24 augustus 2017: zie ook dit artikel: 

https://kanker-actueel.nl/NL/nivolumab-obvio-alleen-en-samen-met-ipilimumab-yervoy-geeft-uitstekende-resultaten-bij-gevorderde-niercelkanker-ook-in-vergelijking-met-sunitinib.html

25 december 2015: Bron: N Engl J Med. 2015 Nov 5;373(19):1803-13. doi: 10.1056/NEJMoa1510665. en FDA website approvals

Nivolumab (Obdivo) , een zogeheten anti PD medicijn (anti programmed death medicijn), en als zodanig ook als immuuntherapeutisch medicijn aangemerkt omdat deze medicijnen de apoptose (zelfdoding) van de kankercel stimuleren, is door de FDA - Food and Drug Administration goedgekeurd om als tweedelijns behandeling te gebruiken bij gevorderde nierkanker na progressie van de ziekte na behandelingen plus avastin - bevacizumab.

Klik hier voor de goedkeuringstekst van de FDA per 23 november 2015.

De goedkeuring van de FDA is verstrekt op basis van de resultaten uit een langjarige grote fase III studie bij totaal 821 patiënten met gevorderde zogeheten 'clear-cell renal-cell carcinoma, veruit de meest voorkomende vorm van nierkanker, waarbij nivolumab werd vergeleken met everolimus, een medicijn dat al eerder goede resultaten had laten zien in vergelijking met andere eerdere behandelingen voor nierkanker.

De overall overleving was 25 maanden voor nivolumab (en kan nog beter worden omdat einde studie-follow-up voor nivolumab nog niet is bereikt) tegenover 19,6 maanden voor Everolimus. Van de 410 patiënten bereikte 21,5 % een complete remissie of gedeeltelijke remissie (50% of meer minder tumoren en/of tumorgrootte)  in de nivolumabgroep  tegenover slechts 3,9% in de everolimusgroep (Afinitor)

Uit studieresults: Additionally, 21.5 percent of those treated with Opdivo experienced a complete or partial shrinkage of their tumors, which lasted an average of 23 months, compared to 3.9 percent of those taking Afinitor, lasting an average of 13.7 months.

Bovendien was het bijwerkingenprofiel voor nivolumab de helft van dat van everolimus 19% vs 37%.

De resultaten zijn ongeacht de status van de zogeheten PD-1/PD-L1 ligand expressie, die expressie zou noodzakelijk zijn voor de werking van nivolumab. Als patiënten daarop geselecteerd zouden zijn dan zouden de resultaten wellicht nog beter zijn geweest.

Alle reden dus om de tweedelijns behandeling (nog beter zou zijn nivolumab eerstelijns behandeling te maken) van gevorderde nierkanker te wijzingen lijkt mij.

PD-1 schema werklingsmechanisme nivolumab

Grafiek: geeft werkingmechanisme weer van anti-PD medicijnen zoals Nivolumab - Obvido

Studieresultaten:

Totaal 821 patiënten met gevorderde nierkanker - clear-cell renal-cell carcinoma - die eerder 1 of twee keer waren behandeld met een behandeling met ook een angiogeneseremmer werden gerandomiseerd ingedeeld (in een 1:1 verhouding) om of 3 mg nivolumab per kilogram lichaamsgewicht te krijgen intraveneus elke 2 weken of een tablet met 10-mg everolimus tablet oraal een keer per dag in te nemen. Het primaire einddoel was overall overleving. Het tweede doel was de objecteive respons en de veiligheid - het bijwerkingenprofiel. 

Statistisch significant betere resultaten voor nivolumab:

De median overall overleving was 25.0 maanden (95% confidence interval , 21.8 maanden tot nog niet bereikt) voor de groep die nivolumab kreeg en 19.6 maanden (95% CI, 17.6 tot 23.1 maanden) voor everolimus. De hazard ratio voor overlijden in de groep van de nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), welke statistisch significant is (P≤0.0148).
De objectieve respons was ook beter voor nivolumab dan voor everolimus (25% versus. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001).
De mediane progressie-vrije overleving was 4.6 maanden (95% CI, 3.7 to 5.4) voor nivolumab en 4.4 maanden (95% CI, 3.7 to 5.5) voor everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11).
Graad 3 of 4 behandelings gerelateerde bijwerkingen deden zihc voor bij 19% van de patiënten uit de  nivolumabgroep en bij 37% van de patiënten uit de everolimusgroep.   De meest voorkomende bijwerking bij nivolumab was vermoeidheid (bij 2% van de patiënten), en de meest voorkomende bijerking bij everolimus was bloedarmoede (bij 8%).

Conclusie:

Conclusie van de onderzoekers: onder patiënten met vooraf behandelde gevorderde nierkanker - clear-cell renal carcinoma -  bleek de overall overleving na behandeling met nivolumab significant langer en met minder bijwerkingen - graad 3/4 - gepaard gaande  dan na een behandeling met everolimus.

Het volledige studierapport: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. is gratis in te zien.

Het studieprotocol van de CheckMate 025 ClinicalTrials.gov is nummer, NCT01668784

Hier abstract van de studie zoals gepubliceerd in NEJM:

Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus.

N Engl J Med. 2015 Nov 5;373(19):1803-13. doi: 10.1056/NEJMoa1510665. Epub 2015 Sep 25.

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.

Abstract

Supporting Efficacy Data

Approval was based on improved overall survival in a phase III trial (CheckMate 025) in which 821 patients with advanced renal cell carcinoma who had received prior antiangiogenic therapy were randomly assigned to nivolumab at 3 mg/kg intravenously every 2 weeks (n = 410) or oral everolimus (Afinitor) at 10 mg once daily (n = 411).2,3 Patients had a median age of 62 years (40% ≥ 65 and 9% ≥ 75 years), 75% were male, 88% were white, Karnofsky performance score was 70 to 80 in 34% and 90 to 100 in 66%, 77% had received prior antiangiogenic therapy, and Memorial Sloan Kettering risk was favorable in 34%, intermediate in 47%, and poor in 19%.

At a prespecified interim analysis based on 70% of planned events, median overall survival, the primary endpoint, was 25.0 months (95% confidence interval = 21.7 months to not estimable) in the nivolumab group vs 19.6 months (95% CI = 17.6–23.1 months) in the everolimus group (hazard ratio = 0.73, P = .0018). A survival benefit was observed regardless of programmed cell death ligand 1 (PD-L1) expression level. The confirmed response rate was 21.5% vs 3.9%, median response duration was 23.0 vs 13.7 months, and median time to response was 3.0 to 3.7 months

BACKGROUND:

Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.

METHODS:

A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.

RESULTS:

The median overall survival was 25.0 months (95% confidence interval , 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).

CONCLUSIONS:

Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).

PMID:
26406148
[PubMed - indexed for MEDLINE]

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