ARRY-614 Plus Immune Checkpoint Inhibition Can Induce Durable Responses in Advanced Solid Tumors

The combination of the p38 MAPK inhibitor ARRY-614 plus nivolumab (Opdivo) with or without ipilimumab (Yervoy) was well tolerated and elicited disease control in high-risk, PD-(L)1–refractory patients with advanced solid tumors, according to data from a phase 1/2 trial (NCT04074967) presented at the 2022 Society for Immunotherapy of Cancer Annual Meeting.¹

Of the 20 evaluable patients, 3 had partial responses (PRs), 7 achieved stable disease (SD), 2 patients had immune-related SD (irSD), and the remaining 8 patients experienced disease progression. The median duration of response was not reached with PRs ongoing in 2 patients.

Moreover, 6 additional patients reached 6-month progression-free survival, which included 2 patients who had SD/irSD for longer than 1 year and 3 with ongoing benefit despite early drug cessation because of toxicities.

“Ongoing correlative biomarker analyses in responding vs non-responding subjects will help identify patient populations most likely to receive benefit from this therapy,” Ryan C. Augustin, MD, of the UPMC Hillman Cancer Center, in Pittsburgh, PA, and colleagues, wrote in a poster on the data.

Despite the tremendous success observed with immune checkpoint inhibitors, most cancers will develop resistance to these agents. In preclinical models, it was found that the MAPK pathway inhibits dendritic cell priming. By blocking the p38 pathway, antigen presentation, costimulatory signaling, and proinflammatory cytokine secretion, can all be restored.

In murine breast cancer models, ARRY-614 enhanced efficacy derived with PD-1 inhibition. With the current phase 1/2 trial, investigators set out to determine the safety and tolerability of ARRY-614 plus nivolumab or nivolumab plus ipilimumab in patients with advanced solid tumors.

The trial enrolled patients with metastatic or unresectable solid tumors in whom standard of care was failing. The 15 patients with advanced solid tumors were given nivolumab at 480 mg every 4 weeks. The 13 patients with melanoma were administered ipilimumab at 3 mg/kg or nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks. All patients received ARRY-614 at 800 mg, which was reduced to 200 mg once daily.

A secondary end point of the trial is preliminary activity via RECIST v1.1 criteria in the form of overall response rate. An exploratory end point is correlative biomarker analysis in responders vs non-responders, IFN-γ gene signature, immune cell Ki67, whole exome sequencing, circulating tumor DNA, germline DNA, and fecal microbiota.

A prior trial of ARRY-614 calculated a maximum tolerated dose of 800 mg; it was selected as an initial starting dose. The patients with melanoma and advanced solid tumors were examined in parallel. Investigators leveraged a Bayesian model to allocate doses and describe the dose-toxicity relationship for each cohort. A probability of dose-limiting toxicity (DLT) of higher than 0.2 was determined to be unacceptable.

After 11 patients were accrued, 4 DLTs were observed at the 800-mg dose of ARRY-614 indicative of a dose-exposure relationship with DLT via area under the curve. Further evaluation of the pharmacokinetics of the agent prompted further dose reduction to 200 mg for the rest of the study.

Of the 28 patients enrolled to the trial, 13 patients had melanoma; 10 had cutaneous disease, 2 had uveal disease, and 1 had mucosal disease. The remainder of the patients had non–small cell lung cancer (n = 7), renal cell carcinoma (n = 5), mesothelioma (n = 2), and gastroesophageal cancer (n = 1). The median age was 67 years, and 71.4% of patients were male.

Regarding ECOG performance status, 60.7% of patients had a status of 1 and the remaining 39.3% had a status of 0. The median number of prior lines of therapy was 3. The median albumin was 4 g/dL, the median lactate dehydrogenase was 204.5 U/L, the median absolute lymphocyte count was 1.3.

Regarding safety, 90.4% of patients experienced grade 1 or 2 treatment-related adverse effects (TRAEs), which included lymphopenia (60.7%), rash (60.7%), diarrhea (42.9%), and fatigue (42.9%). Grade 3 or higher TRAEs were experienced by 9.6% of patients, and they included colitis (17.9%), rash (21.4%), anemia (14.3%), and hypokalemia (10.7%). Immune-related toxicities were experienced by 7.0% of patients.

DLTs were experienced by 8 patients, but all received ARRY-614 at a dose of 400 mg or higher. DLTs included rash (n = 4), colitis (n = 3), visual disturbance (n = 3), hypotension (n = 1), anaphylaxis (n = 1), atrial fibrillation (n = 1), and dyspnea (n = 1).

Reference

Augustin RC, Poklepovic A, Gao X, et al. Phase Ib study of the p38 inhibitor ARRY-614 with nivolumab, ipilimumab or nivolumab + ipilimumab in advanced solid tumors. Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. http://bit.ly/3EIrqFm