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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: lees ook dit artikel: 

https://kanker-actueel.nl/immuuntherapie-met-pembrolizumab-voorkomt-veel-beter-recidief-met-43-procent-van-operabele-melanoom-stadium-iii-in-vergeljiking-met-placebo-ook-zonder-pd-1-mutatie.html

16 januari 2018: Lees ook dit artikel 

https://kanker-actueel.nl/bepaalde-darmbacterien-kunnen-de-effectiviteit-van-immunotherapie-met-anti-pd-medicijnen-verhogen-bij-de-behandeling-van-melanomen.html

1 september 2017: Bron: The Lancet

Pembrolizumab (Keytruda), zowel 2 wekelijks als drie wekelijks blijkt ook bij de definitieve analyse van de Kyenote-006 studie) betere resultaten te geven in vergelijking met ipilimumab op overall overleving en ziektevrije tijd bij gevorderde inoperabele melanomen stadium III en IV.

Na mediaan bijna twee jaar (22,9 maanden) follow-up bleek 55% van de melanoompatienten die pembrolizumab hadden gekregen nog in leven in vergelijking met 43% van de patiënten die ipilimumab hadden gekregen.

Uit het studierapport:

  • In patiënten met een inoperabele melanoom stadium III of IV, geeft pembrolizumab (met 10 mg/kg elke twee weken or elke 3 weken) langere overall overleivng in vergelijking met ipilimumab.
  • Twee jaars overall ovrleving was 55% in elke pembrolizumab groep versus 43% in de ipilimumab groep.

pembrolizumab vs ipilimumab(2)

Zie verderop in dit artikel gedetailleerde beschrijving van de studie. Het nieuwe studierapport is gepubliceerd in The Lancet en is tegen betaling in te zien: Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006) 

Findings

Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio 0·68, 95% CI 0·53–0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53–0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group.

De studie staat geregistreerd in ClinicalTrials.gov, onder nummer NCT01866319.

12 mei 2015: Bron: NEJM 2015 Apr 19. [Epub ahead of print]

Pembrolizumab (Keytruda), een anti-PD medicijn blijkt superieure resultaten te geven in vergelijking met ipilimumab (Yervoy), een vorm van immuuntherapie in de behandeling van inoperabele vergevorderde melanomen. Aldus blijkt uit tussenresultaten van de wereldwijd uitgevoerde fase III KEYNOTE-006 studie (834 patienten uit 83 ziekenhuizen in 16 verschillende landen).

Pembrolizumab verbeterde significant overall overleving , progressie-tijd, en overall response vergeleken met ipilimumab, wat nu nog de standaard behandeling is voor dit stadium van de ziekte bij vergevorderde melanomen.

Na een mediane follow-up van 13,8 maanden de 1-jaars overall overleving waren 74.1% (voor 2 wekelijkse dosis en 68.4% voor de 3-wekelijkse dosis in de pembrolizumab groupen versus 58.2% voor ipilimumab, Dit betekent statistisch significant een verbetering met 37% in overleving (P = .00052 and P = .00358, respectievelijk).

pembrozulimab overall overlevingsgrafiekpembrozulimab overall overlevingsgrafiek 2

Bovendien gaf pembrolizumab minder bijwerkingen en toxicieit, zeker de ernstigere bijwerkingen die soms kunnen optreden bij ipilimumab.

pembrolizumab bijwerkingen grafiek

Pembrolizumab is een zogeheten checkpoint remmer, een anti-PD medicijn, zoals ook nivolumab dat is. In feite zetten deze medicijnen het immuunsysteem weer aan waar het niet functioneerde / faalde bij het ontstaan van tumorcellen. M.i. ligt de oplossing van kanker heel dichtbij.

De tussenresultaten van de KEYNOTE-006 studie zijn nu al gepubliceerd in The New England Journal of Medicine en is gepresenteerd op 19 april op ASCO 2015

Pembrolizumab wordt nieuwe standaard behandeling:

De KEYNOTE-006 studie is gestopt omdat de resultaten dermate groot waren dat het ethisch niet verantwoord is om patiënten ipilimumab te geven waar een ander medicijn veel betere resultaten geeft. 

De data uit de KEYNOTE-006 zal de standaard zorg voor inoperabele en/of gevorderde melanomen, stadium III en IV veranderen. ook voor die patiënten die al ipilimumab hebben gekregen.” aldus senior auteur van de studie, Antoni Ribas, MD, PhD, Professor of Medicine and Hematology/Oncology and Director of Tumor Immunology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

“Nog niet zo lang geleden discussieërden we over behandelingen die 1 op de 10 patiënten zou kunnen helpen. Met de ontwikkeling van nieuwe medicijnen die het immuunsysteem opnieuw activeren praten we over 1 op de 3 patiënten. Dat wordt de nieuwe standaard,” aldus dr. Antoni Ribas.

Ipilimumab, is een anti–cytotoxische T-lymphocyte gerelateerd eiwit 4 (CTLA-4) behandeling en was het eerste medicijn van zijn soort dat overall overleving verbeterde bij patieënten met gevorderde melanomen en het werd de standaard behandeling. Pembrolizumab is een anti–PD medicijn (anti-programmed cell death) (PD-1) antibody. Beiden zijn zogeheten immuun checkpoint remmers.

Twee anti–PD-1 remmers, pembrolizumab en nivolumab ­(Opdivo), zijn door de FDA de Food and Drug Administration (FDA) goedgekerud als behandeling voor melanomen als ipilimumab resistentie laat zien en als de receptoren BRAF V600 mutatie–positief zijn, na behandeling met een BRAF remmer.

Studieresultaten (heb ik nog niet vertaald maar komt uit artikel in ASCO Post:

KEYNOTE-006 included 834 patients from 83 sites in 16 different countries with unresectable stage III or IV advanced melanoma and no more than one prior systemic therapy. Patients were excluded if they received previous therapy with CTLA-4, PD-1, or PD-L1 inhibitors. Study participants were randomly assigned 1:1:1 to pembrolizumab at 10 mg/kg every 2 weeks (n = 279), pembrolizumab at 10 mg/kg every 3 weeks (n = 277), or four cycles of ipilimumab at 3 mg/kg every 3 weeks (n = 278).

Dr. Ribas explained that at the time KEYNOTE-006 was designed, the best dosing regimen of pembrolizumab was not known. The currently approved dosing regimen for pembrolizumab is 2 mg/kg every 3 weeks.

“There seems to be little difference between these dosing regimens [ie, all three pembrolizumab regimens],” he noted, “and there is no evidence that one of the two dosing regimens in ­KEYNOTE-006 is better.”

At a median follow-up of 7.9 months, median progression-free survival was 5.5 months for the every-2-week pembrolizumab group and 4.1 months for the every-3-week group, vs 2.8 months for ipilimumab, reflecting a 42% reduction in risk of disease progression with pembrolizumab (P < .00001).

Estimated 6-month progression-free survival rates were 47.3%, 46.4%, and 26.5%, respectively. “Progression-free survival is close to double with pembrolizumab,” Dr. Ribas noted.

At a median follow-up of 13.8 months, 1-year overall survival rates were 74.1% and 68.4% for the 2-week and 3-week pembrolizumab groups, respectively, vs 58.2% for ipilimumab, reflecting a 37% improvement in survival that was statistically significant (P = .00052 and P = .00358, respectively).

“This study exceeded our expectations, even for the control arm,” he said.

Objective response rates according to RECIST criteria for tumor shrinkage were about 33% in the pembrolizumab arms vs 11.9% in the ipilimumab arm. Complete response rates were 5%, 6.1%, and 1.4%, respectively. Responses were ongoing in 89.4% of the 2-week pembrolizumab group, 96.7% of the 3-week pembrolizumab group, and 87.9% of the ipilimumab group.

Improved Tolerability

“The toxicity profile favored pembrolizumab, with fewer side effects even though there was greater continuous exposure to the drug than with ipilimumab,” Dr. Ribas commented. Grade 3/4 toxicities were reported in 19% of the ipilimumab-treated patients and in 10% to 13% of those receiving pembrolizumab.

Treatment-related autoimmune- or immune-related adverse events with pembrolizumab were hypothyroidism (10.1% for the 2-week group and 8.7% for the 3-week group) and hyperthyroidism (6.5% and 2.5%, respectively). Colitis was reported in 8.2% of those assigned to ipilimumab.

Disclosure: Dr. Ribas has consulted for Merck, with the honoraria paid to his institution.

Het volledige studierapport: Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma is gratis in te zien op de website van de N Engl J Med. April 19, 2015 (early release online).

Het abstract staat hieronder:

The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma.

N Engl J Med. 2015 Apr 19. [Epub ahead of print]

Pembrolizumab versus Ipilimumab in Advanced Melanoma.

Abstract

Background:

The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma.

Methods:

In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival.

Results:

The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals , 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).

Conclusions:

The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319 .).

PMID:
25891173
[PubMed - as supplied by publisher]

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