NEW YORK – Jounce Therapeutics said on Thursday that it identified a new predictive biomarker that can be used to select lung cancer patients for the firm's upcoming Phase II trial evaluating vopratelimab and Jounce's investigational PD-1 inhibitor JTX-4014.
The trial will look at vopratelimab and JTX-4014 in second-line non-small cell lung cancer patients who have not had immunotherapy and will evaluate whether an RNA tumor inflammation signature, dubbed TISvopra, can predict response. Jounce estimates that 20 percent of prescreened NSCLC patients will be TISvopra positive. The team chose to zero in on the NSCLC subgroup based on earlier data, which confirmed this was a well-defined population with a history of responding well to immunotherapy.
The Phase II trial is expected to start in mid-2020 and will enroll up to 75 patients. It will compare the efficacy of vopratelimab and JTX-4014 versus JTX-4014 alone.
"[Immuno-oncology therapy] is bringing very strong benefit to some cancer patients, [but] not all. If you are one of the cancer patients responding, there's a good chance you're going to get substantial long-term benefits," said Jounce CEO Rich Murray. Drugmakers working in the immuno-oncology space have been hunting for ways to home in on that population of patients who are likely to see durable benefit and are testing out combination therapeutic strategies to increase the proportion of patients who derive long-term benefits.
This is also very much the focus at Jounce. In the previously conducted Phase I/II ICONIC trial, Jounce assessed vopratelimab, an investigational ICOS agonist antibody, as a monotherapy and in combination with nivolumab (Bristol Myers-Squibb's Opdivo) in heavily pretreated patients with advanced solid tumors. ICOS is a costimulatory molecule upregulated on activated T cells, and when vopratelimab binds to it, it results in activation and proliferation of CD4 T cells, since CD4 T cells have much higher levels of ICOS on the cell surface.
Jounce set up an analysis that ran adjacent to the trial where patients can opt in to have their blood sample and tumor biopsies further studied. From the blood sample analysis is where the team found the pharmacodynamic biomarker of the ICOS high CD4 T cells that ultimately led them to the predictive RNA signature. The data was presented last week at the 2020 American Society of Clinical Oncology-Society for Immunotherapy of Cancer's Clinical Immuno-Oncology Symposium.
Jounce found that patients who had CD4 T cells with upregulated levels of ICOS derived the most benefit from vopratelimab treatment. They tended to have on average greater tumor shrinkage, and longer overall survival and progression-free survival, whether they received vopratelimab monotherapy or the vopratelimab/nivolumab combination.
Notably, the ICOS high CD4 T Cell population was not detected at baseline, but emerged as the patients were being treated. So, the team then went back to the baseline tumor samples and used a mix of technologies to look at various factors like tumor mutation burden, cancer-linked gene mutations within the tumors, and T cell functions, and investigated genes that contained elements of or was related to CD4 T cell biology. Ultimately, investigators concluded that ICOS high CD4 T cell emergence was associated with vopratelimab, not nivolumab.
The ICOS high CD4 T cell biomarker was identified based on analyzing multiple samples and responses from around 45 patients in the Phase I/II trial. Jounce then looked to relate that biomarker to an RNA signature that investigators from NanoString Technologies previously described in the Journal of ImmunoTherapy of Cancer. In that paper, Cesano et al. described using an 18-gene expression signature to try to identify tumor profiles within The Cancer Genome Atlas with adaptive immune responses that may be suppressed. That biomarker, which Jounce now refers to as TISvopra, factors in the activity of genes that are connected to CD4 T cell activation, antigen presentation, lymphocyte and monocyte abundance, and immune cell activity, all of which the team claims contribute to a more comprehensive immune response in patients.
"[TISvopra] is based off of our Tumor Inflammation Signature that was developed during our partnership with Merck," a NanoString spokesperson said over email. NanoString and Merck had inked a 2015 partnership to validate this immune-related 18-gene expression signature and Merck even evaluated its use within trials for pembrolizumab (Keytruda). However, the drugmaker ultimately determined that TIS was not needed to select which patients should receive Keytruda, which ended up being approved in a tissue-agnostic indication for cancer patients with microsatellite instability and mismatch repair deficiency.
The Merck collaboration around TIS ended, but Jounce has been a NanoString customer for a number of years and have utilized some of its immuno-oncology offerings. Jounce is not exploring TIS for predicting response to a checkpoint inhibitor, but for identifying patients who are likely to have ICOS high CD4 T cells after receiving vopratelimab. "Jounce identified a novel cutoff that is a predictive biomarker for the emergence of ICOS high/CD4 T-cells," the NanoString spokesperson said.
Murray said that the cut point Jounce ultimately settled on for TISvopra from the Phase I/II study with an 89 percent positive predictive value and 78 percent negative predictive value for the emergence of ICOS high CD4 T cells will be applied in the Phase II trial.
Jounce is collaborating with NanoString, which will test samples from patients enrolled in the Phase II trial for the TISvopra biomarker using its nCounter Dx Analysis System.
Murray added that the partnership with NanoString also offers potential for the development of a companion diagnostic down the line.