8 december 2020: Bron: FDA en Journal of Clinical Oncology 

FDA verleent versnelde goedkeuring aan pembrolizumab ( Keytruda) voor lokaal terugkerende inoperabele of uitgezaaide triple-negatieve borstkanker gebaseerd op de resultaten uit de KEYNOTE-355 (NCT02819518) studie, een multicenter, dubbelblinde, gerandomiseerde, placebo gecontroleerde fase III studie bij patiënten met lokaal recidiverende inoperabele of uitgezaaide triple negatieve borstkanker (TNBC), die niet eerder waren behandeld met chemotherapie in de gemetastaseerde setting.

1000

Background: Pembrolizumab (pembro) monotherapy showed promising antitumor activity and manageable safety in patients (pts) with metastatic TNBC in KEYNOTE-012, -086 and -119. KEYNOTE-355 (ClinicalTrials.gov, NCT02819518) compared pembro + chemotherapy (chemo) vs placebo (pbo) + chemo for previously untreated locally recurrent inoperable or metastatic TNBC. 

Methods: Pts with ≥6 mo DFI were randomized 2:1 to pembro + chemo (nab-paclitaxel; paclitaxel; or gemcitabine/carboplatin) or pbo + chemo for up to 35 administrations of pembro/pbo or until progression/intolerable toxicity. Pts were stratified by chemo type (taxane vs gemcitabine/carboplatin), PD-L1 status (CPS ≥1 vs <1), and prior (neo)adjuvant treatment with same-class chemo (yes vs no). Dual primary endpoints are PFS (RECIST v1.1, blinded independent central review) and OS by tumor PD-L1 expression (CPS ≥10 and ≥1) and in all pts. PFS was estimated using the Kaplan-Meier method. Stratified log-rank tests were used to assess treatment group differences. HR and 95% CIs were based on a stratified Cox regression model. AEs were monitored throughout the study and graded per NCI CTCAE v4.0. 

Results: As of Dec 11 2019, median follow-up was 17.5 mo for pembro + chemo (n=566) and 15.5 mo for chemo (n=281). Pembro + chemo significantly improved PFS vs chemo alone in pts with CPS ≥10 tumors (Table), meeting one of the protocol-defined primary objectives. Although the boundary for a statistically significant benefit of pembro + chemo in pts with CPS ≥1 tumors was not met and formal testing in ITT was not performed, the pembro treatment effect increased with PD-L1 enrichment (Table). OS follow-up is ongoing. Grade 3-5 treatment-related AE rates were 68.1% with pembro + chemo (2 deaths) vs 66.9% with chemo (0 deaths); rates of grade 3-4 immune-mediated AEs and infusion reactions were 5.5% vs 0%. Clinical trial information: NCT02819518

Conclusion: Pembro combined with several chemo partners showed a statistically significant and clinically meaningful improvement in PFS vs chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 (CPS ≥10). Pembro + chemo was generally well tolerated, with no new safety concerns.

PopulationTreatmentMedian PFS, moHR
(95% CI)
P-valueP-value boundary
CPS ≥10 P + C (n=220) vs C (n=103) 9.7 vs 5.6 0.65
(0.49-0.86)
0.0012 0.00411
CPS ≥1 P + C (n=425) vs C (n=211) 7.6 vs 5.6 0.74
(0.61-0.90)
0.0014 0.00111
ITT P + C (n=566) vs C (n=281) 7.5 vs 5.6 0.82
(0.69-0.97)
- n/a

© 2020 American Society of Clinical Oncology

Research Sponsor:

Merck & Co., Inc.

Hier het persbericht van de FDA - Food and Drug Administration

FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer

On November 13, 2020, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co.) in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA approved test.

FDA also approved the PD-L1 IHC 22C3 pharmDx (Dako North America, Inc.) as a companion diagnostic for selecting patients with TNBC for pembrolizumab.

Approval was based on KEYNOTE-355 (NCT02819518), a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC, who had not been previously treated with chemotherapy in the metastatic setting. Patients were randomized (2:1) to receive pembrolizumab 200 mg on day 1 every 3 weeks or placebo in combination with different chemotherapy treatments (paclitaxel protein-bound, or paclitaxel, or gemcitabine plus carboplatin) via intravenous infusion.

The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent review according to RECIST 1.1, tested in the subgroup of patients with CPS ≥10. Median PFS was 9.7 months (95% CI: 7.6, 11.3) in the pembrolizumab plus chemotherapy arm and 5.6 months (95% CI:5.3, 7.5) in the placebo arm (HR 0.65; 95% CI: 0.49, 0.86; one-sided p-value=0.0012).

The most common adverse reactions (incidence ≥20%) in patients receiving pembrolizumab plus chemotherapy in KEYNOTE-355 were fatigue, nausea, diarrhea, constipation, vomiting, alopecia, rash, cough, decreased appetite, headache. The most common laboratory abnormalities (incidence ≥20%) in patients receiving pembrolizumab plus chemotherapy were anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia, elevated ALT and AST, hyperglycemia, hypoalbuminemia, increased alkaline phosphatase, hypocalcemia, hyponatremia, hypophosphatemia, and hypokalemia.

The recommended pembrolizumab dose for adult patients with locally recurrent unresectable or metastatic TNBC is 200 mg every 3 weeks or 400 mg every 6 weeks administered prior to chemotherapy until disease progression, unacceptable toxicity, or up to 24 months. When given with pembrolizumab, either paclitaxel protein bound 100 mg/m2 on days 1, 8 and 15 every 28 days, or paclitaxel 90 mg/m2 on days 1, 8 and 15 every 28 days, or gemcitabine 1000 mg/m2 plus carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days is administered via intravenous infusion.


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1 Reactie op "FDA verleent versnelde goedkeuring aan pembrolizumab voor lokaal terugkerende inoperabele of uitgezaaide triple-negatieve borstkanker"

  • e.valstar :
    Pembroluzimab levert 2 maanden extra mediane overleving op. De belangrijkste chemo's leveren bij elkaar dik 8 maanden, maar soms ook meer op. Uiteraard komt dit bovenop de overleving die men sowieso al heeft en is het effect van non-toxische tumortherapie nog niet meegerekend. Feit is dat immuuntherapie een nieuw belangwekkend hoofdstuk aan het worden is. Met name bij het melanoom, bepaalde typen longkanker, nierkanker en bij darmkanker (als er microsatellaire instabiliteit is) is immuuntherapie interessant. Individueel kan immuuntherapie spectaculaire resultaten geven.
    Duidelijk is dat vrouwen met uitgezaaide borstkanker die hormoon- en/of herceptingevoelig met immuuntherapie ook hun kansen verbeteren.

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