Large phase III study of carbo/taxol+pembro x 6 followed by pembro alone x 14 cycles in metastatic endometrial cancer. There was a benefit in both pMMR and dMMR patients, although the magnitude was unsurprisingly higher in those with dMMR. OS results are still pending, and carcinosarcoma-type histology was excluded. This combination has been approved and is on NCCN as a cat-1 recommendation.
TP53 Sequencing and p53 Immunohistochemistry Predict Outcomes When Bevacizumab Is Added to Frontline Chemotherapy in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study
The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with TP53 NGS, predicts the outcome.
From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and TP53 NGS data. An analysis was designed to integrate p53 expression by IHC with the presence or absence of a TP53 mutation. These variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy plus bevacizumab arms versus the chemotherapy plus temsirolimus arm.
In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with TP53 missense mutations and p53 protein overexpression had a similar treatment effect on PFS (HR: 0.41, 95% CI, 0.22 to 0.83) and OS (HR: 0.28, 95% CI, 0.14 to 0.59) favoring bevacizumab plus chemotherapy relative to temsirolimus plus chemotherapy. Concordance between TP53 NGS and p53 IHC was 88%. Concordance was 92% when cases with TP53 mutations and POLE mutations or mismatch repair deficiency were removed.
IHC for p53 alone or when integrated with sequencing for TP53 identifies a specific, high-risk tumor genotype/phenotype for which bevacizumab is particularly beneficial in improving outcomes when combined with chemotherapy.
Author Affiliations1Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA; 2NRG Oncology, Clinical Trial Development Division, Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY; 3Washington University School of Medicine, Siteman Cancer Center, St Louis, MO; 4Stephenson Cancer Center, Gynecologic Cancers Clinic, University of Oklahoma Health Sciences Center, Oklahoma City, OK; 5Duke University Institute, Duke University Health System, Durham, NC; 6University of California Irvine Medical Center, Irvine, CA; 7Women and Infants Hospital in Rhode Island/The Warren Alpert Medical School of Brown University, Providence, RI; 8Ohio State University Medical Center, James Cancer Hospital and Solove Research Institute, Obstetrics and Gynecology, Columbus, OH; 9Rush University Medical Center, Gynecology, Chicago, IL; 10Memorial Sloan Kettering Cancer and Weill Cornell Medical Center, New York, NY; 11Biopathology Center, The Research Institute at Nationwide Children’s Hospital, Columbus, OH; 12The University of New Mexico Health Sciences Center, Albuquerque, NM
Chemo + IO may become the SOC for 1L treatment of met-endometrial adenoCa. For pembro + chemo, there was a 70% lower risk of disease progression in dMMR and a 46% lower risk in pMMR compared to placebo + chemo. For pMMR patients, the impact on 2L therapy responses will need to be considered carefully, as lenvantinib + pembro has been found to be superior to either agent alone after chemo.
Chemo + IO may become the SOC for 1L treatment of met-endometrial adenoCa. For dostarlimab + chemo, there was an OS at 24 months of 83 vs. 58% in the dMMR and 67% vs. 55% in the pMMR groups compared to placebo + chemo. The question remains if chemo + IO is superior to IO alone in dMMR patients.
Another win for combined target-IO Rx with meaningful OS difference and reasonable/expected tolerability.