Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study
© 2024. The Author(s)..
BACKGROUND: In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4).
METHODS: In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations.
RESULTS: In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs.
CONCLUSIONS: The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC.
TRIAL REGISTRATION: NCT03271047 (09/01/2017).
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
|---|---|
| Enthalten in: |
BMC cancer - 24(2024), 1 vom: 11. Apr., Seite 446 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Elez, Elena [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 12.04.2024 Date Revised 25.04.2024 published: Electronic ClinicalTrials.gov: NCT03271047 Citation Status MEDLINE |
|---|
| doi: |
10.1186/s12885-024-12153-5 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM37089796X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM37089796X | ||
| 003 | DE-627 | ||
| 005 | 20240425233758.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240411s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1186/s12885-024-12153-5 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1386.xml |
| 035 | |a (DE-627)NLM37089796X | ||
| 035 | |a (NLM)38600471 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Elez, Elena |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.04.2024 | ||
| 500 | |a Date Revised 25.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03271047 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a BACKGROUND: In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4) | ||
| 520 | |a METHODS: In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations | ||
| 520 | |a RESULTS: In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs | ||
| 520 | |a CONCLUSIONS: The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC | ||
| 520 | |a TRIAL REGISTRATION: NCT03271047 (09/01/2017) | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Binimetinib | |
| 650 | 4 | |a Colorectal cancer | |
| 650 | 4 | |a Ipilimumab | |
| 650 | 4 | |a MEK1 | |
| 650 | 4 | |a MSS | |
| 650 | 4 | |a Nivolumab | |
| 650 | 4 | |a RAS | |
| 650 | 7 | |a Nivolumab |2 NLM | |
| 650 | 7 | |a 31YO63LBSN |2 NLM | |
| 650 | 7 | |a Ipilimumab |2 NLM | |
| 650 | 7 | |a binimetinib |2 NLM | |
| 650 | 7 | |a 181R97MR71 |2 NLM | |
| 650 | 7 | |a Benzimidazoles |2 NLM | |
| 700 | 1 | |a Cubillo, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Alfonso, Pilar Garcia |e verfasserin |4 aut | |
| 700 | 1 | |a Middleton, Mark R |e verfasserin |4 aut | |
| 700 | 1 | |a Chau, Ian |e verfasserin |4 aut | |
| 700 | 1 | |a Alkuzweny, Baha |e verfasserin |4 aut | |
| 700 | 1 | |a Alcasid, Ann |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaosong |e verfasserin |4 aut | |
| 700 | 1 | |a Van Cutsem, Eric |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t BMC cancer |d 2001 |g 24(2024), 1 vom: 11. Apr., Seite 446 |w (DE-627)NLM111431948 |x 1471-2407 |7 nnns |
| 773 | 1 | 8 | |g volume:24 |g year:2024 |g number:1 |g day:11 |g month:04 |g pages:446 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1186/s12885-024-12153-5 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 24 |j 2024 |e 1 |b 11 |c 04 |h 446 | ||