Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006

G V Long; A Arance; L Mortier; P Lorigan; C Blank; P Mohr; J Schachter; J-J Grob; M Lotem; M R Middleton; B Neyns; N Steven; A Ribas; E Walpole; M S Carlino; C Lebbe; M Sznol; E Jensen; M A Leiby; N Ibrahim; C Robert

doi:10.1016/j.annonc.2021.10.010

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006

Ann Oncol. 2022 Feb;33(2):204-215. doi: 10.1016/j.annonc.2021.10.010. Epub 2021 Oct 25.

Authors

G V Long¹, A Arance², L Mortier³, P Lorigan⁴, C Blank⁵, P Mohr⁶, J Schachter⁷, J-J Grob⁸, M Lotem⁹, M R Middleton¹⁰, B Neyns¹¹, N Steven¹², A Ribas¹³, E Walpole¹⁴, M S Carlino¹⁵, C Lebbe¹⁶, M Sznol¹⁷, E Jensen¹⁸, M A Leiby¹⁸, N Ibrahim¹⁸, C Robert¹⁹

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine & Health, The University of Sydney, Sydney, Australia; Charles Perkins Centre, The University of Sydney, Sydney, Australia; Royal North Shore and Mater Hospital, Sydney, Australia. Electronic address: [email protected].
² Hospital Clinic de Barcelona and IDIBAPS, Barcelona, Spain.
³ Université Lille, Inserm U1189, Centre Hospitalier Régional Universitaire de Lille, Lille, France.
⁴ Division of Cancer Sciences, University of Manchester, Manchester; Christie NHS Foundation Trust, Manchester, UK.
⁵ Netherlands Cancer Institute, Amsterdam, Netherlands.
⁶ Elbe-Klinikum Buxtehude, Buxtehude, Germany.
⁷ Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center at Tel Hashomer, Ramat Gan, Israel.
⁸ Aix Marseille University, Hôpital de la Timone, Marseille, France.
⁹ Sharett Institute of Oncology, Hadassah Hebrew Medical Center, Jerusalem, Israel.
¹⁰ The Churchill Hospital and The University of Oxford, Oxford, UK.
¹¹ Universitair Ziekenhuis Brussel, Brussels, Belgium.
¹² Queen Elizabeth Hospital, Birmingham, UK.
¹³ David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹⁴ Princess Alexandra Hospital, Brisbane, Australia; University of Queensland, Brisbane, Australia.
¹⁵ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Westmead and Blacktown Hospitals, New South Wales, Australia.
¹⁶ Université de Paris, APHP Hôpital Saint-Louis, Dermatology Department, DMU ICARE, INSERM U-976, France.
¹⁷ Yale Cancer Center, New Haven, CT, USA.
¹⁸ Merck & Co., Inc., Kenilworth, NJ, USA.
¹⁹ Department of Oncology, Service of Dermatology, Gustave Roussy, Villejuif, France; Paris-Saclay University, Orsay, France.

PMID: 34710571
DOI: 10.1016/j.annonc.2021.10.010

Abstract

Background: Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized.

Patients and methods: In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled.

Results: At data cut-off (4 December 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi ± MEKi for 59 (10.6%) [33 received BRAFi + MEKi, 26 BRAFi alone; 37 (62.7%) were BRAFi ± MEKi naïve]. In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% [1 complete response (CR); 17 partial response (PR)]; 79.6% had discontinued pembrolizumab due to progressive disease (PD); median overall survival (OS) was 21.5 months. ORR with subsequent ipilimumab was 15.5%; 11/16 responses (8 CRs; 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi ± MEKi group, ORR with previous pembrolizumab was 13.5% (8 PR); 76.3% had discontinued pembrolizumab due to PD; median OS was 17.9 months. ORR with subsequent BRAFi ± MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi ± MEKi initiation was 12.9 months. ORR for BRAFi ± MEKi-naïve patients who received subsequent BRAFi ± MEKi was 43.2%; 6/16 were ongoing (3 CR, 3 PR).

Conclusions: Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma.

Keywords: BRAF inhibition; MEK inhibition; advanced melanoma; ipilimumab; pembrolizumab.

Publication types

Clinical Trial, Phase III
Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal, Humanized
Humans
Ipilimumab / adverse effects
Melanoma* / pathology
Mitogen-Activated Protein Kinase Kinases / therapeutic use
Proto-Oncogene Proteins B-raf*

Substances

Antibodies, Monoclonal, Humanized
Ipilimumab
pembrolizumab
BRAF protein, human
Proto-Oncogene Proteins B-raf
Mitogen-Activated Protein Kinase Kinases