Speakers presented study data that explored the use of biomarkers to identify subgroups of patients who may respond best to novel combination therapies during the American Association for Cancer Research Annual Meeting 2024.

The clinical trials plenary session Biomarkers: Quantifying Pharmacodynamic Modulation on Tuesday, April 9, was chaired by Nilofer S. Azad, MD, professor of oncology at Johns Hopkins University, and Ryan J. Sullivan, MD, director of the Center for Melanoma at Massachusetts General Hospital. Registered Annual Meeting attendees can watch a recording of the full session on demand through July 10, 2024, on the virtual meeting platform.

Entinostat in combination with nivolumab in patients with advanced pancreatic ductal adenocarcinoma (PDA)

Marina Baretti, MD, assistant professor of oncology at Johns Hopkins University, presented results from a single-center, open-label, phase II study of the histone deacetylase (HDAC) inhibitor entinostat in combination with the programmed cell death protein 1 (PD-1) inhibitor nivolumab in patients with advanced PDA.

“The majority of patients present with advanced-stage disease at the time of diagnosis with a dismal overall prognosis that has remained virtually unchanged for many decades,” Baretti said. She added that the immune suppressive PDA microenvironment has historically rendered most immunotherapies, including PD-1 inhibitors, ineffective.

Preclinical studies demonstrated that HDAC inhibitors could modulate the PDA tumor microenvironment, converting PDA from a T-cell-excluding cancer type into a T-cell permissive one. Based on these results, researchers launched a phase II clinical trial to assess the efficacy of entinostat plus nivolumab in patients with advanced PDA.

Entinostat and nivolumab did not meet the prespecified threshold of success. However, treatment with entinostat and nivolumab demonstrated durable radiological responses in a subset of patients with PDA. Further, entinostat treatment favorably reprogrammed the tumor-associated myeloid cells population toward a less immunosuppressive phenotype and promoted dendritic cell maturation within the tumor. This study can be used as a roadmap for future trials of combinatorial therapy to enhance efficacy in PDA patients, Baretti said.

EGFR mutated (EGFRm) dynamics in patients with EGFRm advanced non-small cell lung cancer (NSCLC) treated with osimertinib and platinum-pemetrexed

Pasi A. Jänne, MD, PhD, FAACR, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, presented an exploratory analysis of plasma EGFRm dynamics to identify patients who may benefit from osimertinib and platinum-pemetrexed.

“EGFRm lung cancer represents about 15% to 50% of newly diagnosed patients with advanced non-small cell lung cancer,” Jänne said.

Based on findings from the FLAURA trial, osimertinib monotherapy is the preferred first-line treatment for EGFRm advanced non-small cell lung cancer (NSCLC). In the FLAURA2 trial, osimertinib plus platinum-pemetrexed chemotherapy significantly improved progression-free survival (PFS) in patients with EGFRm NSCLC compared to osimertinib alone.

Results from FLAURA2 supported findings from previous studies that baseline EGFRm detected in plasma was associated with worse outcomes. Further, patients with baseline EGFRm had improved PFS with osimertinib plus chemotherapy but not with osimertinib alone. Clearance of EGFRm was prognostic but not predictive of benefit with osimertinib plus chemotherapy versus osimertinib alone.

TMPRSS2-ERG and RB1 as candidate predictive biomarkers for efficacy in patients treated with talazoparib plus enzalutamide

Josep M. Piulats, MD, PhD, medical oncologist at the Catalan Institute of Oncology- Bellvitge Biomedical Research Institute in Spain, presented results from a post-hoc analysis of a TALAPRO-2 dataset of prospectively collected/retrospectively analyzed plasma circulating tumor DNA (ctDNA).

Because treatment with an androgen receptor inhibitor, such as enzalutamide, may boost cancer cells’ reliance on DNA damage repair via poly (ADP-ribose) polymerase (PARP), researchers hypothesized that combining enzalutamide with the PARP inhibitor talazoparib may boost efficacy, Piulats said. TALAPRO-2 was a phase III study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). Results demonstrated that treatment with talazoparib plus enzalutamide improved efficacy outcomes.

While researchers have known for some time that homologous recombination repair (HRR) deficiencies are associated with improved response to PARP inhibitors, they observed that some patients without alterations in 12 canonical HRR genes (HRR12) responded as well. “For this analysis, we wanted to identify non-HRR12 gene alterations that might be associated with clinical benefit from the combination of talazoparib plus enzalutamide,” Piulats said.

The analysis identified TMPRSS2-ERG fusions and RB1 mutations as potential predictive biomarkers of response to talazoparib plus enzalutamide. PARP inhibitors may induce a synthetically lethal interaction with TMPRSS2-ERG-mediated inhibition of non-homologous end joining and help overcome enzalutamide resistance mediated by mutations in RB1.

Biological mechanisms underlying objective responses in recurrent glioblastoma patients treated with sequential bortezomib (BTZ) and temozolomide (TMZ)

Mohummad Aminur Rahman, PhD, researcher at the University of Bergen in Norway, presented results from an interim analysis of the phase Ib/II clinical trial BORTEM17.

“Glioblastoma is the most frequent malignant brain tumor in adults,” Rahman said. With current treatments, median survival is only 15 months, largely due to TMZ resistance mediated by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), he added.

Preclinical studies showed that the proteasome inhibitor BTZ, administered prior to TMZ, depleted MGMT, shrunk tumors, crossed the blood-brain barrier, and prolonged animal survival. Treatment with BTZ and TMZ in patients with recurrent glioblastoma was safe and effective.

Rahman and colleagues sought to identify biomarkers of response to BTZ plus TMZ and found EGFR amplification in three of four patients with objective responses. Further, treatment with BTZ and TMZ increased immune response and tumor cell death in these responders. Rahman and colleagues hypothesized that EGFR amplification activates downstream nuclear factor kappa B (NFκB) signaling, leading to the inhibition of MGMT protein expression, which increases TMZ sensitivity in tumor cells.