Reference Detail

Ref Type

Journal Article

PMID

(28351930)

Authors

Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R

Title

Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	15	2017 Aug 01	4242-4250	Clin Cancer Res

URL

Abstract Text

Purpose: Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be "hyperprogressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with "hyperprogression" after immunotherapy.Experimental Design: Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N = 155). We defined hyperprogression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace.Results: Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared with the 2 months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF <2 months. Two of 10 patients with EGFR alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase).Conclusions: Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed. Clin Cancer Res; 23(15); 4242-50. ©2017 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
TP53	S127Y	missense	unknown	TP53 S127Y lies within the DNA-binding domain of the Tp53 protein (PMID: 21760703). S127Y has been identified in the scientific literature (PMID: 28351930, PMID: 23967324, PMID: 29979965), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Feb 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MDM2 amp	Advanced Solid Tumor	no benefit	N/A	Clinical Study	Emerging	In a clinical study, 100% (5/5) of solid tumor patients harboring MDM2 amplification experienced disease progression within 2 months of anti-PD1/PD-L1 monotherapy, indicating a risk for hyperprogression on immunotherapy (PMID: 28351930).	28351930
MDM2 amp	urinary bladder cancer	no benefit	Atezolizumab	Case Reports/Case Series	Actionable	In a clinical case study, a patient with metastatic bladder cancer that harbored MDM2 amplification and other mutations quickly progressed after receiving Tecentriq (atezolizumab), resulting in new liver metastasis and a 258% increase of existing liver metastasis size 1.9 months after treatment (PMID: 28351930).	28351930
MDM2 amp	endometrial stromal sarcoma	no benefit	Nivolumab	Case Reports/Case Series	Actionable	In a clinical case study, a patient with endometrial stromal sarcoma that harbored MDM2 amplification quickly progressed after receiving Opdivo (nivolumab), resulted in new abdominal metastasis and a 242% increase of existing liver metastasis size within 1.5 months of treatment (PMID: 28351930).	28351930
MDM2 amp	triple-receptor negative breast cancer	no benefit	Pembrolizumab	Case Reports/Case Series	Actionable	In a clinical case study, a patient with triple-receptor negative breast cancer that harbored MDM2 amplification quickly progressed after receiving Keytruda (pembrolizumab), resulted in new chest wall metastasis and a 55% increase of existing lung metastasis size 1.5 months after treatment (PMID: 28351930).	28351930