Cytokine Release Syndrome and Neurotoxicity Emerge as Primary AEs of Interest With Solid Tumor T-Cell Receptor Therapy

In the phase 1 SURPASS trial, 72% of patients with solid tumors developed any-grade cytokine release syndrome following an infusion of ADP-A2M4CD8. The median time to resolution was 5 days.

Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANs), and prolonged cytopenia are the key adverse events (AEs) of interest linked with treatment with ADP-A2M4CD8, a next-generational autologous T-cell receptor designed to target solid tumors, according to an updated analysis of the SURPASS trial (NCT04044859). However, most cases of these AEs resolved during the SURPASS trial, and the efficacy data associated with this novel agent warrant further clinical trial investigation in multiple tumor types.

“The efficacy of the ADP-A2M4CD8 as monotherapy in heavily pretreated patients with advanced metastatic disease across multiple major solid tumors are encouraging,” David S. Hong, MD, deputy chair of the Department of Investigational Cancer Therapeutics, in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in a presentation of the findings during the 2022 European Society of Medical Oncology Congress. “The safety profile remains acceptable, and the data to-date support advanced clinical trials and further investigation, including combination approaches.”

CRS emerged as an AE of special interest in the study. Ultimately, 32 patients (72.7%) experienced CRS. Among these, 6 patients (14%) developed grade 3 or worse CRS. The median time to onset was 3 days (range, 1-9) and the median time to resolution was 5 days (range, 1-15). In the case of 27 patients (61%), anti-IL6 therapy was effective in managing the AE.

Cytopenia and ICANS also represented key AEs related to this treatment. A quarter of enrolled patients (n = 11; 25%) developed grade 3 or greater prolonged cytopenia during week 4 post-infusion. In addition, 3 patients (6.8%) in the study experienced an ICANS; of which 5% (n = 2) were grade 3 or greater.

For any-grade AEs, the most common were CRS (72.7%), neutropenia (29.5%), anemia or decreased red blood count (22.7%), pyrexia (22.7%), fatigue (20.5%), leukopenia (15.9%), rash (15.9%), and thrombocytopenia (15.9%).

Some patients also experienced dyspnea (13.6%), hypoxia (13.6%), ICANS (13.6%), pleural effusion (13.4%), febrile neutropenia (11.4%), hypotension (11.4%), and tachycardia (11.4%).

The percentage of patients who developed a SAE (grade 3 or higher) was 61.4%, among these serious cases included CRS (31.8%), hypoxia (6.8%), ICANs (6.8%), and pyrexia (6.8%).

Unfortunately, there were 2 cases of grade 5 (fatal) serious AEs (SAEs). The first was 60-year-old patients with ovarian cancer. This patient had a large tumor burden in her lungs and had received prior lung radiotherapy. The cause of her death was a combination pneumonia and CRS. The other patient was a 71-year-old man who had adenocarcinoma in his esophagus. This patient had a history of chronic anemia and had developed new lesions in his liver. The cause of his death was bone marrow failure.

SURPASS is a phase 1 trial designed to evaluate the safety and tolerability of ADP-A2M4CD8. Its secondary objective is to evaluate the antitumor activity of the investigational agent. Investigators are also using the findings to explore the persistence, phenotype, function of transduced and nontransduced T cells, and the tumor and serum factors that may influence response or resistance.

ADP-A2M4CD8 is a next-generation specific peptide enhance affinity receptor (SPEAR) T-cell therapy which is designed to increased potency by expressing a CD8α coreceptor, which are genetically engineered alongside the T-cell receptor with the intent of increasing CD4-positive T-cell potency. Investigators hypothesize that this will increase the T-cell receptor binding avidity and enhance the polyfunctional response of engineered CD4-positive T cells against MAGE-A4 tumors.

The overall confirmed response rate among patients receiving this treatment for solid tumors was 28% (n = 12); 5% of patients (n = 2) achieved unconfirmed responses and are awaiting confirmatory scans. The median duration of responses was 12 weeks (range; 7-65 weeks) and the disease control rate was 81%. Patients who achieved confirmed clinical responses had diagnoses of ovarian, esophagogastric junction, urothelial, head and neck, and synovial sarcoma cancers.

The screening phase of the SURPASS trial involved screening for human leukocyte antigen and MAGE-A4 immunohistochemistry testing. Patients who were eligible to enroll underwent baseline tumor measurements, followed by lymphodepletion (days –7 to –4) and subsequent ADP-A2M4CD8 infusion. Following the T-cell infusion, patients received nivolumab (Opdivo) every 4 weeks.

Monotherapy was administered to 60 patients. A cohort of 30 patients received combination therapy with an anti–PD1-inhibitor. Long-term follow-up for this study will range between 1 to 15 years.

Among 44 eligible participants, the median age was 59.0 years (range, 31-75). Twenty-three participants were male (52.3%), and the median H-score was 250.0 (range, 95-300). Thirteen patients had an ECOG performance status of 0 (29.5%) and 31 had a performance status of 1 (70.5%). Twenty-nine patients had a target tumor greater than 5 cm (65.9%).

The median number of transduced T cells × 109 was 4.64 (range, 0.95-9.95), and the median number of lines of prior therapies was 3 (range, 1-8).Twenty-three patients received systemic bridging therapy (52.3%).

Tumor types included were as follows: 31.8% of patients had ovarian cancer (n = 14), 29.5% had esophagogastric junction, esophageal, or gastric cancer (n = 13), and 15.9% had urothelial (n = 7), 9% had head and neck cancer (4%), 4.5% had non–small cell lung cancer, 4.5% had melanoma (n = 2), 2.3% had synovial sarcoma (n = 1), and 2.3% had myxoid round cell liposarcoma (n = 1).

“The efficacy and safety results with ADP-A2M4CD8 continues to show an acceptable benefit-to-risk profile in multiple MAGE-A4–positive unresectable or metastatic tumors,” Hong concluded. “The efficacy and safety results with monotherapy support expansion into combination therapy with an anti–PD-1 checkpoint inhibitor.”

Based on the positive findings presented during this update, an additional treatment cohort with nivolumab has been initiated in the SURPASS phase 1 trial. Further, phase 2 studies assessing the agent are planned including for patients with esophageal and esophageal gastric junction (SURPASS-2; NCT04752358), which is recruiting, and for patients with ovarian cancer (SURPASS-3).

Reference

Hong DS, Asch A, Calvo E, et al. Updated safety and efficacy from SURPASS, the phase I trial of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy in previously treated patients with unresectable or metastatic tumors. Presented at: European Society for Medical Oncology Congress 2022; September 9-11, 2022; Paris, France.