Endometriyum kanseri kadınlarda sık görülen ve genel olarak erken dönem tanı konulan bir kanser türüdür. Özelikle obezite ve sedanter yaşam alışkanlıklarının artması ile görülme sıklığı giderek artmaktadır.
Ameliyat olan hastaların bir kısmı ya da tanı anında metastaz ile başvuran hastalarda artık genetik analizle alt tiplendirme yapılarak tedavi verilmektedir. Mikrosatellit instabilite ve HER2 en sık bakılan iki temel alt tip olarak bilinmektedir.
Mikrosatellit instabilite, patolojik bloklarda immün histokimyasal boyalarla tümör supresyon genlerin aktivitesi sonu ortaya çıkan protein ekspresyonlarının (MLH1, PMS2, MSH2, MSH6) kaybının gösterilmesi ya da PCR ile direk gen kayıplarının saptanması ile belirlenir.
Evre IV endometriyum kanserinde yaklaşık üç hastadan birinde Mikrosatellit instabilite mevcut.
Mikrosatellit instabilite olan evre endometriyum kanserlerinde, immünoterapi(dostarlimab) ve kemoterapi (Karboplatin ve paclitaxel) kombinasyonu, yalnız kemoterapiye göre hastalığa bağlı ölümü ve hastalık ilerlemesini %72 oranında azaltıyor.
Mikrosatellit instabilite, patolojik bloklarda immün histokimyasal boyalarla tümör supresyon genlerin aktivitesi sonu ortaya çıkan protein ekspresyonlarının (MLH1, PMS2, MSH2, MSH6) kaybının gösterilmesi ya da PCR ve NGS ile direk gen kayıplarının saptanması ile belirlenir.
Amerika Birleşik Devletleri Gıda ve İlaç Dairesi (FDA) bu veriler sonrası Mikrosatellit instabilite olan evre IV endometriyum kanserinde dostarlimab ve kemoterapiyi ilk basamakta tedavi seçeneği olarak onayladı.
Kaynak
FDA Approves Dostarlimab-gxly Plus Chemotherapy for dMMR or MSI-H Endometrial Cancer
By The ASCO Post Staff
On July 31, the U.S. Food and Drug Administration (FDA) approved dostarlimab-gxly (Jemperli) with carboplatin and paclitaxel followed by single-agent dostarlimab for patients with primary advanced or recurrent endometrial cancer that is mismatch repair–deficient (dMMR), as determined by an FDA-approved test, or microsatellite instability–high (MSI-H).
RUBY Trial
Efficacy was evaluated in RUBY (ClinicalTrials.gov identifier NCT03981796), a randomized, multicenter, double-blind, placebo-controlled trial. Efficacy was assessed in a prespecified subgroup of 122 patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer. MMR/MSI tumor status was determined by local testing assays (immunohistochemistry [IHC], polymerase chain reaction, or next-generation sequencing), or central testing (IHC) using the Ventana MMR RxDx Panel when local results were unavailable.
Patients were randomly assigned 1:1 to receive either dostarlimab with carboplatin and paclitaxel followed by dostarlimab or placebo with carboplatin and paclitaxel followed by placebo. Chemotherapy regimens are described in detail in the prescribing information for dostarlimab. Random assignment was stratified by MMR/MSI status, prior external pelvic radiotherapy, and disease status (recurrent, primary stage III, or primary stage IV).
The primary efficacy outcome measure was investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1.
Progression-Free Survival
A statistically significant progression-free survival improvement was observed in the dMMR/MSI-H population, with a median progression-free survival of 30.3 vs 7.7 months (hazard ratio = 0.29, 95% confidence interval = 0.17–0.50, P < .0001) for the dostarlimab and placebo-containing regimens, respectively.
Immune-mediated adverse reactions occurred in patients receiving dostarlimab, including pneumonitis, colitis, hepatitis, endocrinopathies (such as hypothyroidism), nephritis with renal dysfunction, and dermatologic adverse reactions. The most common adverse reactions (≥ 20%) with dostarlimab in combination with carboplatin and paclitaxel were rash, diarrhea, hypothyroidism, and hypertension.
The recommended dostarlimab dose is 500 mg every 3 weeks for six doses with carboplatin and paclitaxel, followed by 1,000 mg as monotherapy every 6 weeks until disease progression or unacceptable toxicity or for up to 3 years. Dostarlimab should be administered before chemotherapy when administered on the same day.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, Switzerland’s Swissmedic, and the United Kingdom’s Medicines and Healthcare Products Regulatory Agency. The application reviews are ongoing at the other regulatory agencies.
