Melanoma Highlights

Abstract #2506: Ascentage Pharma’s Alrizomadlin (APG-115) shows benefit in combination with Pembrolizumab in Refractory Melanoma.

Ascentage’s Alrizomadlin (APG-115) is a novel, orally active small-molecule mouse double minute 2 homolog (MDM2) inhibitor. Mechanistically, APG-115 increases p53 and p21 overexpression, activates p53 - mediated apoptosis in tumor cells retaining wild-type p53. At ASCO 2021, Ascentage Pharma presented the preliminary results from the phase II study of APG-115-Pembrolizumab combination in patients with metastatic melanoma or advanced solid tumors that have failed IO (Immuno-oncologic) therapies. The study had enrolled 102 patients divided into 6 cohorts including patients with: PD-1/PD-L1 inhibitor-resistant melanoma, non-small cell lung cancer (NSCLC), and urothelial carcinoma; or malignant peripheral nerve sheath tumor (MPNST), liposarcoma, and ATM mutant solid tumors.

In the PD-1/PD-L1 inhibitor-resistant melanoma cohort comprising of 29 patients ORR and DCR was observed to be 24.1% and 55.2%, respectively. Additionally, there was 1 confirmed partial response (PR) out of 7 patients with uveal (ocular) melanoma; 2 PRs out of 5 patients with mucosal melanoma; and 1 complete response and 3 PRs out of 15 patients with cutaneous melanoma. Furthermore, there were few common treatment-related adverse events (TRAEs) observed in more than 10% of patients. 

Considering that Ascentage was quite hopeful and excited for its collaboration with Merck to evaluate this potential combination, we can keep high hopes with the results. As of now we can conclude that Alrizomadlin- Pembrolizumab Combination is well tolerated, and did not exhibit any overlapping toxicity. These preliminary results confirmed that the combination regimen has antitumor activity in patients with IO relapsed/refractory metastatic melanoma, (including uveal melanoma, mucosal melanoma, or cutaneous melanoma), however we still need to wait for a more conclusive and complete data to further analyse the efficacy of this combination.

Expert Views: 

“The clinical data of alrizomadlin presented are encouraging, as they suggest clinical activity in hard-to-treat tumor types across multiple indications, including several without currently available standard of care, such as relapsed or refractory melanoma subtypes”.

“This study of alrizomadlin in combination with Pembrolizumab offers a clinical validation of the therapeutic synergy between MDM2-p53 inhibitors and existing immuno-oncologic drugs and shows the potential as a new treatment option that could bring renewed hope for patients with solid tumors”.

Abstract #9537: Lifileucel/Pembrolizumab Elicits Encouraging ORR in ICI-Naïve Advanced Melanoma

Iovance Biotherapeutics has already presented the long term response of its TIL therapy, Lifileucel as a monotherapy in advanced melanoma patients during the initial days of the ASCO 2021 conference. The company has now presented its abstract which has evaluated the TIL therapy in combination with Merck’s anti-PD-1 inhibtor, Pembrolizumab. 

The company presented the preliminary findings from cohort 1A consisting of patients with immune checkpoint inhibitor (ICI)-naïve advanced melanoma in its Phase II IOV-COM-202 trial. The study enrolled 7 patients with ICI-naive advanced melanoma out of which five of the 7 patients were treatment-naive, while 1 patient had received prior treatment with BRAF inhibitors and MEK inhibitors and the other patient had received prior chemotherapy. The findings from the study suggested that the addition of Lifileucel (LN-144) to Pembrolizumab (Keytruda) resulted in an overall response rate (ORR) of 85.7% compared with Pembrolizumab alone in patients with immune checkpoint inhibitor (ICI)–naive advanced melanoma. Six patients had a confirmed objective response to the treatment. In particular, 1 patient had a complete response, and 5 patients had a partial response. Additionally, treatment-related adverse events occurred in at least 30% of patients in the study. It was good to know that there were no grade 5 treatment-emergent adverse events during this study, and unexpected toxicity was seen in patients related to Pembrolizumab after TIL therapy.

In conclusion, these preliminary data suggests the response rate for Lifileucel and Pembrolizumab may be additive in patient with immune checkpoint inhibitor naive advanced metastatic melanoma, with an objective response rate of 85.7%, with a complete response/unconfirmed complete response of 42.9%. Currently, there are only few treatment options that exist for patients with advanced melanoma who are refractory to or develop resistance to an immune checkpoint inhibitor, including retreatment with immunotherapy or chemotherapy, and neither has a significant impact on response or survival, therefore we assume that autologous TIL therapy can be the most efficacious therapy in melanomas, as the antitumor efficacy has already been demonstrated in these therapies.

Expert Views: 

“Advanced melanoma remains a significant health burden with a high unmet clinical need despite treatment advances in immunotherapy. Lifileucel TIL [tumor-infiltrating lymphocyte]-cell therapy has demonstrated efficacy and durability of response in patients with advanced metastatic melanoma who have progressed while on or following treatment with anti-PD-1 or PD-L1 therapy”.

“Anti-PD-1 therapy has become standard of care in frontline melanoma, yet we are still looking for ways to help more patients respond and to improve upon the depth and durability of responses. The 86% Overall Response Rate (ORR) for Lifileucel in combination with Pembrolizumab is remarkable and suggests a potential additive effect for early-line treatment of patients with melanoma.”