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Lees ook: 

https://kanker-actueel.nl/NL/studiepublicaties-van-voeding-voedingstoffen-niet-toxische-middelen-en-behandelingen-uit-literatuurlijst-van-arts-bioloog-drs-engelbert-valstar-specifiek-bij-melanomen.html

20 april 2018: Bron: NEJM en persbericht / website AvL

Opnieuw een succesvolle studiepublicatie van immuuntherapie met anti-PD medicijnen (pembrolizumab / Keytruda) ingezet bij patiënten waarbij de primaire tumor eerst is verwijderd door operatie of anderszins en daarna immuuntherapie hebben gehad.

In deze studie gaat het om operabele huidkanker van het type melanoom met stadium III, dat betekent dat bij de operatie al kankercellen waren gevonden in nabijgelegen lymfklieren en dus hoog risico liepen op een recidief.  Met het gebruik van pembrolizumab / Keytruda werd dit risico op 1 jaars meting verminderd met 43 procent minder kans op een recidief in vergelijking met een placebo. Opvallend ook dat deze resultaten niet alleen maar weden beënvloed door een PD-1 mutatie. Ook patiënten zonder PD-1 mutatie bereikten een goed resultaat.

Onderaan het artikel de resultaten in het Engels uit het originele studierapport. Let wel dit gaat om een analyse na 1 jaar en is 75 procent geen recidief niet een garantie dat dit percetage ook gehaald wordt op 5 jaar meting bv. Bij melanomen komt een recidief wel vaker voor na enkele jaren, dus om nu te zeggen dat drie kwart van de melanoompatiënten genezen lijkt (zoals in sommeige Nederlandse media wordt gesuggereerd) is te optimistisch gesteld.

Wat wel klopt is dat het verschil met een placebogroep op 1-jaars meting echt groot was en is het relatieve risico op een recidief binnen een jaar met 43 procent gedaald (77 procent van pembrolizumabgroep vs 61 procent van placebogroep hadden geen recidief na 1 jaar).

Grafiek uit de studie (tekst gaat verder onder grafiek):

Studieopzet:

Van augustus 2015 tot november 2016 werden in totaal 1019 patiënten verdeeld over maar liefst 123 ziekenhuizen in 23 verschillende landen gerandomiseerd ingedeeld in twee groepen: 514 patiënten werden toegewezen aan de pembrolizumab-groep en 505 werden toegewezen aan de placebogroep.

Van de 509 patiënten die met pembrolizumab begonnen, stopten er binnen 1 jaar 70 (13,8%) de behandeling vanwege een bijwerking; bij 66 patiënten (13,0%) werd de bijwerking beschouwd door de onderzoekers als gerelateerd aan de behandeling / medicijn. Van de 502 patiënten die placebo kregen, stopten er binnen 1 jaar 11 (2,2%) met de behandeling vanwege een bijwerking; bij 8 patiënten (1,6%) werd de gebeurtenis als placebo-gerelateerd beschouwd.

In totaal 109 patiënten (21,4%) in de pembrolizumab-groep stopten met de behandeling of moesten stoppen wegens een recidief van de ziekte. 179 patiënten (35,7%) in de placebogroep stopten wegens een recidief. Een totaal van 282 patiënten (55,4%) in de pembrolizumab-groep en 294 (58,6%) in de placebogroep voltooiden de 1-jarige behandelingsperiode (Figure 1). De totale mediane duur van de follow-up was 15,1 maanden - 14,7 maanden in de pembrolizumab-groep en 15,4 maanden in de placebogroep.

Het volledige studierapport: Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanomais tegen betaling in te zien en gepubliceerd in New Engeland Journal of Medicin (NEJM) (Abstract staat onderaan artikel met de orginele resultaten en referentielijst want heb zelf wel het volledige studierapport ingezien).

Hier zoals op de website van het Anthonie van Leeuwenhoek Ziekenhuis (AvL) deze studiepublicatie is vermeld en in een persbericht hoe zij deze studiepublicatie aankondigen:

Aanvullende immuuntherapie na melanoom-operatie verkleint kans op terugkeer kanker

20apr 2018

Akkooi en Blank

Bij melanoompatiënten die na een operatie aanvullend behandeld worden met de immuuntherapie pembrolizumab, is de kans op terugkeer van de ziekte bijna tweemaal zo klein als bij patiënten die een placebo krijgen. Dit blijkt uit een grote gerandomiseerde studie in 23 landen en meer dan 100 ziekenhuizen, onder meer dan 1000 melanoompatiënten, van wie 50 van het Antoni van Leeuwenhoek.

De resultaten van het onderzoek zijn 15 april gepubliceerd in de New England Journal of Medicine (NEJM) en dezelfde dag gepresenteerd op het jaarcongres van de American Association for Cancer Research in Chicago. Het artikel is beschikbaar voor iedereen.

De studie is gedaan onder melanoompatiënten bij wie de kankercellen al naar de dichtstbijzijnde lymfeklier waren uitgezaaid maar nog niet verder. De kans op terugkeer van de ziekte is dan groot. De helft van de patiënten kreeg na operatieve verwijdering van de tumor als adjuvante behandeling een jaar lang pembrolizumab en de andere helft een placebo. Een adjuvante behandeling, ook wel aanvullend preventieve behandeling genoemd, is bedoeld om na een operatie het risico op terugkeer van de kanker te verkleinen.

Na een jaar was bij 75 procent van de patiënten die pembrolizumab kregen, de kanker nog niet teruggekeerd. Bij de placebo-groep was dat bij 61 procent het geval. Het risico van  terugkeer van de kanker was daarmee in de pembrolizumab-groep 43 procent kleiner dan in de placebo-groep.>>>>>>lees verder het hele artikel

Het abstract van het studierapport: 

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma: volgt hier,. plus referentielijst:

N Engl J Med. 2018 Apr 15. doi: 10.1056/NEJMoa1802357. [Epub ahead of print]

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.

Abstract

Background The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. Methods Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. Results At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. Conclusions As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

PMID:
29658430
DOI:
10.1056/NEJMoa1802357

RESULTS:
Overall Intention-to-Treat Population

Figure 2. Kaplan–Meier Estimate of Recurrence-free Survival, as Assessed by Local Investigators, in the Overall Intention-to-Treat Population and According to Tumor Programmed Death Ligand 1 (PD-L1) Expression.

In the overall intention-to-treat population, the 12-month rate of recurrence-free survival was 75.4% (95% CI, 71.3 to 78.9) in the pembrolizumab group and 61.0% (95% CI, 56.5 to 65.1) in the placebo group (Figure 2A). Recurrence-free survival was significantly longer in the pembrolizumab group than in the placebo group (hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) (Figure 2A). The results were similar in the per-protocol population (hazard ratio for recurrence or death, stratified according to stage, 0.56; 98.4% CI, 0.43 to 0.74; P<0.001). At 18 months, the rates of recurrence-free survival in the intention-to-treat population were 71.4% (95% CI, 66.8 to 75.4) in the pembrolizumab group and 53.2% (95% CI, 47.9 to 58.2) in the placebo group.

A total of 351 patients had a first recurrence of disease or died: 135 in the pembrolizumab group and 216 in the placebo group. There were 78 patients (15.2%) in the pembrolizumab group in whom distant metastases developed, alone or combined with locoregional recurrences, as compared with 138 patients (27.3%) in the placebo group (Figure 2A). The 18-month cumulative incidence of distant metastasis being the first site of recurrence was 16.7% and 29.7% respectively (hazard ratio, 0.53; 99% CI, 0.37 to 0.76) (Fig. S2 in the Supplementary Appendix).

Recurrence-free Survival According to Tumor PD-L1 Expression

Figure 3. Forest Plot of Recurrence-free Survival According to Subgroup.

In the subgroup of 853 patients with PD-L1–positive tumors (melanoma score, ≥2), the 12-month recurrence-free survival rate was 77.1% (95% CI, 72.7 to 80.9) in the pembrolizumab group and 62.6% (95% CI, 57.7 to 67.0) in the placebo group (Figure 2B). Recurrence-free survival was significantly longer in the pembrolizumab group than in the placebo group (hazard ratio for recurrence or death, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Pembrolizumab was also consistently effective in patients with PD-L1–negative tumors (Figs. Figure 2C and Figure 3) and in those with undetermined tumor PD-L1 expression (Fig. S3 in the Supplementary Appendix).

Recurrence-free Survival According to Other Variables

The between-group difference in recurrence-free survival was consistently observed across subgroups that were based on baseline characteristics (Figure 3). The benefit from pembrolizumab was similar in patients with stage IIIA, IIIB, and IIIC disease; the 12-month rate of recurrence-free survival among patients with stage IIIB or IIIC disease in the pembrolizumab group was 72.2% (95% CI, 67.6 to 76.2). The benefit from pembrolizumab was also similar in patients with microscopic or macroscopic nodal involvement; it was greater, but not significantly so, in patients with ulcerated melanomas (hazard ratio, 0.52) than in patients with nonulcerated melanomas (hazard ratio, 0.69). BRAF status, sex, and baseline body-mass index (the weight in kilograms divided by the square of the height in meters) did not significantly influence the difference in recurrence-free survival between the pembrolizumab and placebo groups (Figure 3, and Figs. S4 and S5 in the Supplementary Appendix). For instance, the between-group difference was similar among men regardless of whether they were obese or had a normal body-mass index.

Discussion

In this randomized, phase 3 trial involving patients with resected, high-risk stage III melanoma, pembrolizumab was associated with a rate of recurrence-free survival at 1 year that was significantly higher than that with placebo. The risk of recurrence or death in the total population was 43% lower in the pembrolizumab group than in the placebo group; the risk was 46% lower in the pembrolizumab group than in the placebo group among patients with PD-L1–positive tumors, with similar results in the subgroup with PD-L1–negative tumors. In the overall intention-to-treat population, the estimated between-group difference in the 18-month rate of recurrence-free survival was 18.2 percentage points (71.4% for pembrolizumab vs. 53.2% for placebo). These data provide more evidence that drugs that are effective in advanced melanoma also have effectiveness as adjuvant therapy.18

The EORTC 1325 trial will continue to its secondary end points, distant metastasis-free survival and overall survival. We recently found that the effects of treatment on recurrence-free survival correlate very well with the effects on overall survival in trials of adjuvant therapy with interferon alfa and with ipilimumab in high-risk melanoma.19 Therefore, one may reasonably expect that the benefit of pembrolizumab for relapse-free survival that we have found in our trial will translate into an overall survival benefit, unless effective post-relapse treatments compensate for the initial disadvantage; this is a question that may be answered by the crossover design of the trial.

Pembrolizumab as adjuvant therapy, which in this analysis had a rate of grade 3 or higher treatment-related adverse events of 14.7%, appears to be less toxic than ipilimumab (45.9%) and similar to nivolumab (14.4%). There was one pembrolizumab-related death (0.2%), as compared with none with nivolumab and five (1.1%) with ipilimumab in the respective trials of these agents as adjuvant therapy.7,8,10 The immune-related adverse events that were relatively frequent in association with pembrolizumab were hypothyroidism (14.3%) and hyperthyroidism (10.2%), pneumonitis (3.3%), and sarcoidosis (1.4%), with the majority of events being of grade 1 or 2. The incidence of grade 3 or 4 immune-related adverse events was low (7.1%), and most events resolved within 2 months after the last dose of pembrolizumab, findings similar to those in advanced melanoma.20,21

Adjuvant therapy for high-risk melanoma has improved, with pembrolizumab and nivolumab now available as effective agents, along with the combination of dabrafenib and trametinib as an additional option for BRAF-mutant melanoma. In countries where access to these drugs can take years, the use of interferon alfa may continue; however, on the basis of the EORTC 18952 and 18991 trials22-26 and an individual-patient data meta-analysis comprising all trials in which interferon alfa was compared with observation only,27 interferon alfa treatment would be limited to patients with stage IIB or III disease with ulcerated melanoma.

Although completion lymph-node dissection has been a mandatory component in all adjuvant phase 3 trials to date, in light of the results of the Multicenter Selective Lymphadenectomy Trial (MSLT-II) and the Dermatologic Cooperative Oncology Group (DeCOG) trial18,28-30 it is no longer considered mandatory. Since the hazard ratios for recurrence or death among the sentinel node–positive patients in the nivolumab, pembrolizumab, and dabrafenib–trametinib trials are low, adjuvant therapy also seems reasonable in patients in this group who are not undergoing a completion lymph-node dissection; however, it must be acknowledged that data from these trials do not speak directly to this point.

In conclusion, pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma was associated with a significantly longer recurrence-free survival than placebo and had a safety profile consistent with the toxicity spectrum that has already been defined for the drug.

Supported by Merck.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. Eggermont reports receiving advisory board fees from Actelion, Agenus, Bayer, Bristol-Myers Squibb (BMS), GlaxoSmithKline (GSK), Incyte, ISA Pharmaceuticals, HalioDX, MedImmune, Merck Serono, Merck Sharpe and Dohme (MSD), Nektar, and Sanofi, and advisory board fees and fees for data and safety monitoring board membership from Novartis and Pfizer; Dr. Blank, receiving grant support and fees for advising, paid to his institution, from BMS and Novartis, and fees for advising, paid to his institution, from GSK, Lilly, MSD, Pfizer, and Roche; Dr. Mandala, receiving consulting fees, lecture fees, and fees for serving on speakers’ bureaus from MSD and BMS; Dr. Long, receiving consulting fees from Array, BMS, Novartis, Roche, Amgen, Pierre Fabre, MSD, and Incyte; Dr. Atkinson, receiving advisory board fees, lecture fees, and travel support from BMS, advisory board fees from Merck Serono, Pierre Fabre, and Roche, and advisory board fees and lecture fees from MSD and Novartis; Dr. Dalle, receiving grant support and travel support from BMS and travel support from MSD; Dr. Haydon, receiving advisory board fees from Novartis and Pierre-Fabre; Dr. Khattak, receiving lecture fees and travel support from MSD; Dr. Carlino, receiving advisory board fees from MSD, BMS, and Novartis; Dr. Sandhu, receiving advisory board fees from Merck and BMS; Dr. Larkin, receiving consulting fees from Eisai, GSK, Kymab, Roche–Genentech, Secarna, Pierre Fabre, and EUSA Pharma, and grant support and consulting fees from BMS, MSD, Pfizer, and Novartis; Dr. Puig, receiving patients’ fees, paid to her institution, from Amgen, Biofrontera, Regeneron Pharmaceuticals, and Philiogen, advisory board fees from Isdin, course fees paid on her behalf by Lilly, lecture fees and training fees paid of her behalf by LaRoche Posay, grant support, advisory board fees, and patients’ fees, paid to her institution, from Leo Pharma and Almirall, grant support, honoraria, and fees to attend a seminar paid on her behalf by Novartis, grant support and lecture fees from Roche, lecture fees from Pierre Fabre, and lecture fees and patients’ fees, paid to her institution, from BMS; Dr. Ascierto, receiving grant support, consulting fees, and advisory fees from BMS, Roche–Genentech, and Array, and consulting fees and advisory fees from MSD, Novartis, Amgen, Merck Serono, Pierre Fabre, Incyte, Genmab, NewLink Genetics, MedImmune, Syndax, and AstraZeneca; Dr. Rutkowski, receiving lecture fees and advisory board fees from MSD, Roche, and Amgen, grant support, lecture fee, and advisory board fees from BMS and Novartis, advisory board fees from Blueprint Medicines, and lecture fees from Pfizer; Dr. Schadendorf, receiving advisory board fees from Amgen, Leo Pharma, AstraZeneca, Pfizer, and Array, lecture fees from Boehringer Ingelheim, advisory board fees, lecture fees and patients’ fees from Roche, Novartis, BMS, and Merck-EMD, advisory board fees and lecture fees from Incyte and Pierre Fabre, advisory board fees and patients’ fees from Regeneron and Philiogen, and honoraria from 4SC; Dr. Koornstra, receiving advisory board fees and lecture fees from Novartis and BMS, advisory board fees from Roche and Pierre Fabre Medicament, and lecture fees from MSD; Dr. Hernandez-Aya, receiving fees to conduct clinical trials, paid to his institution, from BMS, Merck, Amgen, Roche, Regeneron, Novartis, Immunocore, Merck-EMD, Corvus, Polynoma, and Genentech; Dr. Maio, receiving advisory board fees from BMS, Roche, MSD, AstraZeneca, GSK, and Incyte; Dr. van den Eertwegh, receiving advisory board fees from BMS, MSD, Amgen, Novartis, and Roche; Dr. Grob, receiving advisory board fees from MSD, BMS, Novartis, Amgen, Merck-Pfizer, and Pierre-Fabre, grant support and advisory board fees from Roche, and grant support from Sun Pharma; Dr. Gutzmer, lecture fees, honoraria, and patients’ fees from Amgen, lecture fees from Boehringer Ingelheim and AstraZeneca, honoraria from Leo Pharma and Incyte, lecture fees, honoraria, support for meeting participation, and patients’ fees from Roche and BMS, grant support, lecture fees, honoraria, and patients’ fees from Novartis, honoraria and patients’ fees from Regeneron and 4SC, lecture fees, honoraria, and support for meeting participation from Pierre Fabre, lecture fees and honoraria from Merck-EMD and Almirall-Hermal, grant support from Pfizer and Johnson & Johnson, and patients’ fees from Philiogen and Array; Dr. Jamal, receiving grant support and patients’ fees, paid to her institution, from BMS and Merck, and patients’ fees, paid to her institution, from Pfizer, Roche–Genentech, AstraZeneca, Novartis, MedImmune, and GSK; Dr. Lorigan, receiving grant support, advisory board fees, fees for serving on a speakers’ bureau, and travel support from Bristol-Myers Squibb, advisory board fees, fees for serving on a speakers’ bureau, and travel support from MSD, advisory board fees and fees for serving on a speakers bureau from Novartis and Roche, and advisory board fees from Amgen, Nektar, Pierre Fabre, and Nera Care; Dr. Ibrahim, being employed by and owning stock in Merck, and owning stock in GSK; Dr. van Akkooi, receiving grant support, consulting fees, and honoraria from Amgen and Novartis, and consulting fees and honoraria from MSD, Merck-Pfizer, and BMS; and Dr. Robert, receiving consulting fees and advisory board fees from BMS, GSK, Novartis, Amgen, Merck, and Roche. No other potential conflict of interest relevant to this article was reported.

Drs. Suciu and Robert contributed equally to this article.

This article was published on April 15, 2018, at NEJM.org.

We thank the European Organization for Research and Treatment of Cancer team members who have not been included in the author list of this article and who contributed to the success of the trial: the data-management team (Sven Janssen, Alexander Parmentier, Anneleen Durnez, Katrien Wuyckens, Leen Wijnen, Miguel Remis, Nathalie Elaut, Robby Louis, Stef Van Hul, Laetitia Martins, Kelly Pelsmaekers, Marion Wargnies, Katrien Baus, and Larissa Polders), project-management team (Patrizia Favaloro and Gaetan de Schaetzen), medical department (Florence Defresne, Béatrice Fournier, and Konstantine Tryfonidis), statistical/SAS team (Michal Kicinski, Lei Ding, Catherine Fortpied, and Gaëlle Isaac), and pharmacovigilance team (Sandrine Rivrain and Benjamin Lacroix); and the Merck team members for trial oversight (Veronica Rivas, Lam Calderon, Suzanne Jones, Shilpa Patel, Robert Lupinacci, and Clemens Krepler) and for trial design and protocol conception discussions (Eric Rubin, Emmett Schmidt, and Scot Ebbinghaus).

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