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Medicine Matters oncology

I was the principal investigator for the PrE0505 study. This was a multi-center study in newly diagnosed unresectable mesothelioma. And the study involved a single arm of combining standard chemotherapy, which is cisplatin and pemetrexed, with the anti-PD-L1 antibody durvalumab. And the rationale for this study was that we have seen single-agent activity with PD-1 pathway blockade and mesothelioma patients who've received prior chemotherapy. And we've also seen synergy in other tumor types between chemotherapy and PD-1 pathway blockades, such as lung cancer, for example.



So we commenced this study in 2017, and the plan was to accrue a total of 55 patients across 15 centers here in the United States. Patients would receive up to six cycles of chemotherapy combined with durvalumab. And then would continue on single-agent durvalumab for up to one year in total of treatment and if there was no progression of their disease.



The primary endpoint of the study was looking at overall survival compared to historical control. And the historical control was the registration study which led to approval of pemetrexed cisplatin back in 2004, where the median survival was 12 months. So in this study, we were aiming for a median overall survival of 19 months in order to declare the study positive.



As I said, we accrued the patients in just over a year. We completed accrual in mid-2018. And now we have mature overall survival from the study. And that shows that the median overall survival from the study was 20.4 months, and it was a positive study by definition of the study plan-- so showing that median survival was prolonged compared to historical control. We also found that the treatment was well tolerated in general with no unusual or unexpected side effects and noted other than those which are known to occur with chemotherapy and immunotherapy.



We also performed a number of correlative analysis, including whole exam sequencing of tumor and normal, and PD-L1 and CD8 dual immunohistochemical staining of the primary tumors, and TCR sequencing- T-cell receptor- sequencing of the primary as well. So at the ASCO meeting, we are presenting some of those correlative data, including analysis showing that there was no correlation between PD-L1 positive staining and survival with chemoimmunotherapy. Equally, there was no significant difference in overall survival between those patients who had higher tumor mutation burden compared to those with lower tumor mutation burden.



The third correlative analysis we're presenting at ASCO uses an assay called manifest, which is an immune assay trying to show functional T-cell responses to neoantigens or abnormal peptides from mutations in the tumor. And we know that mesothelioma has a low tumor mutation burden. However, somewhat surprisingly, Dr. Kellie Smith, who's a colleague of mine at Hopkins, was able to show that despite relatively low numbers of mutations, some of those mutations appear to be immunogenic and led to T-cell responses which were detectable using the patient's autologous T-cells.



So overall, these are the initial results from the study. And there are additional correlative analysis going forward. In collaboration with colleagues from Australia, Dr. Anna Nowak, who's based in Perth-- we are conducting a phase 3 study evaluating cisplatin, pemetrexed, durvalumab compared to the standard of cisplatin, pemetrexed. And that study should commence accrue over the next few months in the US and Australia. And it's known as the Dreamer study.



Could you discuss these results in the context of the PROMISE-meso study of pembrolizumab that did not meet its primary endpoint?

Yeah, I think it's an interesting point. And it's one that we're trying to tease out with some of the correlative analysis. The PROMISE-meso was obviously end patients who had received prior chemotherapy. And we have seen in other tumor types that it appears that, at least in some tumor types, there appears to be more benefit from immunotherapy when given in the first-line setting. So for example, in lung cancer, in unselected patients the response to immunotherapy is about 15% to 20%.



However, when it's moved forward to the first-line setting and in those patients with higher PD-L1, that response rate can go up closer to 50%. And we also see benefit from chemoimmunotherapy in the first-line setting in lung cancer, even though there was a relatively modest benefit from single-agent immunotherapy in the second and third line setting.



So it could be that we're recapitulating those findings in mesothelioma, where there is a negative study in the second-line setting compared to chemotherapy. But potentially, combination chemoimmunotherapy may have more benefit in the first line. However, we have to show that in a phase 3 study, which is the plan for the ongoing Dreamer study. We are also, as a group, we're looking at single-agent immunotherapy in other settings, including looking at anti-PD-1 in the neoadjuvant setting in mesothelioma and another study where we're planning to do similar correlative analysis.