Raadpleeg ook literatuurlijst niet-toxische middelen en behandelingen specifiek bij darmkanker van arts-bioloog drs. Engelbert Valstar

8 december 2020:

Nieuwe studiegegevens bevestigen dat immuuntherapie met pembrolizumab als eerstelijns na diagnose superieur is aan chemo voor progressievrije overleving bij darmkankerpatiënten (met hoge waarden van microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR), die niet eerder waren behandeld.

Thierry André, M.D., van de Sorbonne Université en Hôpital Saint Antoine in Parijs, en collega's voerden een fase 3, open-label studie uit met 307 patiënten met uitgezaaide MSI-H-dMMR darmkanker die niet eerder waren behandeld. Deelnemers werden willekeurig toegewezen in een verhouding van 1: 1 om ofwel pembrolizumab (200 mg elke drie weken) ofwel chemotherapie om de twee weken te krijgen.

Na een mediane follow-up van 32,4 maanden, bij de tweede tussentijdse analyse, ontdekten de onderzoekers dat pembrolizumab superieur was aan chemotherapie met betrekking tot progressievrije overleving (mediaan 16,5 versus 8,2 maanden; hazard ratio 0,60).

Na 24 maanden follow-up was de geschatte gemiddelde overleving 13,7 maanden voor de pembrolizumabgroep vergeleken met 10,8 maanden voor de chemogroep. In totaal waren respectievelijk 56 en 69 patiënten in de pembrolizumab- en chemotherapiegroep overleden op de cut-off-datum van de gegevens; gegevens over de algehele overleving waren nog in ontwikkeling.

Een algehele respons werd gezien bij respectievelijk 43,8 en 33,1 procent van de patiënten in de pembrolizumab- en chemotherapie-groepen. Onder degenen met een algehele respons had 83 en 35 procent van degenen in respectievelijk de pembrolizumab- en chemotherapie-groepen een aanhoudende duurzame respons na 24 maanden.

Hier het abstract van de studie:

Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer

List of authors.

Thierry André, M.D.,
Kai-Keen Shiu, F.R.C.P., Ph.D.,
Tae Won Kim, M.D., Ph.D.,
Benny Vittrup Jensen, M.D.,
Lars Henrik Jensen, M.D., Ph.D.,
Cornelis Punt, M.D., Ph.D.,
Denis Smith, M.D.,
Rocio Garcia-Carbonero, M.D., Ph.D.,
Manuel Benavides, M.D., Ph.D.,
Peter Gibbs, M.D.,
Christelle de la Fouchardiere, M.D.,
Fernando Rivera, M.D., Ph.D.,
for the KEYNOTE-177 Investigators*

Abstract

BACKGROUND

Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H–dMMR advanced or metastatic colorectal cancer is unknown.

METHODS

In this phase 3, open-label trial, 307 patients with metastatic MSI-H–dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil–based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival.

RESULTS

At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval , 0.45 to 0.80; P=0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group.

CONCLUSIONS

Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H–dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002. opens in new tab.)

16 augustus 2020: Ook de FDA heeft pembrolizumab goedgekeurd voor gebruik bij uitgezaaide darmkanker. Zie hier waarom: FDA Approves First-Line Immunotherapy for Patients with MSI-H/dMMR Metastatic Colorectal Cancer

Zie verder hieronder studieverslag

29 mei 2020: Bron: ASCO 2020

Goed nieuws voor mensen met uitgezaaide darmkanker, stadium IV. Patiënten hadden wel allemaal een hoge zogeheten microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR).

Uit de KEYNOTE-177 (NCT02563002) studie, een gerandomiseerde, open-label fase 3-studie blijkt dat immuuntherapie met het anti-PD medicijn pembrolizumab veel betere mediane overall overleving geeft dan chemotherapie met ook veel minder ernstige bijwerkingen. Op 2-jaars meting was het verschil in mediane progressievrije ziekte (PFS) maar liefst 30 procent, 48,3 maanden versus 18,6 maanden.

Daarbij blijkt pembrolizumab ook veel minder ernstige bijwerkingen te geven dan chemo: Behandelingsgerelateerde bijwerkingen (AE) van graad 3-5 waren 22% versus 66% voor pembrolizumab versus chemo.

Conclusie van de onderzoekers:

Pembrolizumab zorgde voor een klinisch betekenisvolle en statistisch significante verbetering in progressievrije ziekte (PFS) in vergelijking met chemo als eerstelijnsbehandeling voor patiënten met MSI-H / dMMR mCRC, waarbij minder behandelingsgerelateerde bijwerkingen werden waargenomen en het zou de nieuwe zorgstandaard voor deze patiëntengroep moeten zijn.

Deze studie is gepresenteerd op ASCO 2020: Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study.

Authors:

Thierry Andre, Kai-Keen Shiu, Tae Won Kim, Benny Vittrup Jensen, Lars Henrik Jensen, Cornelis J. A. Punt, Denis Michel Smith, Rocio Garcia-Carbonero, Manuel Benavides, Peter Gibbs, Christelle De La Fouchardiere, Fernando Rivera, Elena Elez, Johanna C. Bendell, Dung T. Le, Takayuki Yoshino, Ping Yang, Mohammed Zulfiqar Husain Farooqui, Patricia Marinello, Luis A. Diaz; Sorbonne University and...

Abstract Disclosures

Research Funding:

Merck & Co., Inc.

Background:KEYNOTE-177 (NCT02563002) is a phase 3, randomized open-label study evaluating the efficacy and safety of pembrolizumab (pembro) versus standard of care chemotherapy ± bevacizumab or cetuximab (chemo) as first-line therapy for patients (pts) with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). We present results of the final PFS analysis.Methods:A total of 307 pts with MSI-H/dMMR mCRC as determined locally and ECOG PS 0 or 1 were randomly assigned 1:1 to first-line pembro 200 mg Q3W for up to 2 years or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab (chemo chosen prior to randomization). Treatment continued until PD, unacceptable toxicity, pt/investigator decision to withdraw, or completion of 35 cycles (pembro only). Patients receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were PFS (RECIST v1.1, central review) and OS. Key secondary end points included ORR (RECIST v1.1, central review), and safety. The data cutoff date for this interim analysis was Feb 19, 2020. The study will continue without changes to evaluate OS.Results:At data cutoff, 153 pts were randomized to pembro and 154 to chemo. Median (range) study follow-up was 28.4 mo (0.2-48.3) with pembro vs 27.2 mo (0.8-46.6) with chemo. Pembro was superior to chemo for PFS (median 16.5 mo vs 8.2 mo; HR 0.60; 95% CI, 0.45-0.80; P=0.0002). The 12- and 24-mo PFS rates were 55.3% and 48.3% with pembro vs 37.3% and 18.6% with chemo. Confirmed ORR was 43.8% vs 33.1%; median (range) duration of response was not reached (2.3+ to 41.4+) with pembro vs 10.6 mo (2.8 to 37.5+) with chemo. Grade 3-5 treatment related adverse event (AE) rates were 22% vs 66% for pembro vs chemo. One pt in the chemo arm died due to a treatment-related AE.Conclusions:Pembro provided a clinically meaningful and statistically significant improvement in PFS versus chemo as first-line therapy for pts with MSI-H/dMMR mCRC, with fewer treatment-related AEs observed and should be the new standard of care for these pts. Clinical trial information: NCT02563002.