APG-115 Plus Pembrolizumab Safe With Preliminary Efficacy in Unresectable or Metastatic Melanoma or Advanced Solid Tumors

Anthony W. Tolcher, MD, FASCO

The combination of alrizomadlin (APG-115) and pembrolizumab (Keytruda) was well tolerated in patients with unresectable or metastatic melanoma or advanced solid tumors that have been resistant to immuno-oncologic (IO) drugs; adverse events (AEs) did not overlap between the 2 agents, according to preliminary results of a phase 2 study presented during the 2021 American Society of Oncology (ASCO) Annual Meeting.

Alrizomadlin is a novel, potent, small molecule, orally bioavailable MDM2-p53 antagonist. The agent has been shown preclinically to block MDM2-p53 protein-protein interaction, as well as revitalize p53-mediated apoptosis in tumor cells that harbor wild-type TP53 or MDM2 amplification. Alrizomadlin has also demonstrated synergy with PD-1 blockade in wild-type TP53 and p53-mutant murine tumor models by promoting the shift from M2 to M1 macrophages in the tumor microenvironment, and balancing host immunologic responses and tumor immune escape mechanisms. Further, the agent enhances T-cell–mediated antitumor immunity and acts as a host immunomodulator.

In the phase 1b portion of the study, alrizomadlin was administered orally once a day for 2 consecutive weeks and 1 week off in a 21-day cycle. The doses of alrizomadlin administered ranged from 50 mg to 200 mg in 50-mg intervals. In combination with alrizomadlin, pembrolizumab was administered at 200 mg via intravenous (IV) infusion for 30 minutes on day 1 of a 21-day cycle. The purpose of the phase 1b portion was to determine dose-limiting toxicities associated with the combination and the recommended phase 2 dose (RP2D) of alrizomadlin.

The RP2D of alrizomadlin was identified as 150 mg once daily and was combined in the phase 2 portion of the study with pembrolizumab 200 mg IV on day 1 of a 21-day cycle. All treatment in the study was continued until disease progression, unacceptable toxicity, or discontinuation. Pembrolizumab could be administered for up to 35 cycles.

In addition to patients with IO-resistant melanoma, cohorts included patients with non–small cell lung cancer (NSCLC), liposarcoma, IO-resistant urothelial carcinoma, malignant peripheral nerve sheathe tumor (MPNST), and other solid tumors with ATM mutations and wild-type p53.

Those included in the study were males or females aged 18 years or older with histologically confirmed, unresectable or metastatic solid tumors that is refractory to standard-of-care therapies. Patients were required to have an ECOG performance status of 2 or lower and measurable disease per RECIST v1.1. In patients with melanoma, NSCLC, and urothelial carcinoma, the cancer was required to be relapsed/refractory after treatment with a PD-1 or PD-L1 inhibitor.

Determining the safety and efficacy was the key goal of the study and the primary end point was objective response rate (ORR) per RECIST v1.1 and immune-related RECIST criteria (iRECIST).

Out of 102 patients, the melanoma cohort included 32 patients, the ATM mutation–positive and wild-type p53 solid tumor cohort included 11 patients, the NSCLC cancer cohort had 19 patients, the cohort of MPNST included 6 patients, and there were 5 patients with STK11-mutant lung adenocarcinoma. In the remaining 2 cohorts, 17 patients had liposarcoma and 12 had urothelial carcinoma.

The overall population had a median baseline age of 64 years (range, 23-89). The study population was predominantly male (61.8%) and most had an ECOG performance status of 1 (50.0%). The majority of patients also had 3 or more prior lines of therapy (36.3%).

Patients received a median of 2.0 cycles of therapy with the combination regimen, and the discontinuation rate in the study was 74.5%. The most common reason for treatment discontinuation was progressive disease (61.8%) followed by the occurrence of AEs (18.4%).

Objective responses were observed in all but 2 cohorts. In the melanoma group, treatment with alrizomadlin plus pembrolizumab achieved an ORR of 24.1%, which included 1 complete response (CR), 5 partial responses (PRs), and 9 cases of stable disease (SD) for a disease control rate (DCR) of 55.2%. Notably, 2 additional PRs in this cohort were pending confirmation.

Among patients with NSCLC, the ORR was modest at 6.7% with 1 PR and 6 patients with SD for a DCR of 46.7%. In the liposarcoma arm, the ORR observed was 6.2%, which included 1 unconfirmed PR and 12 cases of SD. The DCR in the liposarcoma arm was 81.2%.

Patients treated with alrizomadlin plus pembrolizumab in the urothelial carcinoma arm achieved an ORR of 12.5% consisting of 1 PR; the DCR observed was also 12.5%. In patients with MPNST, the ORR was 16.7%, which was inclusive of 1 unconfirmed PR and 3 patients with SD for a DCR of 66.7%. No objective responses were observed in the STK11-mutant lung adenocarcinoma and ATM-mutant solid tumor cohorts, but the DCRs were 35% and 44%, respectively, due to some patients having SD.

Homing in on the melanoma cohort, there were 8 patients with uveal melanoma, 5 with mucosal melanoma, 16 with cutaneous disease, and 3 with an unknown primary melanoma type. The best ORR was observed in the mucosal melanoma group at 40%, which included 2 PRs, one of which was unconfirmed; the DCR in the group was also 40%. The cutaneous melanoma group had an ORR of 26.7% with 1 CR, 3 PRs, and 3 cases of SD. It was noted that 1 PR was unconfirmed in this group, and the DCR was 46.7%. Among patients with uveal melanoma, the ORR was 14.3% due to 1 PR, and there were 4 cases of SD for a DCR of 71.4%. Those with an unknown melanoma type did not achieve objective responses, but 2 patients had SD for a DCR of 100%.

“The anti-tumor activity of APG-115 and pembrolizumab in the cutaneous melanoma IO-resistant population was further demonstrated in a spider plot for all the target lesions. The patient who experienced the complete response had normalization of the lymph node measurements. Although a smaller number of responses occurred in the mucosal melanoma group, prolonged duration of stable disease in some patients is demonstrated in this spider plot. A similar finding was observed in the preliminary data for the uveal melanoma cohort,” said Anthony W. Tolcher, MD, FASCO, during the ASCO presentation.

Common treatment-emergent AEs (TEAEs) of any grade were seen in greater than 10% of patients in the study. In addition, common grade 3 TEAEs were experienced by more than 2% of patients. The most common TEAEs observed were nausea, thrombocytopenia, vomiting, fatigue, and decreased appetite.

“The preliminary results establish a proof of concept that the combination of APG-115 and pembrolizumab can be active in patients with IO-relapsed and refractory metastatic melanoma, including cutaneous melanoma with a 24% overall response rate and a 55% disease control rate. Early data showing some intriguing anti-tumor activity in patients with peripheral nerve sheath tumors and liposarcoma, indications not known to be pembrolizumab sensitive,” Tolcher, chief executive officer, founder, and director of Clinical Research at NEXT Oncology, stated.

The phase 2 study is ongoing and continues to accrue patients to expand the cohort of patients with NSCLC and MPNST, Tolcher concluded.

_Reference:

_{Tolcher AW, Reeves JA, McKean M, et al. Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs. J Clin Oncol. 2021; 39(suppl 15; abstr 2506). doi:10.1200/JCO.2021.39.15_suppl.2506}