Kato and colleagues (1) reported 4 cancer patients with metastatic disease, hyperprogression under treatment with anti-PD-1/PD-L1 monotherapy, and a cooccurring MDM2/4 amplification in the cancer cells. They defined hyperprogression as time-to-treatment failure <2 months, >50% increase in tumor burden and >2-fold increase in progression compared with baseline staging before immunotherapy. Hyperprogression under treatment with checkpoint inhibitors is discussed worldwide and occurs in about 9% of the patients, but the underlying mechanisms are not understood (2). The four reported patients suffered from metastatic bladder cancer, breast cancer, endometrial stromal sarcoma, and lung adenocarcinoma (1). We have recently seen the same phenomenon in a patient with BRAF, NRAS, and KIT wild-type (determined by Sanger sequencing of a lymph node metastasis) acral lentiginous melanoma.

The 49-year-old female melanoma patient with axillary, soft tissue, and lung metastases was treated with a combination of ipilimumab and nivolumab every 3 weeks. One month after treatment initiation (two cycles of combined immunotherapy had been carried out), a CT scan showed an extremely fast progression (Fig. 1A). Tumor burden had increased by 246% and additional lung metastases had occurred. Follow-up CT scans 57 days later (after three cycles of ipilimumab and nivolumab) revealed further progression with a total increase in tumor burden of 377% compared with baseline. We initiated whole-exome and transcriptome sequencing within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) molecular stratification registry study of the German Cancer Consortium. While the molecular analysis was ongoing, the patient was treated with the PD-1 antagonist pembrolizumab (2 mg/kg bodyweight). Unfortunately, disease progression was not halted after three cycles of pembrolizumab with multiple new metastases, including extradural parietal tumor manifestations. Treatment was changed to polychemotherapy with carboplatin (AUC 6) and paclitaxel (225 mg/m2 body surface). Molecular analysis revealed a rearranged genome with a highly amplified region on chromosome 8q involving the proto-oncogene MYC (14 copies) and with a focal amplification on chromosome 12q, including the MDM2 locus (7 copies). Amplification of MDM2 in our patient was confirmed by chromogene in situ hybridization (CISH) of formalin-fixed tumor tissue (Fig. 1B and C). The MDM2 amplification provides an explanation for why this patient had not responded to immunotherapy. However, there is no definitive evidence that progression was accelerated compared with the natural course of the disease. MDM2 and MDM4 are inhibitors of the tumor suppressor TP53 (3), and MDM2/4 can be overexpressed in cells with such amplifications after interferon-induced JAK–STAT activation by IRF8 (4, 5). Our clinical observations indicate that amplifications of MDM family members could represent a mechanism of resistance toward anti-PD-1/PD-L1 therapies across different cancer entities. It might be useful to systematically assess the MDM2 and MDM4 copy number status and/or expression in patients eligible for anti-PD-1/PD-L1 therapy to identify patients that are unlikely to benefit from it. Therefore, more clinical and experimental data are needed to elucidate the role of MDM2 family members in the context of immunotherapy.

Figure 1.

Hyperprogressive disease of a melanoma patient. A, CT scans of progredient soft tissue metastasis (top row) and lung metastasis (bottom row) document the rapid tumor progression after initiation of an anti-PD-1/anti-CTLA4 immunotherapy (yellow arrows point to the target lesions in purple). B, CISH (ZytoDot 2C SPEC MDM2/CEN 12; ZytoVision) of the tumor biopsy used for the NGS analysis confirmed the amplification of MDM2. C, Molecular analysis revealed a rearranged genome that contains a highly amplified region (14 copies) on chromosome 8q that includes the proto-oncogene MYC and a focal amplification (7 copies) on chromosome 12q that includes the MDM2 locus.

Figure 1.

Hyperprogressive disease of a melanoma patient. A, CT scans of progredient soft tissue metastasis (top row) and lung metastasis (bottom row) document the rapid tumor progression after initiation of an anti-PD-1/anti-CTLA4 immunotherapy (yellow arrows point to the target lesions in purple). B, CISH (ZytoDot 2C SPEC MDM2/CEN 12; ZytoVision) of the tumor biopsy used for the NGS analysis confirmed the amplification of MDM2. C, Molecular analysis revealed a rearranged genome that contains a highly amplified region (14 copies) on chromosome 8q that includes the proto-oncogene MYC and a focal amplification (7 copies) on chromosome 12q that includes the MDM2 locus.

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See the Response, p. 6376

A. Forschner is a consultant/advisory board member for Novartis and Roche and has received expert testimony from BMS, MSD, Novartis, and Roche. A. Stenzinger has received speakers bureau honoraria from AstraZeneca and Novartis and is a consultant/advisory board member for AstraZeneca, Novartis, and Thermo Fisher. C. Garbe reports receiving a commercial research grant from BMS, reports receiving other commercial research support from Amgen, BMS, MSD, Novartis, and Roche, and is a consultant/advisory board member for Amgen, BMS, MSD, Novartis, Philogen, and Roche. No potential conflicts of interest were disclosed by the other authors.

1.
Kato
S
,
Goodman
AM
,
Walavalkar
V
,
Barkauskas
DA
,
Sharabi
A
,
Kurzrock
R
. 
Hyper-progressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate
.
Clin Cancer Res
2017
;
23
:
4242
50
.
2.
Champiat
S
,
Dercle
L
,
Ammari
S
,
Massard
C
,
Hollebecque
A
,
Postel-Vinay
S
, et al
Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1
.
Clin Cancer Res
2017
;
23
:
1920
8
.
3.
Wade
M
,
Li
YC
,
Wahl
GM
. 
MDM2, MDMX and p53 in oncogenesis and cancer therapy
.
Nat Rev Cancer
2013
;
13
:
83
96
.
4.
Schindler
C
,
Levy
DE
,
Decker
T
. 
JAK-STAT signaling: from interferons to cytokines
.
J Biol Chem
2007
;
282
:
20059
63
.
5.
Zhou
JX
,
Lee
CH
,
Qi
CF
,
Wang
H
,
Naghashfar
Z
,
Abbasi
S
, et al
IFN regulatory factor 8 regulates MDM2 in germinal center B cells
.
J Immunol
2009
;
183
:
3188
94
.