NEW YORK – As immunotherapies move into frontline treatment for some endometrial cancer patients, researchers are searching for biomarkers to better select treatment options for patients who progress after initial treatments with immunotherapy or chemotherapy, where fewer treatment options exist.
Research published in the Journal for ImmunoTherapy of Cancer last month examined biomarkers of response and resistance to treatment of recurrent endometrial cancer with Bristol Myers Squibb's immunotherapy Opdivo (nivolumab) and Exelixis' VEGF inhibitor Cabometyx (cabozantinib). The researchers analyzed samples from 75 patients in a Phase II study evaluating Opdivo monotherapy or Opdivo plus Cabometyx.
Recently, immunotherapies have gained approval for the frontline treatment of endometrial cancer, including GlaxoSmithKline's Jemperli (dostarlimab) with chemo for mismatch repair deficient (dMMR) primary advanced or recurrent endometrial cancer and Merck's Keytruda (pembrolizumab) with chemo for primary advanced or recurrent endometrial carcinoma regardless of mismatch repair status.
However, the researchers noted that later-line treatment of this disease after exposure to immunotherapy and platinum-based chemo remains a challenge.
"Recently they've approved immunotherapy as the first-line treatment, but what happens once some patients unfortunately recur after this treatment, or don't even respond in the first place?" said Sacha Gnjatic, codirector of the Human Immune Monitoring Center at Mount Sinai and co-senior author of the study. "This is an interesting setting because this is probably what is going to be most relevant in years to come [with the frontline immunotherapy approvals], because that's probably where we could see if we can rescue patients who didn't respond [to immunotherapy]."
The research by Gnjatic and colleagues was supported by the National Cancer Institute's Cancer Immune Monitoring and Analysis Centers (CIMAC) and Cancer Immunologic Data Center (CIDC) network. The network supports correlative studies in clinical trials using standardized assays to discover biomarkers that help guide immunotherapy treatment. To date, the CIMAC-CIDC network has collaborated with more than 35 clinical trials across tumor types to analyze biomarkers to optimize immunotherapy, according to Gnjatic.
The initial Phase II trial that evaluated whether the addition of Cabometyx to Opdivo could improve outcomes for this subset of patients found that patients who received the combination regimen had longer progression-free survival, 5.3 months for the combination versus 1.9 months for Opdivo alone.
Once the trial was completed, Gnjatic's team analyzed the blood samples collected in the study at baseline, at two points during treatment, and at progression using four assays: Olink's targeted proteomic assay, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing.
They analyzed the biomarkers identified by each of these assays against response and survival outcomes along with the rate of adverse events and markers associated with the treatments' mechanism of action.
They found that the Olink assay, which measures cytokine markers associated with immune response, was the most informative test in this setting. They found that patients with certain elevated levels at baseline of two proteins associated with macrophage activity, CCL23 and CSF1, had worse survival outcomes on the Opdivo-Cabometyx combination than those with low levels of these proteins.
Gnjatic said macrophage activity has been previously associated with dampening of immune response, suggesting that "the signal from the macrophage is probably detrimental to the [combination] treatment," he said.
They also found that protein markers of immune T-cell activation, such as the CD28 and ICOSLG proteins, were elevated in patients who experienced longer survival on the combination treatment.
"There's this balance between the negative signals from the macrophage activity and positive signals from the T cells that we can detect in blood, which is very convenient," Gnjatic said. "All this was measured before treatment, so this is potentially a preexisting signature that's there [at baseline] in patients who have a better chance of responding."
If these findings are confirmed, they could also be used to guide future treatment approaches. One potential approach is using neoantigen cancer vaccines to boost the immune T-cell environment for patients with low levels of these biomarkers, Gnjatic continued.
Gnjatic and his team are continuing their research to validate these biomarkers. The Phase II Opdivo-Cabometyx trial also collected tumor tissue samples, which the researchers are analyzing to confirm the activity of the macrophage-associated and immune-associated proteins identified in the blood samples at the tumor site. They also hope to integrate this proteomic assay into future clinical trials of immunotherapies in recurrent endometrial cancer to confirm the findings prospectively.
Though the Olink assay, which measures 92 proteins, is not routinely used, Gnjatic said the biomarkers identified in this trial could be packaged into a smaller panel to be ordered from labs in in routine practice.
The CIMAC network aims to produce biomarker research that is consistent and reproducible across different institutions. The network uses the same assays for this research across all four institutions in CIMAC and standardizes them annually to ensure the results are consistent.
"The eventual goal of identifying all these biomarkers is to bring it down to something that the clinician can just order [in the clinic]," Gnjatic said.