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| 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. | ||||||||||||
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| 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. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| 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: 38538867, PMID: 29979965), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Mar 2025). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| 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 | 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 | 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 |
| 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 |