Predictive biomarkers for hyper-progression (HP) in response to immune checkpoint inhibitors (ICI) – analysis of somatic alterations (SAs)

Singavi, Arun K.; Menon, Sreedevi K.; Kilari, Deepak; Alqwasmi, A.; Ritch, Paul S.; Thomas, James P.; Martin, A. Daniel; Oxencis, Carolyn; Ali, Sayed; George, Ben

doi:10.1093/annonc/mdx376.006

Cited by 67 publications

(73 citation statements)

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“…There are inconsistencies between studies in that some have not shown age or sex to be predictors. Furthermore, although it has been described by several groups including ours , the putative genomic correlates (e.g., MDM2/MDM4 and EGFR alterations) require larger sample size validation and an understanding of potential mechanisms by which these alterations could mediate or facilitate accelerated tumor growth after checkpoint blockade.…”

Section: Criteria For and Predictors Of Hpd According To Different Rementioning

confidence: 91%

“…HPD was associated with lower frequency of effector or memory (CCR7 -CD45RA -) circulating CD8+ T cells, and higher frequency of severely exhausted (TIGIT + PD1 + ) circulating CD8+ T cells Abstract only Singavi et al [12] Progression at first restaging on-treatment with increase in tumor size >50%, more than twofold increase in TGR MDM2/MDM4, EGFR, amplifications on 11q13 (CCND1, FGF3, FGF4, FGF19)…”

Section: Female Gendermentioning

confidence: 99%

“…Matos et al [13] TTF <2 months and minimum increase in measurable lesions of 10 mm plus (A) increase of ≥40% in target tumor burden compared with baseline or (B) increase ≥20% in target tumor burden plus multiple new lesions HPD was not associated with age, tumor type, checkpoint inhibitor regimens, previous checkpoint inhibitor, or metastatic site ours [10,12,19,34], the putative genomic correlates (e.g., MDM2/MDM4 and EGFR alterations) require larger sample size validation and an understanding of potential mechanisms by which these alterations could mediate or facilitate accelerated tumor growth after checkpoint blockade.…”

Section: Female Gendermentioning

confidence: 99%

“…Reactivation occurs because these antibodies interfere with checkpoints such as programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 that have been exploited by tumor cells to evade the immune response, a necessity if the cancer is going to survive [8]. The FDA approvals notwithstanding, there are now multiple groups that have reported that a minority of patients (albeit encompassing diverse cancers) experience a dramatic acceleration in the rate of tumor progression after starting checkpoint blockade-a phenomenon designated hyperprogressive disease (HPD; Table 1) [9][10][11][12][13][14][15][16][17][18][19][20]. Unfortunately, in the patients who are deemed to have HPD, their median overall survival is estimated to be roughly 3 months [21].…”

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confidence: 99%

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Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

et al. 2019

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There are currently seven approved immune checkpoint inhibitors (ICIs) for the treatment of various cancers. These drugs are associated with profound, durable responses in a subset of patients with advanced cancers. Unfortunately, in addition to individuals whose tumors show resistance, there is a minority subgroup treated with ICIs who demonstrate a paradoxical acceleration in the rate of growth or their tumors-hyperprogressive disease. Hyperprogressive disease is associated with significantly worse outcomes in these patients. This phenomenon, though still a matter of dispute, has been recognized by multiple groups of investigators across the globe and in diverse types of cancers.Correspondence: Razelle Kurzrock, M.D.

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Section: Criteria For and Predictors Of Hpd According To Different Rementioning

confidence: 91%

Section: Female Gendermentioning

confidence: 99%

Section: Female Gendermentioning

confidence: 99%

mentioning

confidence: 99%

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Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

et al. 2019

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“…22 To date, accelerated progression after anti–PD-1/PD-L1 agents has been reported by at least four groups. 22–25 Although the mechanisms that mediate this phenomenon remain unclear, we and others have demonstrated that MDM2 family gene amplifications and EGFR alterations correlate with hyperprogression. 22,25 …”

Section: Introductionmentioning

confidence: 97%

Analysis of MDM2 Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Kato

Ross

Gay

et al. 2018

JCO Precision Oncology

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Purpose MDM2 amplification can promote tumorigenesis directly or indirectly through p53 inhibition. MDM2 has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and MDM2 amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti–PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain MDM2 amplification status across a large number of diverse cancers. Methods We interrogated the molecular profiles of 102,878 patients with diverse malignancies for MDM2 amplification and co-altered genes using clinical-grade NGS (182 to 465 genes). Results MDM2 amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with MDM2 amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied MDM2 amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), PI3K signaling (25.4% [926 of 3,650]), TP53 (24.9% [910 of 3,650]), and MAPK signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and PD-L1 amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration–approved or investigational agent. MDM2 amplifications were less frequently associated with high tumor mutation burden compared with the MDM2 wild-type population (2.9% v 6.5%; P < .001). An illustrative patient who harbored MDM2 amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented. Conclusion MDM2 amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have MDM2 amplification as well as pharmacologically tractable co-alterations.

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Clarification of Definitions of Hyperprogressive Disease During Immunotherapy for Non–Small Cell Lung Cancer

et al. 2020

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Question Are the different definitions used to assess hyperprogressive disease during immunotherapy for non-small cell lung cancer representative of the same tumoral behavior? Findings For this multicenter cohort study of 406 patients with advanced non-small cell lung cancer treated with programmed cell death 1/programmed cell death 1 ligand inhibitors, the 5 disease definitions assessed resulted in diverse incidences, different patient characteristics, and different associations with survival outcomes. A new criterion of difference in tumor growth rate of greater than 100 showed more accuracy in assessing hyperprogressive disease. Meaning These findings suggest that the 5 definitions assessed are not representative of the same tumoral behavior.

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Predictive biomarkers for hyper-progression (HP) in response to immune checkpoint inhibitors (ICI) – analysis of somatic alterations (SAs)

Cited by 67 publications

References 0 publications

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

Analysis of MDM2 Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Clarification of Definitions of Hyperprogressive Disease During Immunotherapy for Non–Small Cell Lung Cancer

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