ICOS Agonist Development Points to More Biomarkers

Timothy A. Yap, MD, PhD

Professor, Department of Investigational Cancer Therapeutics (Phase I Program); Department of Thoracic/Head and Neck

Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX

Even as newer immune checkpoint inhibitors (ICIs) such as anti-LAG-3 and anti-TIGIT emerge as promising targets, resistance to ICIs remains a clinical challenge. The search continues for unique single and combination agents used with anti–PD-1/ PD-L1 approaches. One such class of agents is the anti–inducible T-cell costimulator (ICOS) agonists, which are activating costimulatory immune checkpoints expressed on T cells. Its ligand, ICOSL, is expressed on antigen-presenting cells and somatic cells, making the ICOS/ICOSL pathway a favorable target for antitumor immune responses.¹

“There was good clinical rationale from different research groups that showed expression of various transcription factors and subsequent T-cell proliferation,” Timothy A. Yap, MD, PhD, associate professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, said in an interview with Targeted Therapies in Oncology.

“Signaling through the [ICOS/ICOSL] pathway may regulate costimulatory activity, and may aid in overcoming resistance to PD-1 mediator T-cell exhaustion.”

ICONIC Trial

Yap was the lead investigator for the ICONIC trial (NCT02904226), a 4-part, first-in-human phase 1/2 trial that evaluated ICOS agonist, vopratelimab, as a single agent or in combination with nivolumab (Opdivo) in patients with advanced solid tumors that enrolled 201 patients.²

In the phase 1 portion of the trial, patients received escalating doses of vopratelimab either alone or in combination. Primary end points were safety, tolerability, and recommended phase 2 dose (RP2D). Phase 1 was designed as a 3 + 3 dose escalation, with doses ranging from 0.003 mg/kg to 1.0 mg/kg as monotherapy (part A) or in combination with fixed-dose nivolumab (240 mg every 3 weeks; part B). Expansion cohorts were included in parts A and B.

In the phase 2 portion of the trial, vopratelimab efficacy, both alone and in combination, was determined for specific tumors. Preclinical data had suggested a high ICOS immunohistochemistry (IHC) score would lead to optimal clinical benefit to an ICOS agonist. In ICONIC, tumor types were based on ICOS expression.

Part C evaluated vopratelimab in patients with head and neck squamous cell carcinoma (HNSCC) and non–small cell lung cancer (NSCLC) who had been previously treated with a PD-L1 inhibitor, patients with gastric or gastroesophageal junction cancer who were PD-L1 inhibitor naïve, patients with triple-negative breast cancer (TNBC) and other advanced tumors. Combination therapy with vopratelimab and nivolumab (Part D) evaluated patients with HNSCC and NSCLC who had been treated with a PD-L1 inhibitor, were PD-1/PD-L1 inhibitor naïve, and who experienced TNBC and gastric or gastroesophageal junction cancer.

Lawrence Fong, MD

Efim Guzik Distinguished Professor in Cancer Biology

Codirector

Parker Institute for Cancer Immunotherapy

University of California San Francisco

Coleader

Cancer Immunology Program

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, CA

The trial was enriched for patients with ICOS-positive tumors and patients received single-agent vopratelimab at RP2D or in combination with nivolumab. Secondary end points were pharmacokinetics, pharmacodynamics, and predictive biomarkers to response.

Findings demonstrated that vopratelimab alone and in combination was well tolerated, and phase 1 established the 0.3 mg/kg dose every 3 weeks as the RP2D for the ICOS agonist. Investigators reported an objective response rate of 1.4% alone and 2.3% with nivolumab. Further, ICOS-positive tumors did not enrich for responses. ICOS-high CD4 T cells was established as a vopratelimab- specific peripheral blood biomarker, according to investigators.

Yap said the response rate was modest in unselected patients, that is, in patients without known molecular biomarkers to predict for response to vopratelimab. “In terms of collecting tumor specimens, both pretreatment and on treatment, we collected blood specimens sequentially in all patients and interestingly we identified a vopratelimab-specific blood biomarker in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells. We then also identified a potential predictive biomarker of response to vopratelimab alone and with a PD-1 inhibitor, comprising an RNA-based tumor inflammation signature with a specific threshold,” Yap said.

As a result, the manufacturer of vopratelimab developed a genomic predictive biomarker that identified patients who would develop these ICOS-high CD4 T cells on treatment, which led to a predictive biomarker assay to be evaluated in a randomized phase 2 trial in patients with NSCLC (SELECT, NCT04549025).³ However, the SELECT trial of vopratelimab (JTX-2011) plus pimivalimab (JTX-4014) vs pimivalimab alone did not meet its primary end point of mean tumor change in patients with metastatic non–small cell lung cancer (NSCLC) who are PD-1/PD-L1 inhibitor naïve and have progressed on a platinum-based chemotherapy regimen.⁴

Although the trial demonstrated the agent’s low rate of adverse events (AEs) and modest clinical activity, Yap was somewhat circumspect in his takeaway when looking to the future.

“In the field of immunotherapy, we find that an all-comer approach is not the best way forward,” he said. “We need to know which patient population to target using novel molecular data generated from the translational analyses of clinical trial specimens, as were undertaken on the ICONIC trial. It’s not enough to focus simply on targeting defined tumor types, but we need to know about the underlying molecular abnormalities impacting the tumor immune microenvironment and the biology of the actual tumor. We can then ideally use this knowledge to match patients with the right drugs. We need better predictive biomarkers of both response and resistance for immunotherapy—that’s the bottom line,” Yap said.

In a commentary⁵ to the findings from ICONIC, coauthors, Lawrence Fong, MD, and Jerry Lee, MD, MPhil, commended Yap et al at completing a large, first-in-human trial of an ICOS agonist. Fong is the Efim Guzik Distinguished Professor in Cancer Biology, University of California San Francisco, and leader, Cancer Immunotherapy Program, and co-leader of the Cancer Immunology & Immunotherapy Program at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, and Lee is a clinical fellow at UCSF.

“The results from the ICONIC trial were modest but the follow up from the trial was the identification of a potential biomarker that was induced by the agent,” Lawrence said. Based on the data presented, in an unselected patient population, the benefit of the agent may not be clear. However, “if there is a way to identify ICOS-expressing patients, a biomarker-guided approach to enrich for a clinical response is a possibility.”

MEDI-570

Safety, pharmacokinetics, pharmacodynamics, and clinical activity data were reported for MEDI-570 in a phase 1, first-in-human trial (NCT02520791) for patients with relapsed/ refractory T-cell non Hodgkin lymphoma sponsored by the National Institutes of Health.⁶ A total of 23 patients were enrolled and received intravenous MEDI-570 every 3 weeks for up to 12 cycles, with the primary objectives of safety, dose-limiting toxicities (DLTs), and recommended phase 2 dose (RP2D). Efficacy and correlative studies were secondary objectives.

Five dose levels of MEDI-570 were evaluated and ranged from 0.01 mg/kg to 3 mg/kg. The median age of patients was 67 years (range, 29-86) and they experienced a median of 3 lines of prior therapy (range, 1-16).

The most common grade 3 or 4 AEs was decreased CD4-positive T cells (57%), lymphopenia (22%), anemia (13%), and infusion-related reactions (9%). Investigators reported on DLTs and the RP2D was 3 mg/kg. When T-cell subsets were evaluated, investigators reported reductions in CD4-positive ICOS-positive T cells demonstrating the agent’s activity on T-follicular helper cells. Overall the agent was well tolerated with promising activity in refractory patients with angioimmunoblastic T-cell lymphoma.

Feladilimab (GSK3359609)

The phase 1 first-in-human INDUCE-1 trial (NCT02723955) demonstrated safety, pharmacology, and preliminary antitumor activity of feladilimab (GSK3359609) in patients with advanced solid tumors.⁷ The trial was characterized by 2 primary parts, and each included a dose escalation and dose expansion phase. In part 1A, feladilimab was evaluated as a monotherapy; part 1b involved cohort expansion. In part 2A, pembrolizumab (Keytruda) or feladilimab or dostarlimab-gxly (Jemperli) or dostarlimab-gxly plus cobolimab or bintrafusp alfa combination were evaluated. Part 2B was the expansion phase that included pembrolizumab.

Subsequent trials evaluating feladilimab— INDUCE-3 (NCT04128696) and INDUCE-4 (NCT04428333)—simultaneously halted enrollment for patients with PD-L1-positive recurrent locally advanced or metastatic HNSCC after the recommendation of the independent data monitoring committee, according to a press release by the organization.⁸

KY1044

A phase 1 dose-escalation trial (NCT03829501) evaluated KY1044, a fully human IgG1 anti-ICOS antibody, for safety, tolerability, and maximum-tolerated dose.⁸ The study enrolled 103 patients who received either KY1044 as a monotherapy or in combination with atezolizumab (Tecentriq). In the monotherapy arm (n = 38), patients were stratified to 6 cohorts, with doses ranging from 0.8 mg to 240 mg. In the combination arm (n = 66), patients were stratified to 5 cohorts and received doses ranging from 0.8 mg to 80 mg.

Investigators reported that 63% of patients in the monotherapy arm and 55% in the combination arm received 4 or more prior therapies.

During the first 21 days of treatment, patients in both arms reported no DLTs. In the monotherapy arm, 47.4% of patients experienced treatment-related AEs (TRAEs) but all were mild (grade 1 or 2). In the combination arm, 58% of patients reported TRAEs. The majority were mild; however, 8 TRAEs were grade 3 or higher, which occurred in less than 8% of patients.

Infusion-related reactions, pyrexia and lymphopenia were the most commonly occurring TRAEs in at least 10% of patients.

The search continues for improved monoclonal antibodies to enhance immune response, whether as monotherapy or in combination with ICIs and other targeted therapies. Anti-ICOS antibodies continue to be a work in progress.

However, for community oncologists, the bigger challenge is to have patients “molecularly characterized in order to maximize the chances of understanding their underlying biology so we can match patients to the optimal drugs,” Yap said.

REFERENCES:

1. Solinas C, Gu-Trantien C, Willard-Gallo K. The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy. ESMO Open. 2020;5(1):e000544. doi:10.1136/esmoopen-2019-000544

2. Yap TA, Gainor JF, Callahan MK, et al. First-in-human phase I/II ICONIC trial of the ICOS agonist vopratelimab alone and with nivolumab: ICOS-high CD4 T-cell populations and predictors of response. Clin Cancer Res. 2022;28(17):3695-3708. doi:10.1158/1078-0432.CCR-21-4256

3. Yap TA, Gainor JF, Burris HA, et al. Association of an RNA signature (RS) with emergence of ICOS hi CD4 T cells and efficacy outcomes for the ICOS agonist vopratelimab (vopra) and nivolumab (nivo) in patients (pts) on the ICONIC trial. J Clin Oncol. 2020;38(suppl 5):14-14. doi: 10.1200/ JCO.2020.38.5_suppl.14

4. Jounce therapeutics reports results from phase 2 randomized SELECT trial testing 2 different doses of vopratelimab in TISvopra biomarker-selected patients. News release. Jounce Therapeutics. August 30, 2022. Accessed August 31, 2022. https://yhoo.it/3KxSGYe

5. Lee JC, Fong L. Agonizing over the stimulatory immune checkpoint ICOS. Clin Cancer Res. 2022;28(17):3633-3635. doi:10.1158/1078-0432.CCR-22-1520

6. Chavez JC, Foss FM, William BM, et al. Targeting the inducible T-cell costimulator (ICOS) in patients with relapsed/ refractory T-follicular helper phenotype peripheral T-cell and angioimmunoblastic T-cell lymphoma. Clin Cancer Res. 2023;29(10):1869-1878. doi:10.1158/1078-0432.CCR-22-2955

7. Massarelli E, Balmanoukian AS, Vieito M, et al. INDUCE-1: report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors. J Clin Oncol. 2020;38(suppl 15):6544-6544. doi:10.1200/JCO.2020.38.15_suppl.6544

8. GSK provides update on feladilimab, an investigational inducible T cell co-stimulatory (ICOS) agonist. News Release. GSK. April 14, 2021. Accessed September 3, 2023. https://bit. ly/32lr4Aj.

9. Patel MR, Naing A, Burris HA, et al. A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies. J Clin Oncol. 2021;39(suppl 15):2624-2624. doi:10.1200/ JCO.2021.39.15_suppl.2624