Patiënten met therapienaïef inoperabel maligne pleuraal mesothelioom kunnen reageren op behandeling met durvalumab in combinatie met cisplatine en pemetrexed, zo suggereren resultaten van het fase II-onderzoek PrE0505.
Zoals gemeld door Patrick Forde (Johns Hopkins University, Baltimore, Maryland, VS) tijdens het virtuele ASCO-congres 2020, werd bij de eerste 15 patiënten die deelnamen aan deze multicenterstudie geen dosisbeperkende toxiciteit gemeld na behandeling met durvalumab 1120 mg, cisplatine 75 mg/m2 en pemetrexed 500 mg/m2 elke 3 weken.
Patrick Forde bespreekt de bevindingen van de fase II-studie PrE0505 in het licht van de PROMISE-meso-studie met pembrolizumab in de tweedelijnssetting (6:23).
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Transcript
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.
Daarom ging de inclusie door tot in totaal 55 deelnemers. De meerderheid (75%) van de patiënten had epithelioïde histologie, 13% sarcomatoïde, 11% bifasische en 2% desmoplastische. De patiënten kregen maximaal zes cycli durvalumab plus chemotherapie, gevolgd door een jaar onderhoudsbehandeling met alleen durvalumab.
De mediane totale overleving (OS) was 20,4 maanden. Dit was hoger dan de vooraf gespecificeerde criteria voor klinisch betekenisvolle verbetering van 19,0 maanden, wat overeenkwam met een verbetering van 58% op de mediane OS van 12,0 maanden geassocieerd met een historische controle met pemetrexed-cisplatine.
De 6-, 12- en 24-maanden OS-percentages waren respectievelijk 87,2%; 70,4% en 44,2% terwijl de overeenkomstige progressievrije overleving (PFS) 69,1%; 16,4% en 10,9% was. De mediane PFS was 6,7 maanden.
Op 24 april 2020 (data cutt-off) had 56,4% van de patiënten een partiële respons, 40,0% stabiele ziekte en 1,8% had progressieve ziekte.
Forde beschreef de combinatie met durvalumab als “goed verdragen”, met treatment emergent bijwerkingen van graad 3 of hoger bij 36 patiënten. Hij benadrukte dat “veel van deze bijwerkingen vergelijkbaar zijn met die bij op platina gebaseerde chemotherapie.”
Forde benadrukte dat de bijwerkingen die “mogelijk verband houden met immunotherapie”, namelijk hypothyreoïdie (n = 7), huiduitslag (n = 5), pruritus (n = 3), ASAT-verhoging (n = 3), hyperthyreoïdie (n = 3), dermatitis (n = 2), neuropathie (n = 2), ALAT-verhoging (n = 1), stijging van lipase (n = 1) en pneumonitis (n = 1), alle van graad 1-2 waren en er geen sprake was van onverwachte bijwerkingen.
De studie had een translationeel karakter, volgens Forde, die liet weten dat de OS en PFS niet correleerden met verschillende tumorkenmerken, waaronder de tumor mutational burden (TMB) en PD-L1-expressie.
Hij voegde er echter aan toe dat een langere, zij het niet significante, mediane OS werd gezien bij patiënten met een TMB ≥ 24 sequentieveranderingen, namelijk 27,9 maanden versus 14,2 maanden voor patiënten met een TMB ≤ 23.
Aanvullende analyses toonden significante autologe T-celexpansie in 3 van 48 mutatiegeassocieerde neoantigenen in een responsieve tumor. Forde benadrukte dat deze potentiële T-celresponsen bijzonder interessant zijn bij patiënten met een maligne pleuraal mesothelioom, omdat dit type kanker een lage TMB heeft.
In het licht van deze “veelbelovende” overlevingsresultaten, benadrukte Forde de komende fase III-studie DREAM3R (PrE0506) waarin de toevoeging van durvalumab aan cisplatine en pemetrexed verder zal worden onderzocht bij patiënten met een maligne pleuraal mesothelioom.
Bron: 2020 ASCO Annual Meeting; 29–31 May
Provided by Medicine Matters oncology; ©2020 Springer Healthcare Ltd, part of the Springer Nature Group.