Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti-PD-L1, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer
© 2024 F. Hoffmann-La Roche. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society..
BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC).
METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized.
RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively.
CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Cancer - (2024) vom: 30. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mutch, David [VerfasserIn] |
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| Links: |
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| Themen: |
Immune checkpoint blockade |
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| Anmerkungen: |
Date Revised 30.01.2024 published: Print-Electronic ClinicalTrials.gov: NCT03695380 Citation Status Publisher |
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| doi: |
10.1002/cncr.35222 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367792036 |
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| 245 | 1 | 0 | |a Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti-PD-L1, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Revised 30.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03695380 | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a © 2024 F. Hoffmann-La Roche. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. | ||
| 520 | |a BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC) | ||
| 520 | |a METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized | ||
| 520 | |a RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively | ||
| 520 | |a CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a NF1 | |
| 650 | 4 | |a PARP inhibitor | |
| 650 | 4 | |a immune checkpoint blockade | |
| 650 | 4 | |a ovarian cancer | |
| 700 | 1 | |a Voulgari, Athina |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xian Marissa |e verfasserin |4 aut | |
| 700 | 1 | |a Bradley, William H |e verfasserin |4 aut | |
| 700 | 1 | |a Oaknin, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Perez Fidalgo, José Alejandro |e verfasserin |4 aut | |
| 700 | 1 | |a Montosa, Fernando Galvez |e verfasserin |4 aut | |
| 700 | 1 | |a Herraez, Antonio Casado |e verfasserin |4 aut | |
| 700 | 1 | |a Holloway, Robert W |e verfasserin |4 aut | |
| 700 | 1 | |a Powell, Matthew A |e verfasserin |4 aut | |
| 700 | 1 | |a Nowicka, Malgorzata |e verfasserin |4 aut | |
| 700 | 1 | |a Schaefer, Gabriele |e verfasserin |4 aut | |
| 700 | 1 | |a Merchant, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Yibing |e verfasserin |4 aut | |
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