Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.

Abstract

BACKGROUND:

Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).

METHODS:

This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.

FINDINGS:

We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.

INTERPRETATION:

In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma.

FUNDING:

None.

• Authors: Ines Pires da Silva, Tasnia Ahmed, Irene L M Reijers, Alison M Weppler, Allison Betof Warner, James Randall Patrinely, Patricio Serra-Bellver, Clara Allayous, Joanna Mangana, Khang Nguyen, Lisa Zimmer, Claudia Trojaniello, Dan Stout, Megan Lyle, Oliver Klein, Camille L Gerard, Olivier Michielin, Andrew Haydon, Paolo A Ascierto, Matteo S Carlino, Celeste Lebbe, Paul Lorigan, Douglas B Johnson, Shahneen Sandhu, Serigne N Lo, Christian U Blank, Alexander M Menzies, Georgina V Long
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 22 Issue 6 Pg. 836-847 (06 2021) ISSN: 1474-5488 [Electronic] England
• PMID: 33989557 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Immune Checkpoint Inhibitors
• Ipilimumab
• Programmed Cell Death 1 Receptor
• Nivolumab
• pembrolizumab

Topics

• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• Cohort Studies
• Drug Resistance, Neoplasm (genetics, immunology)
• Female
• Humans
• Immune Checkpoint Inhibitors (administration & dosage, adverse effects)
• Ipilimumab (administration & dosage, adverse effects)
• Male
• Melanoma (drug therapy, genetics, immunology, pathology)
• Middle Aged
• Neoplasm Metastasis
• Nivolumab (administration & dosage, adverse effects)
• Positron Emission Tomography Computed Tomography
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, genetics)
• Progression-Free Survival
• Retrospective Studies