Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study
Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival an...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Weber, Jeffrey S [verfasserIn] Carlino, Matteo S [verfasserIn] Khattak, Adnan [verfasserIn] Meniawy, Tarek [verfasserIn] Ansstas, George [verfasserIn] Taylor, Matthew H [verfasserIn] Kim, Kevin B [verfasserIn] McKean, Meredith [verfasserIn] Long, Georgina V [verfasserIn] Sullivan, Ryan J [verfasserIn] Faries, Mark [verfasserIn] Tran, Thuy T [verfasserIn] Cowey, C Lance [verfasserIn] Pecora, Andrew [verfasserIn] Shaheen, Montaser [verfasserIn] Segar, Jennifer [verfasserIn] Medina, Theresa [verfasserIn] Atkinson, Victoria [verfasserIn] Gibney, Geoffrey T [verfasserIn] Luke, Jason J [verfasserIn] Thomas, Sajeve [verfasserIn] Buchbinder, Elizabeth I [verfasserIn] Healy, Jane A [verfasserIn] Huang, Mo [verfasserIn] Morrissey, Manju [verfasserIn] Feldman, Igor [verfasserIn] Sehgal, Vasudha [verfasserIn] Robert-Tissot, Celine [verfasserIn] Hou, Peijie [verfasserIn] Zhu, Lili [verfasserIn] Brown, Michelle [verfasserIn] Aanur, Praveen [verfasserIn] Meehan, Robert S [verfasserIn] Zaks, Tal [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2024 |
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| Übergeordnetes Werk: |
Enthalten in: No title available - 403, Seite 632-644 |
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| Übergeordnetes Werk: |
volume:403 ; pages:632-644 |
| DOI / URN: |
10.1016/S0140-6736(23)02268-7 |
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| Katalog-ID: |
ELV067082866 |
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| 024 | 7 | |a 10.1016/S0140-6736(23)02268-7 |2 doi | |
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| 041 | |a eng | ||
| 100 | 1 | |a Weber, Jeffrey S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study |
| 264 | 1 | |c 2024 | |
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| 520 | |a Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. | ||
| 700 | 1 | |a Carlino, Matteo S |e verfasserin |4 aut | |
| 700 | 1 | |a Khattak, Adnan |e verfasserin |4 aut | |
| 700 | 1 | |a Meniawy, Tarek |e verfasserin |4 aut | |
| 700 | 1 | |a Ansstas, George |e verfasserin |4 aut | |
| 700 | 1 | |a Taylor, Matthew H |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Kevin B |e verfasserin |4 aut | |
| 700 | 1 | |a McKean, Meredith |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Georgina V |e verfasserin |4 aut | |
| 700 | 1 | |a Sullivan, Ryan J |e verfasserin |4 aut | |
| 700 | 1 | |a Faries, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Tran, Thuy T |e verfasserin |4 aut | |
| 700 | 1 | |a Cowey, C Lance |e verfasserin |4 aut | |
| 700 | 1 | |a Pecora, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Shaheen, Montaser |e verfasserin |4 aut | |
| 700 | 1 | |a Segar, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Medina, Theresa |e verfasserin |4 aut | |
| 700 | 1 | |a Atkinson, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Gibney, Geoffrey T |e verfasserin |4 aut | |
| 700 | 1 | |a Luke, Jason J |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Sajeve |e verfasserin |4 aut | |
| 700 | 1 | |a Buchbinder, Elizabeth I |e verfasserin |4 aut | |
| 700 | 1 | |a Healy, Jane A |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Mo |e verfasserin |4 aut | |
| 700 | 1 | |a Morrissey, Manju |e verfasserin |4 aut | |
| 700 | 1 | |a Feldman, Igor |e verfasserin |4 aut | |
| 700 | 1 | |a Sehgal, Vasudha |e verfasserin |4 aut | |
| 700 | 1 | |a Robert-Tissot, Celine |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Peijie |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Lili |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Aanur, Praveen |e verfasserin |4 aut | |
| 700 | 1 | |a Meehan, Robert S |e verfasserin |4 aut | |
| 700 | 1 | |a Zaks, Tal |e verfasserin |4 aut | |
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10.1016/S0140-6736(23)02268-7 doi (DE-627)ELV067082866 (ELSEVIER)S0140-6736(23)02268-7 DE-627 ger DE-627 rda eng Weber, Jeffrey S verfasserin aut Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. Carlino, Matteo S verfasserin aut Khattak, Adnan verfasserin aut Meniawy, Tarek verfasserin aut Ansstas, George verfasserin aut Taylor, Matthew H verfasserin aut Kim, Kevin B verfasserin aut McKean, Meredith verfasserin aut Long, Georgina V verfasserin aut Sullivan, Ryan J verfasserin aut Faries, Mark verfasserin aut Tran, Thuy T verfasserin aut Cowey, C Lance verfasserin aut Pecora, Andrew verfasserin aut Shaheen, Montaser verfasserin aut Segar, Jennifer verfasserin aut Medina, Theresa verfasserin aut Atkinson, Victoria verfasserin aut Gibney, Geoffrey T verfasserin aut Luke, Jason J verfasserin aut Thomas, Sajeve verfasserin aut Buchbinder, Elizabeth I verfasserin aut Healy, Jane A verfasserin aut Huang, Mo verfasserin aut Morrissey, Manju verfasserin aut Feldman, Igor verfasserin aut Sehgal, Vasudha verfasserin aut Robert-Tissot, Celine verfasserin aut Hou, Peijie verfasserin aut Zhu, Lili verfasserin aut Brown, Michelle verfasserin aut Aanur, Praveen verfasserin aut Meehan, Robert S verfasserin aut Zaks, Tal verfasserin aut Enthalten in No title available 403, Seite 632-644 (DE-627)270128484 0140-6736 nnns volume:403 pages:632-644 GBV_USEFLAG_U GBV_ELV SYSFLAG_U GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_213 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 403 632-644 |
| spelling |
10.1016/S0140-6736(23)02268-7 doi (DE-627)ELV067082866 (ELSEVIER)S0140-6736(23)02268-7 DE-627 ger DE-627 rda eng Weber, Jeffrey S verfasserin aut Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. Carlino, Matteo S verfasserin aut Khattak, Adnan verfasserin aut Meniawy, Tarek verfasserin aut Ansstas, George verfasserin aut Taylor, Matthew H verfasserin aut Kim, Kevin B verfasserin aut McKean, Meredith verfasserin aut Long, Georgina V verfasserin aut Sullivan, Ryan J verfasserin aut Faries, Mark verfasserin aut Tran, Thuy T verfasserin aut Cowey, C Lance verfasserin aut Pecora, Andrew verfasserin aut Shaheen, Montaser verfasserin aut Segar, Jennifer verfasserin aut Medina, Theresa verfasserin aut Atkinson, Victoria verfasserin aut Gibney, Geoffrey T verfasserin aut Luke, Jason J verfasserin aut Thomas, Sajeve verfasserin aut Buchbinder, Elizabeth I verfasserin aut Healy, Jane A verfasserin aut Huang, Mo verfasserin aut Morrissey, Manju verfasserin aut Feldman, Igor verfasserin aut Sehgal, Vasudha verfasserin aut Robert-Tissot, Celine verfasserin aut Hou, Peijie verfasserin aut Zhu, Lili verfasserin aut Brown, Michelle verfasserin aut Aanur, Praveen verfasserin aut Meehan, Robert S verfasserin aut Zaks, Tal verfasserin aut Enthalten in No title available 403, Seite 632-644 (DE-627)270128484 0140-6736 nnns volume:403 pages:632-644 GBV_USEFLAG_U GBV_ELV SYSFLAG_U GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_213 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 403 632-644 |
| allfields_unstemmed |
10.1016/S0140-6736(23)02268-7 doi (DE-627)ELV067082866 (ELSEVIER)S0140-6736(23)02268-7 DE-627 ger DE-627 rda eng Weber, Jeffrey S verfasserin aut Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. Carlino, Matteo S verfasserin aut Khattak, Adnan verfasserin aut Meniawy, Tarek verfasserin aut Ansstas, George verfasserin aut Taylor, Matthew H verfasserin aut Kim, Kevin B verfasserin aut McKean, Meredith verfasserin aut Long, Georgina V verfasserin aut Sullivan, Ryan J verfasserin aut Faries, Mark verfasserin aut Tran, Thuy T verfasserin aut Cowey, C Lance verfasserin aut Pecora, Andrew verfasserin aut Shaheen, Montaser verfasserin aut Segar, Jennifer verfasserin aut Medina, Theresa verfasserin aut Atkinson, Victoria verfasserin aut Gibney, Geoffrey T verfasserin aut Luke, Jason J verfasserin aut Thomas, Sajeve verfasserin aut Buchbinder, Elizabeth I verfasserin aut Healy, Jane A verfasserin aut Huang, Mo verfasserin aut Morrissey, Manju verfasserin aut Feldman, Igor verfasserin aut Sehgal, Vasudha verfasserin aut Robert-Tissot, Celine verfasserin aut Hou, Peijie verfasserin aut Zhu, Lili verfasserin aut Brown, Michelle verfasserin aut Aanur, Praveen verfasserin aut Meehan, Robert S verfasserin aut Zaks, Tal verfasserin aut Enthalten in No title available 403, Seite 632-644 (DE-627)270128484 0140-6736 nnns volume:403 pages:632-644 GBV_USEFLAG_U GBV_ELV SYSFLAG_U GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_213 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 403 632-644 |
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10.1016/S0140-6736(23)02268-7 doi (DE-627)ELV067082866 (ELSEVIER)S0140-6736(23)02268-7 DE-627 ger DE-627 rda eng Weber, Jeffrey S verfasserin aut Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. Carlino, Matteo S verfasserin aut Khattak, Adnan verfasserin aut Meniawy, Tarek verfasserin aut Ansstas, George verfasserin aut Taylor, Matthew H verfasserin aut Kim, Kevin B verfasserin aut McKean, Meredith verfasserin aut Long, Georgina V verfasserin aut Sullivan, Ryan J verfasserin aut Faries, Mark verfasserin aut Tran, Thuy T verfasserin aut Cowey, C Lance verfasserin aut Pecora, Andrew verfasserin aut Shaheen, Montaser verfasserin aut Segar, Jennifer verfasserin aut Medina, Theresa verfasserin aut Atkinson, Victoria verfasserin aut Gibney, Geoffrey T verfasserin aut Luke, Jason J verfasserin aut Thomas, Sajeve verfasserin aut Buchbinder, Elizabeth I verfasserin aut Healy, Jane A verfasserin aut Huang, Mo verfasserin aut Morrissey, Manju verfasserin aut Feldman, Igor verfasserin aut Sehgal, Vasudha verfasserin aut Robert-Tissot, Celine verfasserin aut Hou, Peijie verfasserin aut Zhu, Lili verfasserin aut Brown, Michelle verfasserin aut Aanur, Praveen verfasserin aut Meehan, Robert S verfasserin aut Zaks, Tal verfasserin aut Enthalten in No title available 403, Seite 632-644 (DE-627)270128484 0140-6736 nnns volume:403 pages:632-644 GBV_USEFLAG_U GBV_ELV SYSFLAG_U GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_213 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 403 632-644 |
| allfieldsSound |
10.1016/S0140-6736(23)02268-7 doi (DE-627)ELV067082866 (ELSEVIER)S0140-6736(23)02268-7 DE-627 ger DE-627 rda eng Weber, Jeffrey S verfasserin aut Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. Carlino, Matteo S verfasserin aut Khattak, Adnan verfasserin aut Meniawy, Tarek verfasserin aut Ansstas, George verfasserin aut Taylor, Matthew H verfasserin aut Kim, Kevin B verfasserin aut McKean, Meredith verfasserin aut Long, Georgina V verfasserin aut Sullivan, Ryan J verfasserin aut Faries, Mark verfasserin aut Tran, Thuy T verfasserin aut Cowey, C Lance verfasserin aut Pecora, Andrew verfasserin aut Shaheen, Montaser verfasserin aut Segar, Jennifer verfasserin aut Medina, Theresa verfasserin aut Atkinson, Victoria verfasserin aut Gibney, Geoffrey T verfasserin aut Luke, Jason J verfasserin aut Thomas, Sajeve verfasserin aut Buchbinder, Elizabeth I verfasserin aut Healy, Jane A verfasserin aut Huang, Mo verfasserin aut Morrissey, Manju verfasserin aut Feldman, Igor verfasserin aut Sehgal, Vasudha verfasserin aut Robert-Tissot, Celine verfasserin aut Hou, Peijie verfasserin aut Zhu, Lili verfasserin aut Brown, Michelle verfasserin aut Aanur, Praveen verfasserin aut Meehan, Robert S verfasserin aut Zaks, Tal verfasserin aut Enthalten in No title available 403, Seite 632-644 (DE-627)270128484 0140-6736 nnns volume:403 pages:632-644 GBV_USEFLAG_U GBV_ELV SYSFLAG_U GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_213 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 403 632-644 |
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Weber, Jeffrey S @@aut@@ Carlino, Matteo S @@aut@@ Khattak, Adnan @@aut@@ Meniawy, Tarek @@aut@@ Ansstas, George @@aut@@ Taylor, Matthew H @@aut@@ Kim, Kevin B @@aut@@ McKean, Meredith @@aut@@ Long, Georgina V @@aut@@ Sullivan, Ryan J @@aut@@ Faries, Mark @@aut@@ Tran, Thuy T @@aut@@ Cowey, C Lance @@aut@@ Pecora, Andrew @@aut@@ Shaheen, Montaser @@aut@@ Segar, Jennifer @@aut@@ Medina, Theresa @@aut@@ Atkinson, Victoria @@aut@@ Gibney, Geoffrey T @@aut@@ Luke, Jason J @@aut@@ Thomas, Sajeve @@aut@@ Buchbinder, Elizabeth I @@aut@@ Healy, Jane A @@aut@@ Huang, Mo @@aut@@ Morrissey, Manju @@aut@@ Feldman, Igor @@aut@@ Sehgal, Vasudha @@aut@@ Robert-Tissot, Celine @@aut@@ Hou, Peijie @@aut@@ Zhu, Lili @@aut@@ Brown, Michelle @@aut@@ Aanur, Praveen @@aut@@ Meehan, Robert S @@aut@@ Zaks, Tal @@aut@@ |
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Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. 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Weber, Jeffrey S |
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Weber, Jeffrey S Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study |
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Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study |
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Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study |
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Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study |
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Weber, Jeffrey S Carlino, Matteo S Khattak, Adnan Meniawy, Tarek Ansstas, George Taylor, Matthew H Kim, Kevin B McKean, Meredith Long, Georgina V Sullivan, Ryan J Faries, Mark Tran, Thuy T Cowey, C Lance Pecora, Andrew Shaheen, Montaser Segar, Jennifer Medina, Theresa Atkinson, Victoria Gibney, Geoffrey T Luke, Jason J Thomas, Sajeve Buchbinder, Elizabeth I Healy, Jane A Huang, Mo Morrissey, Manju Feldman, Igor Sehgal, Vasudha Robert-Tissot, Celine Hou, Peijie Zhu, Lili Brown, Michelle Aanur, Praveen Meehan, Robert S Zaks, Tal |
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Weber, Jeffrey S |
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10.1016/S0140-6736(23)02268-7 |
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individualised neoantigen therapy mrna-4157 (v940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (keynote-942): a randomised, phase 2b study |
| title_auth |
Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study |
| abstract |
Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. |
| abstractGer |
Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. |
| abstract_unstemmed |
Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB–IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309–1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0–85·6) versus 62% (46·9–74·3). Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. |
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| title_short |
Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study |
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| author2 |
Carlino, Matteo S Khattak, Adnan Meniawy, Tarek Ansstas, George Taylor, Matthew H Kim, Kevin B McKean, Meredith Long, Georgina V Sullivan, Ryan J Faries, Mark Tran, Thuy T Cowey, C Lance Pecora, Andrew Shaheen, Montaser Segar, Jennifer Medina, Theresa Atkinson, Victoria Gibney, Geoffrey T Luke, Jason J Thomas, Sajeve Buchbinder, Elizabeth I Healy, Jane A Huang, Mo Morrissey, Manju Feldman, Igor Sehgal, Vasudha Robert-Tissot, Celine Hou, Peijie Zhu, Lili Brown, Michelle Aanur, Praveen Meehan, Robert S Zaks, Tal |
| author2Str |
Carlino, Matteo S Khattak, Adnan Meniawy, Tarek Ansstas, George Taylor, Matthew H Kim, Kevin B McKean, Meredith Long, Georgina V Sullivan, Ryan J Faries, Mark Tran, Thuy T Cowey, C Lance Pecora, Andrew Shaheen, Montaser Segar, Jennifer Medina, Theresa Atkinson, Victoria Gibney, Geoffrey T Luke, Jason J Thomas, Sajeve Buchbinder, Elizabeth I Healy, Jane A Huang, Mo Morrissey, Manju Feldman, Igor Sehgal, Vasudha Robert-Tissot, Celine Hou, Peijie Zhu, Lili Brown, Michelle Aanur, Praveen Meehan, Robert S Zaks, Tal |
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270128484 |
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c |
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false |
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false |
| doi_str |
10.1016/S0140-6736(23)02268-7 |
| up_date |
2024-07-06T20:01:49.375Z |
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Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB–IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. 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| score |
7.3987617 |