26 maart 2021: FDA approvals

De FDA - Food and Drug Administration heeft goedkeuring gegeven aan pembrolizumab (Keytruda) in combinatie met platina en op fluoropyrimidine gebaseerde chemotherapie voor patiënten met uitgezaaide of lokaal gevorderde slokdarmkanker of voor gastro-oesofageale tumoren (verbinding van slokdarm en maag) met een epicentrum van 1 tot 5 centimeter boven de gastro-oesofageale overgang waarvoor een operatie of definitieve chemoradiatie geen behandelingsoptie is.

De goedkeuring is gedaan op basis van de resultaten uit de KEYNOTE-590 studie (NCT03189719), een multicenter, gerandomiseerd, placebo gecontroleerd onderzoek waaraan 749 patiënten deelnamen.

Patiënten kregen pembrolizumab 200 mg of placebo op dag 1 om de 3 weken in combinatie met cisplatine 80 mg / op dag 1 om de 3 weken gedurende maximaal zes cycli en fluorouracil 800 mg / vanaf dag 1 tot 5 gedurende maximaal 24 maanden. De behandeling werd voortgezet tot onaanvaardbare toxiciteit of ziekteprogressie.

Over alle patiënten gemeten werden statistisch significante verbeteringen gezien door de toevoeging van pembrolizumab Mediane overall overleving (OS) verbeterde met 3 maanden (12,4 versus 9,8 maanden, hazard ratio 0,73, 95% betrouwbaarheidsinterval 0,62-0,86, p <0,0001),

Mediane progressievrije ziekte (PFS) verbeterde maar licht (6,3 versus 5,8 maanden). maanden, hazard ratio 0,65, 95% betrouwbaarheidsinterval 0,55-0,76, P <.0001) 
De onafhankelijke respons op de behandeling was wel beduidend beter voor pembrolizumab.(ORR) (45% versus 29%, P <.0001).

De beste resultaten werden gezien bij patiënten met een hoge PD-L1-expressie.

Bijwerkingen die optraden bij ten minste 20% van de patiënten in de studiegroep waren misselijkheid, obstipatie, diarree, braken, vermoeidheid / asthenie, stomatitis, verminderde eetlust en gewichtsverlies. Pembrolizumab werd stopgezet vanwege bijwerkingen bij 15% van de patiënten.

De goedkeuring van de FDA is te lezen op deze websitepagina: 

FDA approves pembrolizumab for esophageal or GEJ carcinoma

On March 22, 2021, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck Sharp & Dohme Corp.) in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal (GEJ) (tumors with epicenter 1 to 5 centimeters above the gastroesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation.

Efficacy was evaluated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or gastroesophageal junction carcinoma  who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumor specimens in all patients using the PD-L1 IHC 22C3 pharmDx kit. Patients were randomized (1:1) to pembrolizumab in combination with cisplatin and fluorouracil or placebo with cisplatin and fluorouracil, until unacceptable toxicity or disease progression.

The main efficacy outcome measures were overall survival (OS) and progression-free survival (PFS), as assessed by the investigator according to RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to pembrolizumab with chemotherapy. Median OS was 12.4 months (95% CI: 10.5, 14.0) for the pembrolizumab arm versus 9.8 months (95% CI: 8.8, 10.8) for the chemotherapy arm (HR 0.73; 95% CI: 0.62, 0.86; p<0.0001). Median PFS was 6.3  (95% CI: 6.2, 6.9) and 5.8 months (95% CI: 5.0, 6.0), respectively (HR 0.65; 95% CI: 0.55, 0.76; p<0.0001).

Most common adverse reactions reported in ≥20% of patients who received the pembrolizumab combination in KEYNOTE-590 were nausea, constipation, diarrhea, vomiting, stomatitis, fatigue/asthenia, decreased appetite, and weight loss.

The recommended pembrolizumab dose for esophageal cancer is 200 mg every 3 weeks or 400 mg every 6 weeks.

View full prescribing information for Keytruda.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 3 weeks ahead of the FDA goal date.

This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

For information on the COVID-19 pandemic, see the following resources:


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