All right. Okay. I'm trying to project it in a projection. No, I'm just wondering if you can look at it. Right. Can you see the slides right now? Yes. Yes. Right. So immunotherapy I think is a hot topic for all cancers these days. In gynecological cancer, I think it's not as hot in ovarian cancers as in endometrial, maybe cervical cancer. So I think for myself, I think it gives me an opportunity, thanks to Gayu and everybody, to be able to be involved in this meeting. And it gives me an opportunity to try to look at it from a different angle. So it's my affiliations. So we know immune checkpoint is basically is the key immunotherapy we're talking about these days. So we do know tumor cells can express PD-L1 ligand. They can bind to the PD-1 receptor of immune cytotoxic cells. And this gives a so-called checkpoint. It holds off the normally activated interaction between the antigen or tumor antigen on the tumor cells with the T cell receptor of the immune cytotoxic cells leading to cytotoxicity. But if we do add on immunotherapy, i.e. immune checkpoint inhibitors, either antibodies like anti-PD-1 or anti-PD-L1, which have different binding sites, hopefully this checkpoint or this holding off of the action of the natural defense of our body will be able to proceed and thereby, you know, killing off the tumor cells by immune surveillance. This is how immune checkpoint inhibitors are working these days. And we hope perhaps with the addition of chemotherapy, which is the mainstay treatment for metastatic disease in general in solid tumors, and it's a key important modality in patients with ovarian cancer, be it early or late stage. Maybe there is a hope of we can synergize these two modalities, i.e. immunotherapy together with chemotherapy in improving our patient's outcome. Immunotherapy might not work as quickly as chemotherapy and thereby chemotherapy might be able to step in in the initial phase when there is some delay in the activity of the immunotherapy. However, with the immune system being activated by immunotherapy, I think there is a high chance that memory can be, you know, maintained and thereby there is a high chance that after the stopping or the completion of chemotherapy, immunotherapy might be able to maintain the immune surveillance that can hold off the recurrence of cancers. And thereby, by using these modalities together in many cancers, perhaps not yet in ovarian cancers, hopefully we will be able to improve the survival of our patients and hopefully some of the patients might be, so to speak, to be cured in the long term. But we know immunotherapy has, is relatively new still. So it is basically, it's a treatment that has a slow onset of action and that means we need a longer time. We have to be patient to observe the response in immunotherapy. And there is obviously some suggestion of pseudoprogression, which I think is overemphasized. So we, in clinic, we do not see that very often. It might be true in some cancers like melanoma, but perhaps in other cancers, solid cancers, they are less immune related. Probably it's not something that we observe day in, day out. So overall response rate might be similar to chemotherapy or slightly better. But very often we do observe a shorter progression-free survival if you use single agent immunotherapy compared with chemotherapy. But the upside of using immunotherapy is that we are expecting a longer duration of response and thereby hopefully we can prolong the overall survival in the long term with the memory cells, with the memory in the immune system being activated. Obviously there are potential synergistic effects with the modalities we are using so far, like chemotherapy and other targeted therapies. The chemotherapy and targeted therapies might be able to turn this relatively cold tumor, so to speak, with immunosuppressive TME, to tumors having inflamed signature or phenotype. By, you know, killing off the tumor cells, releasing the tumor antigens to be presented on the cell surface, and they're recognized by the APC and the immune system, and thereby activating the immune system. And chemotherapy and maybe other targeted therapies, which I will come back to, might produce this phenomenon by killing off the tumor cells, releasing the DNA fragments, or inducing DNA damage by some targeted therapy like PARP inhibitors. But obviously immunotherapy basically is something that can cause damage to all parts of our organs. So I think we need a paradigm shift in how we should manage patients receiving immunotherapy. So these are the, this slide summarizes what was observed, or has been observed, using single-region immunotherapy, be it PD-L1 or PD-L1, in treating patients with recurrent ovarian cancers. Most of these patients actually were treated, heavily pre-treated basically, and the numbers actually within these studies actually were very small. We're talking about 20 patients, maybe 100 patients, and most of these patients actually were having plaque-resistant disease, heavily pre-treated. So we are not too surprised to find basically the response rate is not as high as we wish, maybe just about 10 percent, slightly more than 10 percent. And unfortunately we do not have the algorithm of how, or which patients will benefit a bit more by using just a PD-L1 score, because basically it's not consistent with what we observe in other cancers, i.e. patients having PD-L1-positive disease might be having a bit more higher response rate in other cancers, but perhaps not in ovarian cancers yet. So I think this Keynote 100 study basically is the biggest phase 2 clinical trial addressing the issue of if anti-PD-L1 inhibited lipoprolizumab is able to improve immune patients with recurrent disease. So we're talking about, I think, let me see, up to about 280 patients. So all these patients were having recurrent advanced epithelial cancers, or fallopian tube cancer, or primary peritoneal cancers. In the cohort A, the patients included were patients having at least up to three prior lines of, or one to three prior lines of chemotherapy, and they're all plexus-resistant disease, recurrent disease. And the cohort B, they're including more heavily pre-treated patients further, 90 more patients. And patients were treated with single-agent panprolizumab, the standard regimen, 200 milligram once every three weeks until progression. So the overall response rate is not encouraging. The overall response rate for the cohort A patients, less heavily pre-treated, less than 10%, a median progression-free survival, but just about two months. For cohort B, even more heavily pre-treated, again, overall response rate is less than 10%, and similar median PFS. So this is the swimmers plot and the waterfall plot for those patients, very little response rates, short median PFS, be it in cohort A or B, overall survival is something that can be affected by a patient's characteristics. So it's not very meaningful to look at this, but I think in general, the median PFS and the overall survival results were not encouraging. So what about randomized clinical trials for recurrent ovarian cancers? Do we have randomized trials to boost our spirit in looking at immunotherapy in recurrent ovarian cancers? Well, definitely in ovarian, 200 is a randomized clinical trial, phase three, plexus-resistant or refractory disease, more than 500 patients, randomized equally to the standard regimen, with so-called control arm of using percolated doxorubicin at the relative standard dose, 40 milligrams per square, once every four weeks, compared with the experimental arm of using additional NTPDL1 monoclonal antibody, Velumab, on top of the regimen, of the chemotherapy, using the same dosage. We're not reducing the dose of chemotherapy here. And the more ambitious arm is to use a single agent NTPDL1 inhibitor and Velumab, and then look at the co-primary endpoints of PFS and OS. So in conclusion, I think this negative trial, basically, it's been published in Lancelot Oncology two years ago. There's no obvious signal that additional immunotherapy on top of chemotherapy will work. And obviously the single agent Velumab is not working either. So this is the PFS plots, the Kaplan-Meier plot, showing the single arm, a single agent arm of using Velumab is the worst performer. And there's no additional benefit of adding Velumab, which overlap on the blue line, and basically overlaps very much with the control arm of using percolated doxorubicin. Similarly for overall survival, there's no improvement at all. And talking about response rates, overall response rate for the combination of therapy would be around just 13%. The disease control rate, including those having stable disease, 57%, slightly numerically higher than that of the control arm of using single agent percolated doxorubicin, but not statistically significant in terms of difference. So the other randomized clinical trial is performed or has been performed or conducted in Japan using the Velumab versus either gemsolabine or percolated liposomal doxorubicin. This is a NINJA trial, a very Japanese name. Less number of patients, 300 patients, equally randomized to either Nivolumab, a single agent alone, or just chemotherapy alone. It's a very simple design. Overall response rate, again, very disappointing. No difference in terms of overall response rate numerically for patients having stable disease. The proportion of patients having stable disease is much lower with the single agent Nivolumab. Again, patients with resistant disease were randomized or included in the clinical trial. No difference in terms of PFS or by definition, I mean, the PFS is much lower for using the Nivolumab alone compared with chemotherapy. So we are looking forward to this and another clinical trial because in the previously, in the previous two trials, because Zizomab actually was not used, which is something that can be considered as relatively standard by virtue of the publication of the Oceans trial and the one on pectin-resistant disease. So I think Bifazizomab is something that we often use in patients with pectin-resistant or refractory disease. So I think in this clinical trial, patients, the control arm would be the arm using percolated liposomal doxorubicin together with Bifazizomab compared with additional use of Bifazizomab is another PD-L1 monoclonal antibody. And then the other experimental arm would be, you know, excluding the use of Bifazizomab but adding on immunotherapy to chemotherapy. So what about primary ovarian cancer? You might be arguing that in patients with pectin-resistant disease, the patients have been too heavily pre-treated, and thereby we are not observing any response or minute improvement in outcome by addition of immunotherapy. So what about in patients who are fresh or treatment naive, so to speak, for any treatment? So this IMA-Gyne-O05 study is a design, again, randomizing patients with previous untreated patients after either primary surgery or patients designed or planned for new therapy. Patients were randomized to using standard carboplatin, Percatexel, and Bifazizomab or, and placebo to be compared with the experimental arm of using a similar regimen of tactotherapy and chemotherapy with Bifazizomab for 22 cycles. So it's less than one year. So why 22 cycles? I think perhaps they are bundling that together with Bifazizomab. So in the GOG-218 clinical trial, 22 cycles of high-dose Bifazizomab was used. So I think they limited the number of, the immunotherapy to the number of cycles given with Bifazizomab. And again, they are using the co-primary endpoint of PFS and OS. Again, a simple conclusion, no evidence that the use of immune checkpoint inhibitors for the IDT population benefits the patients. The IDT population, PFS, no difference. In those patients having PD-L1 positive disease as defined by the IC positive disease, immune cells being positive, there is a suggestion there might be some improvement in the PFS for patients treated with additional immunotherapy. OS, no difference. Even for patients having PD-L1 positive subpopulation of tubers. So this is another clinical trial, again, a randomized phase three clinical trial published and presented, Charvelin Ovarian 100. Again, using a similar design of using chemotherapy as the control arm compared with chemotherapy followed by just anti-PD-L1 inhibitor, but not concurrent. And the third arm would be the concurrent use of Evalumab upfront together with chemotherapy, followed by maintenance. And they are talking about using two years of maintenance Evalumab, not just 22 cycles as in the other clinical trial. And Bifazizomab use is not mandated. I think it's not included in the design. Again, including patients with treatment naive stage three and four ovarian or prior paternal fallopian tube cancers, either treated primarily with surgery first or treated with an intention of using newer treatment chemotherapy. Again, simple conclusion, no new safety signals were observed and the results do not support the use of Evalumab in the frontline treatment setting. So, details of the results. So, we're talking about PFS. So, the arm with chemotherapy followed by just observation is the arm, is the patient, other patients represented here by the red Kepler-Meyer curve, sits on top of the other two arms being treated with Evalumab, either alone in the maintenance phase or concurrent chemotherapy followed by maintenance. So, nothing very, very stimulating and supportive, but what about combination PARP and NIL, which is again, something that might be a bit more encouraging. So, we do have rationale to try to combine these two together. We have combined chemotherapy with immunotherapy. That doesn't work very well. What if we use PARP inhibitors? So, I think there's some rationale. So, basically in my opinion, we have to combine chemotherapy with immunotherapy. Basically, in patients having maybe HLD or even BRCA mutations, I think there would be DNA damage and the DNA fragments will be outflowing from the nucleus to the cytoplasm and then being presented on the cell surface as new antigen production. And the PD-L1 will be overexpressed as well. And these two will turn on the immune system, basically. On the other hand, within the cells, the DNA fragments will again migrate to the cytoplasm being recognized by the C gas and the stain pathway, which in turn will be involving the algorithm of producing NF-KB and interferon. And this immune mechanism will activate the immune system outside the cells as well. So, there are a number of ways that the use of PARP inhibitors in appropriate patients might be able to generate or may be able to turn the relatively cold TME to a microenvironment to a relatively hot or inflamed TME to facilitate the activity of using immune checkpoint inhibitors together with the PARP inhibitors. Indeed, we do have publications, though mostly in phase two clinical trials only, using this combination. In either platinum-resistant disease, as highlighted here in the two clinical trials, phase two clinical trials, or in platinum-sensitive disease, as exemplified by the Mediola clinical trial. So, you've talked about the Topasio trial is a keynote 162 clinical trial. So, in this trial, 62 patients with platinum-resistant recurrent ovarian cancers were included for looking at the use of combination panbolizumab together with norepirib. And they're observing a relatively modestly satisfactory overall response rate up to 20% across patients with or without BRCA mutation. We're going to look at the details later. And in this Mediola study, interestingly, again, subpopulation of the patients were looked at individually, and patients were being treated with divalumab, it's an NTPDL1 inhibitor, together with olaparib in the usual dose. And in one particular interesting arm, or the subarm, patients with platinum-resistant disease were treated with divalumab together with olaparib, together with anti-BGF1, anti-BGF inhibitor, bifazizumab. And high overall response rate was observed, even in patients with a BRCA mutation wild type sort of signature. So, it's very interesting to look at if the addition of immunotherapy pop inhibitors together with anti-BGF inhibitor will work better synergistically. So, this is the Topacio study, single arm phase 1 and 2 clinical trial using norepirib in combination with panbolizumab in patients with recurrent active-resistant ovarian cancers. I think the conclusion is the responses observed in patients without tumor, BRCA mutations, or non-HRD patients were higher than expected. So, I think it's something, it's a signal that we would be able to follow through with additional clinical trials. So, in the original design, patients with mucinous or clear cell were involved, were included as well, or enrolled for the clinical trial. Up to five lines of chemotherapy were allowed in such patients. Whereas in the phase 2 patients, only high-grade series of early mid-trial ovarian cancers were included. So, this is the waterfall plot on the left-hand side, showing response in many patients, not solely in patients having tumor mutation, BRCA mutation, or HRD-positive status. We do have patients having good response, having HRD-negative or HRD-unknown status. And swimmer's plots showing relatively long control of the cancer, up to maybe more than three or four years in some patients. And again, not all these long responders actually were patients having tumor, BRCA mutation, or HRD-positive status. Response rate, again, not different between the different subgroups as classified by the BRCA mutation status or the HRD status. So, we're talking about maybe up to 20% response rate using this combination, irrespective of the BRCA or HRD status. So, indeed, we do now have many, many more clinical trials looking at the combination of PARP inhibitors together with immunotherapy, and sometimes with bifazizumab as the third pillar of the combination. So, I think in conclusion, I think immunotherapy alone, or when added to chemotherapy without the usual targeted therapy of NTVGF, appears not adding additional benefit in recurrent ovarian cancers in randomized phase three clinical trials. Upfront immunotherapy, again, fails to improve the PFS and OS in stage three and four ovarian cancers currently treated with the center of care chemotherapy, or state of the art chemotherapy together with NTVGF. There is some suggestion, perhaps, PDI-1 score might help to triage patients. If those patients having PDI-1 positive disease in one clinical trial did show some benefit to the use of additional immunotherapy, but not in the ITT population. On the other hand, when the use of immunotherapy is combined with PARP inhibitors, there is some suggestion, perhaps, overall response rate in patients with recurrent cancer, irrespective of the HRD or BRCA status, might benefit, and is worthy of further study. I think, in general, the potential benefits of immunotherapy, first line, in patient, in various HRD subgroups, they are not being clearly defined and studied. So, in the clinical trials that I just brought up, for two clinical trials using immunotherapy on top of the standard chemotherapy and or additional papazisolab, they do not, they did not classify, or they did not look at subgroups of patients having different HRD or BRCA status yet. We are not sure if such patients with HRD positive disease or BRCA mutation positive disease will be having a lot more inflamed tumor microenvironment, to the extent that these patients might benefit a bit more, even in the first line status, to be using immunotherapy together with chemotherapy. So, I think, thank you very much. I have to thank Gary and everybody for involving me in this meeting. Thank you.

immunotherapy

gynecological cancers

ovarian cancer

immune checkpoint inhibitors

chemotherapy

PARP inhibitors