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
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. |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Elez, Elena [VerfasserIn] |
---|
Links: |
Volltext [kostenfrei] |
---|
BKL: | |
---|---|
Themen: |
Anmerkungen: |
© The Author(s) 2024 |
---|
doi: |
10.1186/s12885-024-12153-5 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
SPR055482902 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | SPR055482902 | ||
003 | DE-627 | ||
005 | 20240411064703.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240411s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1186/s12885-024-12153-5 |2 doi | |
035 | |a (DE-627)SPR055482902 | ||
035 | |a (SPR)s12885-024-12153-5-e | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
082 | 0 | 4 | |a 610 |q VZ |
084 | |a 44.00 |2 bkl | ||
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 Computermedien |b c |2 rdamedia | ||
338 | |a Online-Ressource |b cr |2 rdacarrier | ||
500 | |a © The Author(s) 2024 | ||
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). 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). | ||
650 | 4 | |a Colorectal cancer |7 (dpeaa)DE-He213 | |
650 | 4 | |a MSS |7 (dpeaa)DE-He213 | |
650 | 4 | |a RAS |7 (dpeaa)DE-He213 | |
650 | 4 | |a MEK1 |7 (dpeaa)DE-He213 | |
650 | 4 | |a Binimetinib |7 (dpeaa)DE-He213 | |
650 | 4 | |a Nivolumab |7 (dpeaa)DE-He213 | |
650 | 4 | |a Ipilimumab |7 (dpeaa)DE-He213 | |
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 BioMed Central, 2001 |g 24(2024), 1 vom: 11. Apr. |w (DE-627)SPR027602656 |w (DE-600)2041352-X |x 1471-2407 |7 nnns |
773 | 1 | 8 | |g volume:24 |g year:2024 |g number:1 |g day:11 |g month:04 |
856 | 4 | 0 | |u https://dx.doi.org/10.1186/s12885-024-12153-5 |m X:VERLAG |x 0 |z kostenfrei |3 Volltext |
912 | |a GBV_SPRINGER | ||
912 | |a SSG-OLC-PHA | ||
936 | b | k | |a 44.00 |q VZ |
951 | |a AR | ||
952 | |d 24 |j 2024 |e 1 |b 11 |c 04 |