Preliminary Results of MGC018, an anti B7-H3 Antibody Drug Conjugate in mCRPC – Eugene Shenderov
November 18, 2021
Alicia Morgans and Eugene Shenderov, discuss Dr Shenderov’s recent ESMO 2021 presentation on MGCO18, an anti-B7-H3 antibody-drug conjugate. Dr. Shenderov presented preliminary results of a phase one cohort expansion, testing MGC018, an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody, in patients with metastatic castration-resistant prostate cancer (mCRPC). B7-H3 is an important target, due to overexpression in prostate and lung cancers, and an important delivery vehicle for certain chemotherapies. B7-H3 is expressed on many solid tumors but has limited normal tissue expression. Thus, it has been hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. In an initial phase I dose-escalation, there were two dose-limiting toxicities: one neutropenia grade 4 and one grade 3 fatigue lasting 72 hrs. In this cohort, there was 1 confirmed partial response in a melanoma patient, and five of 9 patients with metastatic castration-resistant prostate cancer (mCRPC) had a 50% prostate-specific antigen (PSA) reduction.
The present cohort expansion characterizes safety and preliminary efficacy with the recommended phase II dose of 3 mg/kg IV every 3 weeks. The authors enrolled patients with advanced mCRPC, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), and melanoma. Treatment response is evaluated per RECIST v1.1 for all participants while, for patients with mCRPC, tumor response and PSA are evaluated using Prostate Cancer Working Group 2 criteria.
Biographies:
Eugene Shenderov, MD, Ph.D., Johns Hopkins University, Baltimore, United States of America
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
The present cohort expansion characterizes safety and preliminary efficacy with the recommended phase II dose of 3 mg/kg IV every 3 weeks. The authors enrolled patients with advanced mCRPC, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), and melanoma. Treatment response is evaluated per RECIST v1.1 for all participants while, for patients with mCRPC, tumor response and PSA are evaluated using Prostate Cancer Working Group 2 criteria.
Biographies:
Eugene Shenderov, MD, Ph.D., Johns Hopkins University, Baltimore, United States of America
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Read the Full Video Transcript
Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I am so excited to have here with me today, a good friend, Dr. Eugene Shenderov, who is an Assistant Professor of Oncology at Johns Hopkins, where he is also a GU Medical Oncologist participating in some really innovative immunotherapy type research. Dr. Shenderov, thank you so much for being here with us tonight.
Eugene Shenderov: Alicia, it's a pleasure. Thank you for having me on.
Alicia Morgans: Wonderful. So I wanted to talk with you about one of your very exciting presentations at ESMO 2021, where you really looked at heavily pretreated patients with prostate cancer and investigated an antibody-drug conjugate in their care. Can you tell us a little bit about that?
Eugene Shenderov: Sure. Thanks for the opportunity. And this is our poster looking at MGCO18, which is an anti-B7-H3 antibody-drug conjugate, in a trial sponsored by MacroGenics in patients with advanced solid tumors. And these are the preliminary results of a phase one cohort expansion, focusing on metastatic castrate-resistant prostate cancer and non-small cell lung cancer.
So B7-H3 is an important target because it is overexpressed on cancers, including prostate and lung cancer. And at the same time, it's an important delivery vehicle potentially, therefore, for giving chemotherapy in a very directed, personalized manner to patients whose tumors overexpress this target.
Now, B7-H3 may be overexpressed in the prostate even more so than a lot of other tumors, even more so than PD-L1 and two that we are all familiar with for PD1 access therapies. And therefore, this becomes a huge area of interest for trying to understand how to increase the therapeutic availability for patients living with metastatic castrate-resistant prostate cancer, who often are facing the fate of not having a curable disease and not too many good treatment options beyond what is FDA approved, which again are not cured.
And so an antibody-drug conjugate, in this case, is for B7-H3 in terms of the biologic portion, and then it uses [inaudible 00:02:30], a cytotoxic payload, which is a very potent alkylating agent, actually about 1000 times more potent than normal taxane-based therapies and allows the sort of delivery that goes hopefully straight to the cancer cells. And it is less toxic to the host.
That is the plan behind the trial and what we present at ESMO 2021 is that there were, I believe 86 patients who were recruited in total that we were able to present at this point in terms of the data cutoff. And we had 46 patients planned for the mCRPC enrollment. We present data on 19 for their PSA at this time, and we presented 16 in terms of having data available for their radiographic response. And there are a few takeaways that are key.
One is that, and I'll go through them, that the agent does appear to have a good degree of clinical activity, which is exciting. It's tempered by the fact that we did see a good bit of toxicity, unfortunately, which is less exciting and not unexpected given the fact that it has a cytotoxic payload. And so we know from experience with ADCs, that they tend to have cytotoxicity. We also know from chemotherapies that they have cytotoxicity and adverse events.
I will give a point of comparison and then kind of go through the rest of the data, including the toxicity. An equivalent patient cohort of metastatic castrate-resistant, prostate cancer after first-line chemotherapy, usually docetaxel taxine therapy and hormonal therapy were studied in the CARD trial. And that was what led to the FDA registration approval of cabazitaxel, a second-line therapy. And so this whole trial takes place in that same group as what cabazitaxel is approved for.
So this is the equivalent population to the cabazitaxel, FDA approval, so heavily pretreated patients. And in this trial, as expected, the median lines of prior therapy were three, anywhere from two to seven, actually for the mCRPC cohort of 40 patients that we presented. And those patients were also seeing to, as expected again with the toxicity, half toxicity that approached about 50% in terms of grade three or above adverse events, which is kind of equivalent to what was seen with cabazitaxel in the CARD trial.
The difference that people need to keep in mind is that biological therapies have a longer half-life. So one needs to make sure that one takes that into account, and that is going to be something for future development that we are keeping an eye on for toxicity, not only that occurring but how to manage it especially when it's got a longer half-life of toxicity.
Keeping that in mind, the efficacy here, again, with about 54% of patients having a PSA greater than 50 response, which is considered darn good in a sense in prostate cancer, for this group of patients. And as well, having about 25% of patients who had at least a partial radiographic response, are pretty good numbers.
In the equivalent CARD trial, it was about 38% for PSA, greater than 50 responses, and about 36 or 37% for radiographic overall response. And so these numbers that we see on efficacy are very promising preliminary numbers, that if they are sustained to the entire cohort, in this expansion cohort will be promising.
And if one can improve the tolerability of the agent, allow more doses given, it was only three and a half doses tolerated on average by the mCRPC cohort here, if one can increase the number of doses, aka, the number of weeks and months that patients can be on this therapy, it could potentially increase the efficacy further.
And so the conclusion that we take away from this work on this B7-H3 targeted ADC, especially in prostate cancer, is that it shows some promising efficacy. It is definitely a candidate for future research in, at the very least this mCRPC arena of patients because of the promising clinical activity.
And we do still need to figure out how to optimize the dosing, to be able to limit the toxicity and potentially even improve, or at least maintain the efficacy signal. And then this could be a promising agent for the future of prostate cancer care. So again, it's a pleasure to share this data and this work on behalf of a large global team. And of course, thanks to all of the patients who have participated because, in them, this work is done to increase their quality of life and of course, the hope for a breakthrough therapy that increases the curing potential for metastatic castrate-resistant prostate cancer and other cancers as shown here. Thank you so much.
Alicia Morgans: Well, I would just like to commend you and the team for this work, I agree with you that is a pretty fantastic PSA50 response in a heavily pretreated population. I imagine that you and the team are developing additional trials and trying to use this drug perhaps in phase two or greater trials that we can really try to understand the effects more broadly. Is that happening?
Eugene Shenderov: Very astute observation. Yes, indeed. We are excited by again, what we've seen and what we've discussed here. We are looking at potential combination therapies, including potentially other checkpoint targets, but also potentially a combination with a B7-H3 targeted agent, like enoblituzumab, which can have an immune harnessing impact. And then to see if the two agents together might allow us to lower the doses of, especially this MGCO18 and thereby potentially allowing this to again, increase the tolerability while maintaining the efficacy. And then I think we might have a very, very promising combo, but a lot of ways to go forward and a lot of pathways to chart. And I think these are sort of early days, and we are trying to figure out what to do, and it will depend on how this trial of course ends up since this is preliminary data, but still an unfinished trial.
Alicia Morgans: Well, I think that's how many things start out. We try to understand what are the pros, what are cons? We try to limit the cons and maximize the pros. And I really commend you and the team for engaging in this type of work and doing this kind of targeted therapy, even as it becomes more and more challenging with so many new drugs that may reach approval for advanced prostate cancer. The bar continues to get higher. So I encourage you and I appreciate your work, the work of your colleagues and team members, as well as the patients who participate in these trials. And I thank you so much for your expertise and your time today.
Eugene Shenderov: Thank you so much for having me on.
Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I am so excited to have here with me today, a good friend, Dr. Eugene Shenderov, who is an Assistant Professor of Oncology at Johns Hopkins, where he is also a GU Medical Oncologist participating in some really innovative immunotherapy type research. Dr. Shenderov, thank you so much for being here with us tonight.
Eugene Shenderov: Alicia, it's a pleasure. Thank you for having me on.
Alicia Morgans: Wonderful. So I wanted to talk with you about one of your very exciting presentations at ESMO 2021, where you really looked at heavily pretreated patients with prostate cancer and investigated an antibody-drug conjugate in their care. Can you tell us a little bit about that?
Eugene Shenderov: Sure. Thanks for the opportunity. And this is our poster looking at MGCO18, which is an anti-B7-H3 antibody-drug conjugate, in a trial sponsored by MacroGenics in patients with advanced solid tumors. And these are the preliminary results of a phase one cohort expansion, focusing on metastatic castrate-resistant prostate cancer and non-small cell lung cancer.
So B7-H3 is an important target because it is overexpressed on cancers, including prostate and lung cancer. And at the same time, it's an important delivery vehicle potentially, therefore, for giving chemotherapy in a very directed, personalized manner to patients whose tumors overexpress this target.
Now, B7-H3 may be overexpressed in the prostate even more so than a lot of other tumors, even more so than PD-L1 and two that we are all familiar with for PD1 access therapies. And therefore, this becomes a huge area of interest for trying to understand how to increase the therapeutic availability for patients living with metastatic castrate-resistant prostate cancer, who often are facing the fate of not having a curable disease and not too many good treatment options beyond what is FDA approved, which again are not cured.
And so an antibody-drug conjugate, in this case, is for B7-H3 in terms of the biologic portion, and then it uses [inaudible 00:02:30], a cytotoxic payload, which is a very potent alkylating agent, actually about 1000 times more potent than normal taxane-based therapies and allows the sort of delivery that goes hopefully straight to the cancer cells. And it is less toxic to the host.
That is the plan behind the trial and what we present at ESMO 2021 is that there were, I believe 86 patients who were recruited in total that we were able to present at this point in terms of the data cutoff. And we had 46 patients planned for the mCRPC enrollment. We present data on 19 for their PSA at this time, and we presented 16 in terms of having data available for their radiographic response. And there are a few takeaways that are key.
One is that, and I'll go through them, that the agent does appear to have a good degree of clinical activity, which is exciting. It's tempered by the fact that we did see a good bit of toxicity, unfortunately, which is less exciting and not unexpected given the fact that it has a cytotoxic payload. And so we know from experience with ADCs, that they tend to have cytotoxicity. We also know from chemotherapies that they have cytotoxicity and adverse events.
I will give a point of comparison and then kind of go through the rest of the data, including the toxicity. An equivalent patient cohort of metastatic castrate-resistant, prostate cancer after first-line chemotherapy, usually docetaxel taxine therapy and hormonal therapy were studied in the CARD trial. And that was what led to the FDA registration approval of cabazitaxel, a second-line therapy. And so this whole trial takes place in that same group as what cabazitaxel is approved for.
So this is the equivalent population to the cabazitaxel, FDA approval, so heavily pretreated patients. And in this trial, as expected, the median lines of prior therapy were three, anywhere from two to seven, actually for the mCRPC cohort of 40 patients that we presented. And those patients were also seeing to, as expected again with the toxicity, half toxicity that approached about 50% in terms of grade three or above adverse events, which is kind of equivalent to what was seen with cabazitaxel in the CARD trial.
The difference that people need to keep in mind is that biological therapies have a longer half-life. So one needs to make sure that one takes that into account, and that is going to be something for future development that we are keeping an eye on for toxicity, not only that occurring but how to manage it especially when it's got a longer half-life of toxicity.
Keeping that in mind, the efficacy here, again, with about 54% of patients having a PSA greater than 50 response, which is considered darn good in a sense in prostate cancer, for this group of patients. And as well, having about 25% of patients who had at least a partial radiographic response, are pretty good numbers.
In the equivalent CARD trial, it was about 38% for PSA, greater than 50 responses, and about 36 or 37% for radiographic overall response. And so these numbers that we see on efficacy are very promising preliminary numbers, that if they are sustained to the entire cohort, in this expansion cohort will be promising.
And if one can improve the tolerability of the agent, allow more doses given, it was only three and a half doses tolerated on average by the mCRPC cohort here, if one can increase the number of doses, aka, the number of weeks and months that patients can be on this therapy, it could potentially increase the efficacy further.
And so the conclusion that we take away from this work on this B7-H3 targeted ADC, especially in prostate cancer, is that it shows some promising efficacy. It is definitely a candidate for future research in, at the very least this mCRPC arena of patients because of the promising clinical activity.
And we do still need to figure out how to optimize the dosing, to be able to limit the toxicity and potentially even improve, or at least maintain the efficacy signal. And then this could be a promising agent for the future of prostate cancer care. So again, it's a pleasure to share this data and this work on behalf of a large global team. And of course, thanks to all of the patients who have participated because, in them, this work is done to increase their quality of life and of course, the hope for a breakthrough therapy that increases the curing potential for metastatic castrate-resistant prostate cancer and other cancers as shown here. Thank you so much.
Alicia Morgans: Well, I would just like to commend you and the team for this work, I agree with you that is a pretty fantastic PSA50 response in a heavily pretreated population. I imagine that you and the team are developing additional trials and trying to use this drug perhaps in phase two or greater trials that we can really try to understand the effects more broadly. Is that happening?
Eugene Shenderov: Very astute observation. Yes, indeed. We are excited by again, what we've seen and what we've discussed here. We are looking at potential combination therapies, including potentially other checkpoint targets, but also potentially a combination with a B7-H3 targeted agent, like enoblituzumab, which can have an immune harnessing impact. And then to see if the two agents together might allow us to lower the doses of, especially this MGCO18 and thereby potentially allowing this to again, increase the tolerability while maintaining the efficacy. And then I think we might have a very, very promising combo, but a lot of ways to go forward and a lot of pathways to chart. And I think these are sort of early days, and we are trying to figure out what to do, and it will depend on how this trial of course ends up since this is preliminary data, but still an unfinished trial.
Alicia Morgans: Well, I think that's how many things start out. We try to understand what are the pros, what are cons? We try to limit the cons and maximize the pros. And I really commend you and the team for engaging in this type of work and doing this kind of targeted therapy, even as it becomes more and more challenging with so many new drugs that may reach approval for advanced prostate cancer. The bar continues to get higher. So I encourage you and I appreciate your work, the work of your colleagues and team members, as well as the patients who participate in these trials. And I thank you so much for your expertise and your time today.
Eugene Shenderov: Thank you so much for having me on.