Site-specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti-PD-1 therapy

Ines Pires da Silva; Serigne Lo; Camelia Quek; Maria Gonzalez; Matteo S Carlino; Georgina V Long; Alexander M Menzies

doi:10.1002/cncr.32522

Site-specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti-PD-1 therapy

Cancer. 2020 Jan 1;126(1):86-97. doi: 10.1002/cncr.32522. Epub 2019 Oct 4.

Authors

Ines Pires da Silva^{1

2}, Serigne Lo^{1

2}, Camelia Quek^{1

2}, Maria Gonzalez¹, Matteo S Carlino^{1

3

4}, Georgina V Long^{1

5

6}, Alexander M Menzies^{1

5

6}

Affiliations

¹ Melanoma Institute Australia, Sydney, New South Wales, Australia.
² Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.
³ Western Clinical School, The University of Sydney, Sydney, New South Wales, Australia.
⁴ Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia.
⁵ Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.
⁶ Northern Clinical School, The University of Sydney, Sydney, New South Wales, Australia.

PMID: 31584722
DOI: 10.1002/cncr.32522

Abstract

Background: Patients with metastatic melanoma have variable responses to combination ipilimumab and nivolumab. The objectives of this study were to examine the patterns of response and survival in patients treated with combination ipilimumab and anti-PD-1 therapy (IPI + PD1) and to explore the nature of pseudoprogression and acquired resistance.

Methods: Patients with metastatic melanoma who received treatment with first-line IPI + PD1 had all metastases ≥5 mm measured on computed tomography/magnetic resonance imaging studies. The lesional response rate (LRR) and the overall response rate (ORR) were determined according to Response Evaluation Criteria in Solid Tumors, version 1.1.

Results: In total, 140 patients who had 833 metastases were studied. The ORR and the overall complete response (CR) rate decreased as tumor burden or the number of metastases increased. Metastases that had a CR (49%) were smaller than metastases without a CR (median, 13 vs 17 mm; P < .0001). Soft-tissue and lung metastases had the highest LRR (79% and 77%, respectively), whereas liver metastases had the lowest (46%). In multivariate analysis, patients with lung metastases had superior ORR (odds ratio [OR], 2.75; P = .02) and progression-free survival (hazard ratio [HR], 0.46; P = .02), whereas those with liver metastases had inferior ORR (OR, 0.33; P = .02), progression-free survival (HR, 4.03; P < .01), and overall survival (HR, 3.17; P = .01). Pseudoprogression occurred in one-third of patients who had progressive disease as their best response, with an overall survival that was comparable to that of patients without disease progression. Acquired resistance occurred in 12% of responders after a median of 9.6 months, with an overall survival rate of 83% at 1 year from progression.

Conclusions: Metastases in different anatomical locations display distinct response patterns and also are associated with overall response and survival with combination immunotherapy. Specific sites of disease may hold unique mechanisms of resistance and should allow for more personalized treatment.

Keywords: acquired resistance; immunotherapy; ipilimumab; melanoma; nivolumab; pembrolizumab; pseudoprogression.

Publication types

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

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Immunological / administration & dosage*
Antineoplastic Agents, Immunological / adverse effects
Antineoplastic Combined Chemotherapy Protocols / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Disease Progression
Female
Humans
Ipilimumab / administration & dosage*
Ipilimumab / adverse effects
Male
Melanoma / drug therapy*
Melanoma / immunology
Melanoma / pathology
Middle Aged
Neoplasm Metastasis
Nivolumab / administration & dosage
Nivolumab / adverse effects
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
Programmed Cell Death 1 Receptor / immunology
Progression-Free Survival

Substances

Antineoplastic Agents, Immunological
Ipilimumab
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Nivolumab