Oncology researchers around the world are paying keen attention to MDM2 (mouse double minute 2 homolog), a gene involved in the amplification of tumor growth, as patients on an immune checkpoint inhibitor who showed hyperprogression had the gene.
Hyperprogression refers to accelerated tumor growth in cancer patients after treatment with immune checkpoint inhibitors. In some cases, the size of a tumor could increase up to 40 folds in a short period.
Immunotherapies such as Keytruda (pembrolizumab), Opdivo (nivolumab), Tecentriq (atezolizumab) and Imfinzi (durvalumab) have raised anticipation for better efficacy such as higher survival rate in various cancer types. As much as efficacy improved, the ratio of patients with early death because of hyperprogression went up, however, challenging researchers to resolve the issue.
In March, a researcher at UC San Diego Moores Cancer Center said at the meeting of the American Association for Cancer Research that MDM2 amplification was “very strongly correlated with hyperprogression.”
Razelle Kurzrock, MD, of UC San Diego Moores Cancer Center, said she discovered that both two patients in the clinic, who showed hyperprogression, had MDM2 amplification.
“The reason that was a strange coincidence is that MDM2 amplification occurs only in about 4 or 5 percent of patients with cancer,” she said in a video posted by MedPage Today.
Kurzrock said she looked at 155 patients with available data to determine if there was a correlation between hyperprogression and the gene, using multivariate analysis. The result showed that MDM2 amplification was strongly correlated with hyperprogression, she said.
On Friday this week, a study will be presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago on how hyperprogression and MDM2 amplification are correlated.
In a poster session on the theme of “Developmental Immunotherapy and Tumor Immunobiology” on Saturday, the research team of the First Affiliated Hospital of Nanchang University, Nanchang, China, will reveal the outcome of their study, “Association between MDM2/MDM4 amplification and PD-1/PD-L1 inhibitors-related hyperprogressive disease: A pan-cancer analysis.”
According to the abstract of the study disclosed for a preview for ASCO 2019 (Abstract No. 2557), the researchers reviewed extensive clinical trials of PD-1/PD-L1 inhibitors in advanced solid tumor patients updated to January 2019, estimated the incidence of hyperpgrogressive disease (HPD), which was defined as time-to-treatment failure (TTF) less than two months, and more than 50 percent increase in tumor burden compared with pre-immunotherapy imaging.
The researchers obtained the proportions of MDM2/MDM4 amplification across different cancer types from the Cancer Genome Atlas (TCGA) and their database at the hospital.
The analysis included 19 published clinical trials of 1,318 patients treated with PD-1/PD-L1 inhibitors, covering 12 types of solid cancer. The results showed that the incidences of HPD ranged from 1.58 percent in renal clear cell carcinoma to 24.3 percent in sarcoma. Correspondingly, the proportions of MDM2/MDM4 amplification for these cancer types in TCGA were 0.74 percent in renal clear cell carcinoma to 20.38 percent in sarcoma.
“Our results suggest that MDM2/MDM4 amplification may be associated with rapid disease progression in patients receiving PD-1/PD-L1 inhibitors among various tumor types,” the research team said. “The exact mechanisms underlying HPD are needed to be further evaluated.”