the PS2+ high expressers as defined in the SORAYA study are a subset of our TPS of greater than 75% as they required 2 plus and 3 plus [ teni ] in this group, but we do not require that. In the greater than 75%, we will take 1 plus, 2 plus and 3 plus. And our response rates compare quite favorably. I know it's always risky to compare different patient populations where baseline characteristics are not identical, and where patient numbers are materially different. But as you can see from our table on Slide 11, we see a 44% overall response rate in a broader high expresser group regardless of intensity. So beyond that, our broader enriched population with TPS of greater than 25% experiences a 40% overall response rates, which we think speaks for itself. And as was mentioned earlier, we believe that this enriched patient population represents about 70%, 75% of advanced ovarian cancer population, which was primarily platinum resistant in our study, but that could obviously apply to platinum-sensitive populations as we continue to study those in the future. Did that answer your question?

Got it. Yes. No. That's very helpful. Okay. And my next one is as far as I can tell from the slide, majority of those responders they are still on treatment, but you have a few patients. They are off treatment. Maybe just any color around those patients. Why they are off treatment?

Yes. So the reason for discontinuation has been primarily disease progression. We have a very low grade of discontinuation from AEs. Only 2 patients have discontinued from AE and the rest have discontinued for PD.

Got it. Okay. And then so maybe last question if I may is for the Grade 5 event you observed in 1 patient. Any kind of description around this patient baseline? And I heard you say he had some prior neutropenia as well. Maybe just give us some kind of color around that patient baseline characteristics.

Yes. The patient who died while dose expansion had sepsis in the context of Grade 5 neutropenia and this patient have had prior neutropenia on previous cycles. The confounding factor in this patient that might have increased the risk of infection included the presence of large pleural effusions that cause shortness of breath and required drainage with thoracentesis before the study and during the study. And additionally, she had a lot of ascites that was also drained, but some of the ascites was loculated. Meaning it could have be drained and that also could have represented a source of infection during the period of neutropenia. Now this event happened early in the course of the study. That happened back in April. And so at that time, in consultation with the principal investigators on the safety evaluation team, we made a protocol amendment to require a dose reduction after any Grade 4 neutropenia. Now this Grade 5 event and protocol change were submitted to the FDA, and we received no further feedback from the agency on this. Since the protocol amendment, which was back in April, we have not had any other Grade 5 events. And it's important to remember that this patient is the only 1 out of 83 total patients in our clinical studies to have had a Grade 5 neutropenia. So we feel that with the protocol amendment, we've also been looking at the rates of neutropenia in those patients who can dose reduce. And there's clearly evidence that the neutropenia is ameliorated when we go from 5.2 to 4.3.

Our next question comes from Boris Peaker with Cowen.

I'd like to add my congratulations on the impressive data. And I guess my question is focused on future steps. Can you comment on your thoughts about dosing for the pivotal study? And is there a prophylaxis strategy that could address febrile neutropenia?

Arturo, would you like to handle that?

Yes. Thank you, Bill. Yes. I think that with the dose -- the planned dose reduction for patients who develop Grade 4, we have seen clearly some amelioration. So we're evaluating that. And we're also monitoring the use of the prophylactic G-CSF. Most PIs do not use it because, in our experience, the neutropenia reverses on its own, usually within a week, but we are considering a prophylactic strategy. And again, we'll let that data set evolves -- after the protocol amendment to help us decide if G-CSF prophylactic requirement is needed or even consider prophylactic antibiotic in a patient with a prior infection or who has a high risk of infection. So all of that is under consideration as the data matures.

Got it. And as my prior question in terms of the dosing for the pivotal trial, what are your thoughts on that and maybe the timing of that pivotal study -- planned pivotal study?

Arturo?

Yes. So let's start out with the dosing. I think what you see here is that when patients start at 5.2 mg per kg, a fair number of them are dose adjusted to 4.3 at the third cycle. But even though we dose adjust, they seem to maintain their response. So our current thinking, which we will be vetting with additional discussions with key opinion leaders, is that we start out by 5.2 for 1 to 2 doses. And if needed, we can try prophylaxis, but try to get those first 2 doses at 5.2 mg per kg and then adjust to 4.3. So we'll still have to discuss that with the FDA. Our current thinking around the design is that the trial would be a single arm study that would support an accelerated approval. And then the folate receptor alpha cutoff is still to be determined and discussed with the FDA. But as you saw from the data, the greater than 25%, which is a pretty broad patient population, is very encouraging. And we plan to start the study in the second half of the year, probably fourth quarter, but in the second half.

Boris, let me add 1 other thing and that is, obviously, we are looking at an enrichment strategy, too. So we'll continue to monitor that. One of the things that we think was encouraging was that when you look at the people who are in the 5.2 mg per kg dose cohort and who are greater than 25% TPS, you had response rates even though the numbers are small in the north of 50%. So really encouraging, and we'll be factoring all of that into our thinking about trial design.

And our next question comes from Nick Abbott with Wells Fargo.

I'd like to add my congratulations as well. Maybe the first one, I know there weren't that many platinum refractory patients in the trial. And so numbers are small. But as you think about the next trial, is it going to be in just resistant patients or refractory patients? And if you're including refractory patients, what response rate did you see in those refractory patients and the expansion cohorts?

Arturo, you want to handle that?

Yes. So in the study, 81% or so of the patients are platinum resistant and the response rates are very similar to the overall population. The platinum-sensitive patients have to have 2 prior platinums, and we're still cleaning the data. But it seems like all the patients who've had 2 prior platinums have also had a PARP inhibitor as well. So as the data matures, we are planning to take that to the FDA and discuss the study. The current regulatory precedents for single-arm studies in this setting include primarily platinum-resistant patients. Whether we can include some platinum-sensitive patients who have progressed up to 2 rounds of platinum and of PARP, I think we would discuss that with the agency as well. Now the platinum refractory -- primary refractory to frontline treatment, defined as having no response or progressing falling treatment or within 3 months upon completing the carbotaxel, those patients are generally excluded from registration-enabling trials, but we will include some of those patients in our combination study to see if we see activity. That group represents about 10% of the patient population and generally does not do very well with any subsequent therapies. Maybe I'll ask Dr. Naumann, if you can comment on the platinum refractory.

As you said, that's a very difficult patient population and they often go -- they get sick very, very quick and are really not a great patient population to give additional treatment to. It's different if people progress right after platinum therapy in the recurrent setting. I think those patients are fundamentally different. So if we see any responses in the combination trial, I think we're going to be encouraged to look there because it certainly is a high unmet need.

Thank you, Dr. Naumann.

So Arturo, so were they platinum refractory recurrent patients, okay, not primary refractory in this trial?

Yes. We are still looking at that. There are some patients who are in the recurrent -- or in the second line treatment. Very few of these patients actually get into remission, but in the second line or third line platinum setting, the patients who are refractory sometimes become refractory in the setting of PARP inhibitor use. So we'll be evaluating that data as well.

And so how many of the 5.2 mg per kg patients were dose reduced? What was the reason given this good safety profile?

Well, remember, we put in the protocol for reducing for Grade 4. So that was one of the reasons. That was, I think, the key reason for dose reduction.

Okay. Okay. And then last one for me is it doesn't seem like there's a higher response rate than increasing folate receptor alpha level. I think I've heard you talk before about this kind of a threshold, but it does suggest that perhaps half the patients who have high levels or patients who have high levels of folate receptor don't necessarily respond to 002. So what do you think the reasons are for that resistance?

Well, I think if you compare the 44% response rate in our TPS greater than 75% and then look at ImmunoGen's high PS2+ with greater than 75% expression in the tumor cells, the 44% response rate we think compares favorably. And that patient population also includes some patients who are 1 plus intensity. The PS2+ scoring requires 2 and 3 plus. So I think that these are very -- strongly positive data for high expressers, medium expressers and even low expressers. We are going to go -- I mean the data suggests that less than 25%, those would be called very low expressers. We will probably not want to study those in the pivotal study. But the fact that we get greater than 40% response across low, medium, high TPS scores is very encouraging and we believe very differentiating.

Thanks, Nick. It might be useful for Trevor to comment a little bit about on the different warheads here and what our warhead does in the way of immunogenic cell death that might perpetuate some of the effect.

Yes. Thanks, Bill. So I mean, the 2 parameters we're looking at here, of course, is just the effect on the overall response rate by actually going through a very simple proportion of number of cells that are folate positive. So 1 plus, 2 plus, 3 plus. And we can do that and we approximate to about 70%, we think, of varying population. And what you're looking at with those ORRs are 40% above 25% expression, so 2 plus, 3 plus, is that's on the 2 doses, 4.3 and 5.2. So if you go to the 5.2 dose and if that's our dose, that goes out of 47%. And with this enrichment, maybe we have indications it's higher, but there are low numbers in the study. The big reason behind all of this, of course, is totally consistent with this efficiency of killing with this molecule. Remember, this is not although it seems to be similar to other ADCs out there and [ 4 ] warhead payloads cytotoxins per antibody. The design of it means that every molecule in that drug is the same, which is very unusual in the ADC field. It's usually a cocktail of different variations of where these linker warheads are attached to the antibody. And that cocktail, that mixture means that there are -- it's inefficient because in some places where those conjugates occur on the antibody, they're not as [ good ] as other positions where you get a much more efficient killing. And so what we're able to do, I think, is to see a good impact. Because every molecule is competent and very optimized to do its job, you're able to make use of every molecule that you dose. And what that has an impact on is that you're seeing clinical impact either at lower doses or the other side of that at lower antigen expression intensity on the surface. Frankly, you just need less internalization events of that folate receptor alpha protein on the tumor cell to view and optimize killing than you would if you had some of the more conventional technologies that are out there. So that's a very exciting platform basis for the design. Being able to go for tolerable and frequent dosing through many cycles, which we had a sort of example of, we felt or at least a directional indicator in our escalation studies, and now we're very interested in seeing how this part of the expansion plays out with time. We have a lot of patients still on. We would expect this efficiency to put that tumor under pressure on many cycles. Based on our preclinical work, we see then a better engagement with the immune system because this novel hemiasterlin payload we use is a very effective stimulus for immunogenic cell death. That's a natural physiological mechanism that all of our bodies have in their cells, which flags up to the immune system that it's under stress usually because it's a viral infection or something like that. This cytotoxin creates similar signals and stimulates the innate immune system to go after it. So if all that plays out, and, of course, we have no evidence yet that this is playing out in the clinic, that's what we'll get in time. We've certainly shown it preclinically. That lends itself not only to good monotherapy or good durability of responses because partly due to the pressure on the cytotoxin but also the innate immune system going in. But it also opens it up to a really solid foundation for various combination strategies, including checkpoint inhibitors, which will be better able to be active if you've already got the immune system getting into those tumors. So I think I'll stop there, but it's quite promising.

And our next question comes from Asthika Goonewardene with Truist Securities.

My congrats as well for some pretty good-looking data here. Maybe I'll just start off with -- let me start off here with maybe just picking into some of the trends here that you're seeing. And I know it's small numbers, but I'm wondering if maybe Dr. Naumann and Arturo can comment here. In the patients that made it past 16 weeks, were there any trends that you noticed in the intensity of IHC score or the level of expression. I'm just wondering as the data sets continue to mature, if we could see any more trends emerge in terms of the cutoff?

Great question. Arturo or Dr. Naumann, thoughts?

Yes, I'll start out and then I'll ask Dr. Naumann. I think that's an important question, and that one requires longer follow-up because we -- still, we just have a few patients with a 24-week mark. But it's encouraging that we're seeing them get there, and we have a fair number of them at the 16-week mark. And I think that analysis will be conducted when we see how many of those patients who were very early in the treatment. A lot of the patients came on towards the completion of enrollment. Dr. Naumann, do you have any other thoughts?

Yes. I've been impressed by the durability of responses, and we have several patients. Remember, these patients generally live only about a year. So they don't have a lot of treatment options left. And I've got a couple of patients on trials on this drug for over a year, which is just phenomenal. But sort of anecdotal observation is that there does seem to be some correlation with the toxicity that they have at the initial treatment with the duration of response. But I don't have any confirmatory data on that.

Got it. Okay. And then in the number of patients that you had confirmed responses even after the data cutoff, what number of them had seen prior bev? I'm just trying to see if there's any difference in prior bev on response rates.

I'll take that.

Yes, Arturo.

Yes. We've already started to look at that prior bev, prior PARP. And we have not seen anything that predicts for a response yet. But it's an important question.

And Bill, if I can be cheeky and ask. The FDA end of Phase I meeting that you plan on having, is there any chance you might be able to get an appointment with the FDA at the end of 2Q? Or is that going to be a 2H objective?

We're working on plans to seek a meeting and we'll let you know when we plan to have that.

Our next question comes from Ted Tenthoff with Piper Sandler.

Great. Happy new year everybody, and thanks for the update. Most of my questions were answered, but I had a question on the Avastin combo study. And really, the potential here being to maybe move into earlier lines of therapy with the combination. Is that the right way to think about it? And just with respect to trends kind of in ovarian cancer, you mentioned the potential to combine with checkpoints. And obviously, as you look at other solid tumors where checkpoint inhibitor therapy is more established, how do you kind of envision sort of moving those -- obviously, the doublet with bev will be in the clinic soon, but how do you envision ultimately moving maybe a triplet into the clinic or a doublet with CPI?

Great question, Ted. Happy new year. Arturo?

Yes. So the -- Ted, happy new year. The doublets that were -- that has already started -- and we're, I think, going to be enrolling very soon, we've done our first site initiation visit -- is the combination study with bevacizumab. And the rationale for that is based on preclinical data, obviously, but the mirvetuximab combo data with bev also looks very encouraging. And to your point, we are interested in exploring this combo in platinum resistant, but also platinum-sensitive patients who have had 2 prior lines of platinum because I think that's another way to keep moving it to earlier lines of treatment. And we're obviously considering even after 1 line of platinum. So all of that is under consideration. The combination with the checkpoint inhibitor is strongly supported by the preclinical data. Trevor just took you through some of the preclinical results where the induction of immunogenic cell death in the combination with checkpoint inhibitors preclinically, again, strongly suggests that type of combination. I think our initial focus is going to be on doublets. And once we get experience with the doublets, I think, we could consider a triple combination. You had several questions, so I want to make sure I answer all of them.

Yes, no, I think that works well.

One more thing just for completeness is that in the combos, that might be a place where we may want to, during the dose escalation part, test in the primary platinum refractory patient population because if we see activity in that patient population, those patients who are truly refractory to primary platinum-based therapies don't really have good therapeutic options. So at least during the dose escalation part of our doublets, we will explore that patient population.

Our next question comes from David Nierengarten with Wedbush Securities.

I had a couple. First off on the neutropenia. Were there any -- you mentioned that it resolved with the dose reduction. Were there any patients who did experience neutropenia after dose reduction or had a maybe a prolonged bout of neutropenia. And then another question kind of related is have you reported or presented at a scientific meeting somewhere or if you could remind us if there is a -- how big the exposure differential is between the 2 dose levels? Is it proportional to the dose? Or is there a different area under the curve exposure for patients?

Arturo, why don't you take that? And maybe Dr. Naumann may have some thoughts on the neutropenia too.

Yes. No, that sounds good. So on the neutropenia -- we'll get to the PK question, but let's focus on the neutropenia first. We've learned quite a bit from the 83 patients that we've treated. And we just did some analysis looking at the impact of the dose reduction. And there clearly seems to be a decrease. Certainly, we're not seeing the Grade 4 tents to go down. So we'll follow up on that. But without a doubt, the dose reduction has been helpful. What we still may need to explore is the role of prophylactic G-CSF. It's not used a lot. And most of the physicians -- we don't require it. We just allow them to use G-CSF per standard of care of their institution. There are very few doctors, I think, qualified or so of the patients are -- have been receiving prophylactic G-CSF because neutropenia in general is asymptomatic. We've only had those 2 cases of febrile neutropenia, the Grade 5, that we've talked about. And then we had a Grade 3 at 4.3 and that patient recovered and went on to continue on treatment. Maybe Dr. Naumann has additional thoughts.

Yes. I mean I agree. From a clinical standpoint, I don't think the neutropenia is that much different than standard taxane platinum chemotherapy. And if you have somebody who's got Grade 4 neutropenia on G-CSF, I mean that is a little bit higher risk patient for developing severe neutropenia. And remember, these patients are generally pretty sick and their performance status as they progress through the disease is poor. And they have a lot of problems like this lady did with the loculated pleural effusion. So it's a difficult patient population, but I've not been impressed. Other than having to dose reduce or delay that neutropenia is particularly bad.

Yes. Thank you, Wendel. And then the question of the exposure based on doses, there is definite dose proportionality with respect to Cmax and AUC. So -- and that's one of the reasons that we think at least getting a couple of cycles at 5.2 to get initial control of what is progressive disease in all these patients. All these patients are progressing when they come on to study. And if you look at Dr. Naumann's patient that we showed the scans on, this patient progressed within 6 months of finishing the initial carbo/taxol and pretty much progressed right through the other agents. And even at 4.3 with this patient, we -- the patient has had a good response. So we know from dose escalation that we saw in that tumor activity at 2.9 mg per kg, 4.3, 5.2, so a dose reduction may not necessarily attenuate the dose response. But in a patient that's progressing, especially if those patients are rapidly progressing, getting disease controlled earlier -- and I think that's what the 5.2 mg dose level shows is that we get control of the disease earlier, shrink it, and then we keep it under control when we go -- dose adjust to the 4.3. So we're following the PK very carefully because, obviously, that's going to be part of the data that we'll discuss with the FDA to support our dosing strategy, if indeed, we decided to go with an initial 5.2 mg [ times ] 2 cycles and then maybe dose adjustment. I mean that's our current thinking right now, but we have to let the data mature, we still patients who we had not gotten scans on. So stay tuned.

And our next question comes from Reni Benjamin with JMP Securities.

Congratulations on the data. Maybe just a couple for me. Maybe for Dr. Naumann. In a world where both like mirvetuximab and STRO-002 are both approved and available to you, can you talk a little bit about how each might fit within your treatment paradigm? And how you make a decision on, I'll say, which one to use? Are you looking more along median PFS? Or is it enrichment strategies? Kind of curious how you think about that. And also whether or not you would actually be able to cycle between ADC given the similar sort of mechanism of action?

Yes. So I think to address the first part of that question, the ocular toxicity is not an insignificant clinical problem. And we're running into this now with the launch of tisotumab. Just trying to find the eye care clinicians that will be able to see these patients in a timely fashion every single cycle is a little bit of a challenge. So that is a big clinical hurdle. I think to have a drug, if I had to choose a drug, particularly if you -- if the TPS score pans out, and I know that the patients -- 70% of my patients with platinum-resistant ovarian cancer will have -- or be eligible for one drug versus only 30% to 40% of the patients for the other drug. I don't think that that's going to be a difficult decision for me. And obviously, some of this is the other toxicities, but that's probably the biggest driver. But I think having the largest number of patients that I can treat is probably most important because I'm going to have to send the assay off before I treat the patient.

And any thoughts, I guess, either for you or management in terms of cycling and utilizing one drug after the other? Or once you've used 1 drug, whether you would might be able to use something with a similar mechanism of action?

From my standpoint, I think, the target is probably not -- or it's probably an issue as well as the mechanism of action of the warhead. I don't know that I would necessarily choose to treat somebody with similar ADCs, even though the warhead is slightly different. If I had a different target and a different warhead, I probably would see those as completely different drugs.

Got it. And as I look at the patient population, Arturo, I know you mentioned or I think during the prepared remarks, we had talked about the median of 2 or so prior therapies. I know with the prior dose escalating study, I think it was closer to a median of 6. I'm just kind of curious as to if you -- have you done any sort of a breakdown of those patients who had like 1 prior therapy versus 3 and how those response rates might be bearing out there?

We're working on that. But we've looked at between the dose levels, and there's no differences in terms of the prior treatment that they have received in terms of 1 to 2 versus 3. But in terms of looking at responses in the number of treatments, we will be -- we're working on that right now. In dose escalation, we looked at that, and it did not seem to have a lot of impact. And I think one of the reasons it might not have a lot of impact is that PARP inhibitors in bev are commonly used, and they're not counted as lines of treatment. So that if somebody has already had 1 or 2 cycles of platinum plus a PARP inhibitor plus bev, even though technically there are 2 lines, it kind of amounts to having 4 different types of treatments. And I think if you think about it, these patients that are getting to platinum resistance are doing it in the first or second line of treatment [indiscernible] as opposed to some of the patients in dose escalation where maybe they didn't become platinum resistant until their fourth line. So we'll let the data tell us what it shows. We'll analyze it and report it. But in a small sample size like this, it's hard to conclude much. Maybe Dr. Naumann has some thoughts on that, too.

I mean I think that pretty much sums it up.

Okay. So we shouldn't necessarily say, just given the data set of the size that it's being driven by -- the responses are being driven by patients that were only exposed to 1 prior therapy versus 2 or 3. It's probably too small to determine that right now. I heard that right, right Arturo?

Correct. But we'll look at that.

I guess -- got it. 1 final one for me. When you -- during the prepared remarks, you mentioned about selecting the dose. It seems to me kind of based on this data and what everyone has said, there's likely going to be the 5.2 induction dose and then there's likely going to be a maintenance dose, right? Almost the way that we might treat any hematological malignancies like ALL or something along those lines. And then whether or not to use an enrichment strategy, it seems to me like that question is also answered, just kind of based on the data that you're seeing here. So what else is needed, I guess, from the ongoing follow-up of these patients for you guys to kind of cement the strategy going forward? Or is it -- it's kind of like what I just mentioned, pretty much it, like you've already decided?

Ren, those are great questions. We still have to get durability, right? That's still an outstanding question and that can play into the overall decision-making as well. So stay tuned. We're actively working it and the data is maturing day by day.

And our final question comes from Zhiqiang Shu with Berenberg.

Great. And I also like to add my congrats on the good data here. My first question, I want to ask about the dosing selection, maybe to follow up with probably the last question on the dosing. The -- I guess, just from the response rates, it seems very obvious to me that the higher dose, 5.2, might be selected given the patients response rates. I guess, what's the gating factor for you to say final -- to select this as a -- for your restoration trial? Is it possible to select something in between when you discuss it with the FDA?

Yes. Thanks, Zhi. 5.2 looks pretty strong. Arturo, do you want to talk a little bit more?

Well, no, exactly what was just mentioned is we obviously have to vet with the FDA and the paradigm of treating like some hematologic malignancies where you go in with a stronger or higher dose or more intense treatment for the initial cycles to get the disease under control and then dose adjusting makes sense. It's not always used in solid tumor. So we will want to vet that with the FDA and support it with the appropriate PK data. But I think if you just look at the data, that's the direction that the data is taking us, and we'll need to vet it and get FDA agreement. But yes, I hope that answered your question.

Yes, it did. And the second question around the diagnostics. Do you see any hurdle in terms of getting your TPS score cleared by the FDA and what are the steps you would need to develop some sort of diagnostic along with your drug?

Thank you. Any diagnostic requires a validation. And so we're working on that. I think we're pretty confident that the percent positive score or TPS would be successful, would be agreed upon by the FDA because that's employed widely for determine eligibility for check on inhibitors. So it's the same scoring algorithm that is used in selecting or determining PD-L1 levels, for example. So there's a lot -- actually, there's a lot more experience using TPS or TPS-like approaches in clinical practice. I think the PS2+ is unique to ImmunoGen and mirvetuximab. I don't think that's used by any other sponsor.

Great. And my final question is around the potential in the lung cancer setting. I guess -- I know it's early and you are still doing some nonclinical work here. Maybe help us understand the potential opportunity there, and how would you approach this cancer setting?

Arturo, Trevor?

Yes. I'll take that. Yes. So the preclinical data in PDX models is very encouraging, but we want to -- we're in the process of running additional models where we've looked at the driver mutations, for example, and are there differences in squamous versus adeno and in those that have driver mutations versus those that have a lot of PD-L1. So -- because, as you know, lung cancer is so heterogeneous. So as part of our development program, the more biology that we incorporate into our thinking, it will enable us to be able to enrich for this appropriate patient population. So again, stay tuned. We're very excited about that. The preliminary data is very encouraging, and I think the Trevor's group is planning to present that data in the future on this as well.

Thank you. And ladies and gentlemen, this concludes today's webcast. You may disconnect at this time. Thank you all for your participation.