Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma
Background Ipilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma. Methods This study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg every 3 weeks for 4 doses (induction), then every 12 weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI. Results All patients who were initially treated with VEM (n = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6 %, 21.7 %, and 4.3 %, respectively. There were no drug-related deaths. At a median follow-up of 15.3 months, median overall survival was 18.5 months. Median progression-free survival was 4.5 months. Conclusions VEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma. Trial registration ClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2016 |
---|---|
Erschienen: |
2016 |
Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
---|---|
Enthalten in: |
Journal for ImmunoTherapy of Cancer - 4(2016), 1 vom: 16. Aug. |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Amin, Asim [VerfasserIn] |
---|
Links: |
Volltext [kostenfrei] |
---|
Themen: |
BRAF inhibitor |
---|
Anmerkungen: |
© The Author(s). 2016 |
---|
doi: |
10.1186/s40425-016-0148-7 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
SPR036434663 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | SPR036434663 | ||
003 | DE-627 | ||
005 | 20230519192137.0 | ||
007 | cr uuu---uuuuu | ||
008 | 201007s2016 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1186/s40425-016-0148-7 |2 doi | |
035 | |a (DE-627)SPR036434663 | ||
035 | |a (SPR)s40425-016-0148-7-e | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Amin, Asim |e verfasserin |4 aut | |
245 | 1 | 0 | |a Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma |
264 | 1 | |c 2016 | |
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). 2016 | ||
520 | |a Background Ipilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma. Methods This study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg every 3 weeks for 4 doses (induction), then every 12 weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI. Results All patients who were initially treated with VEM (n = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6 %, 21.7 %, and 4.3 %, respectively. There were no drug-related deaths. At a median follow-up of 15.3 months, median overall survival was 18.5 months. Median progression-free survival was 4.5 months. Conclusions VEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma. Trial registration ClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012 | ||
650 | 4 | |a Vemurafenib |7 (dpeaa)DE-He213 | |
650 | 4 | |a Ipilimumab |7 (dpeaa)DE-He213 | |
650 | 4 | |a Melanoma |7 (dpeaa)DE-He213 | |
650 | 4 | |a CTLA-4 |7 (dpeaa)DE-He213 | |
650 | 4 | |a Immune checkpoint inhibitor |7 (dpeaa)DE-He213 | |
650 | 4 | |a BRAF inhibitor |7 (dpeaa)DE-He213 | |
650 | 4 | |a Immunotherapy |7 (dpeaa)DE-He213 | |
650 | 4 | |a Targeted agent |7 (dpeaa)DE-He213 | |
700 | 1 | |a Lawson, David H. |4 aut | |
700 | 1 | |a Salama, April K.S. |4 aut | |
700 | 1 | |a Koon, Henry B. |4 aut | |
700 | 1 | |a Guthrie, Troy |4 aut | |
700 | 1 | |a Thomas, Sajeve S. |4 aut | |
700 | 1 | |a O’Day, Steven J. |4 aut | |
700 | 1 | |a Shaheen, Montaser F. |4 aut | |
700 | 1 | |a Zhang, Bin |4 aut | |
700 | 1 | |a Francis, Stephen |4 aut | |
700 | 1 | |a Hodi, F. Stephen |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Journal for ImmunoTherapy of Cancer |d London : BioMed Central, 2013 |g 4(2016), 1 vom: 16. Aug. |w (DE-627)SPR036419966 |w (DE-600)2719863-7 |x 2051-1426 |7 nnns |
773 | 1 | 8 | |g volume:4 |g year:2016 |g number:1 |g day:16 |g month:08 |
856 | 4 | 0 | |u https://dx.doi.org/10.1186/s40425-016-0148-7 |z kostenfrei |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_SPRINGER | ||
912 | |a SSG-OLC-PHA | ||
951 | |a AR | ||
952 | |d 4 |j 2016 |e 1 |b 16 |c 08 |