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ASCO Direct Philadelphia: Updates in Melanoma and Cutaneous Malignancies

Presentation by Marlana Orloff, MD, Sidney Kimmel Cancer Center, Jefferson Health

At the 2023 Total Health ASCO Direct Conference held in Philadelphia, Pennsylvania, Dr Marlana Orloff from Sidney Kimmel Cancer Center at Jefferson Health highlighted several abstracts on melanoma and other cutaneous malignancies from this year’s meeting of the American Society for Clinical Oncology (ASCO). The selected abstracts highlight both immunotherapy approaches, which allow the body’s immune system to more effectively recognize and target cancer cells for destruction, and targeted therapy, which specifically inhibits a molecular alteration in the tumor that allows for its uncontrolled growth. Both of these treatment modalities continue to play a role in the treatment of melanoma and other cutaneous cancers.

[Abstract 9510]: NRAS-Mutant Melanoma

This abstract focused on the use of a targeted therapy, tunlametinib, in melanoma patients who have a mutation in the NRAS gene, typically seen in about 17% of melanoma patients. Dr Orloff noted that NRAS-mutant melanoma is an aggressive subtype, with a poor prognosis and no approved targeted therapy at present. In this multicenter, open-label, single-arm, phase 2 study of 100 patients with unresectable, Stage III or IV NRAS-mutant melanoma, patients received twice-daily treatment with tunlametinib, an orally administered small molecule inhibitor of the MEK 1/2 pathway. Most patients in the study were Stage IV (85.3%), and the results showed an overall response rate (ORR) or 34.7%, which Dr Orloff suggested was impressive for a targeted treatment in this aggressive subtype of melanoma. Additional results showed a progression-free survival (PFS) rate of 4.2 months, a 1-year survival rate of 57.2%, and the treatment was well tolerated. Notably a similar ORR (39.1%) was seen in those patients who had received prior immunotherapy treatment, and Dr Orloff suggested that, while not yet approved, this could be an option for NRAS-mutant patients who have failed prior immunotherapy.

[Abstract 9507]: Cutaneous Squamous Cell Carcinoma (MATISSE)

This abstract described results from the MATISSE trial, which examined outcomes for patients with advanced cutaneous squamous cell carcinoma (CSCC), which frequently requires an extensive and potentially mutilating surgery and subsequent adjuvant radiotherapy (RT). The goal of the trial was to examine whether such patients could avoid more extensive surgeries with 2 doses of pre-surgery (neoadjuvant) immunotherapy, either with nivolumab alone (Nivo), or with the combination of nivolumab + ipilimumab (Combo). The study enrolled 40 patients with CSCC who were otherwise candidates for extensive and/or mutilating surgery with adjuvant RT. The results showed a major pathologic response for 40% and 53% of patients in the Nivo and Combo arms, respectively, and 9 patients declined surgery as they had achieved a substantive clinical remission of their cancer with the neoadjuvant therapy alone, and continued to be disease-free at 12 months. Overall, deep clinical responses were seen for 50% and 61% of patients in the Nivo and Combo arms, respectively. Dr Orloff suggested that, while not currently a standard treatment modality, the use of neoadjuvant immunotherapy could be considered as an option for patients whose CSCC is considered “borderline resectable”, with the potential to avoid subsequent extensive and/or mutilating surgery and RT for some patients.

[Abstract 9509]: Anti-PD-1 Failed Melanoma (IGNYTE)

This abstract described results from the IGNYTE trial, a phase I/II study which examined a novel treatment, RP-1, for melanoma patients who had failed initial immunotherapy using programmed death 1 (PD-1) inhibitors, such as nivolumab. RP-1 is an immune-stimulating protein that is administered intratumorally (injected into the tumors) and in combination with nivolumab treatment. In the cohort of 91 patients with prior anti-PD-1 exposure, the ORR was found to be 37.4%, with complete responses seen in 18.7% of patients, which Dr Orloff considered as impressive in this second line treatment setting. Notably, responses were seen both in the injected an un-injected lesions, and Dr Orloff noted the approach could be useful for treating lesions in metastatic sites such as the liver and lung. Treatment-related adverse events (TRAEs) were mostly of Grade 1 or 2, with fatigue, chills, fever, and nausea being most common. Dr Orloff suggested the combination treatment with RP-1 and nivolumab provided durable and clinically meaningful activity for this group of melanoma patients with limited treatment options - including those who have previously failed the current, ‘best available’ immunotherapy treatment, combining nivolumab with ipilimumab (the ‘Ipi-Nivo’ regimen).

[Abstract LBA9512]: Uveal Melanoma with Liver Metastases (SCANDIUM)

This abstract detailed survival outcomes following isolated hepatic perfusion (IHP), which is a surgical treatment to introduce high dose chemotherapy (melphalan) for liver metastases commonly observed in patients with a rare subtype of melanoma called uveal melanoma (UM). Approximately half of patients with UM will develop life-threatening metastatic disease, with the liver being the most common site for metastasis. The SCANDIUM trial randomized patients (total of 87 patients treated) to receive a one-time treatment with IHP (experimental group), or best alternative care (control group), and results showed a 24-month OS rate of 46.5% for the IHP group, versus 29.5% for the control group, which Dr Orloff described as ‘impressive’ for this group of patients, although the difference was not statistically significant. Median OS was 21.7 and 17.6 months for the IHP and control groups, respectively, favoring the IHP group, and the previously reported response rate (40% vs. 4.5%) and PFS rate (7.4 vs. 3.3 months) was significantly better in this trial with IHP versus the control arm. In light of these recent results, Dr Orloff noted that in the United States a similar catheter-based approach (Hepzato) is now approved for use for liver metastases in UM.

[Abstract 9548]: Fianlimab and Cemiplimab in Advanced Melanoma

This abstract detailed results from a trial of advanced melanoma patients treated with a combination of two distinct immunotherapy modalities, fianlimab, an anti-LAG-3 type immunotherapy, and cemiplimab, an anti-PD-1 type of immunotherapy. Dr Orloff noted that, in the advanced/metastatic setting for melanoma, there is some concern about resistance when using immunotherapy in patients who have already had exposure to prior immunotherapy agents such as PD-1 inhibitors, in the adjuvant (post-surgical) setting. She noted that the two types of immunotherapy used in this trial work to enhance immune system targeting of melanoma through two distinct pathways, and previous studies had shown efficacy of the combination treatment in advanced melanoma. In the present study reported at ASCO 2023, results were presented for patients both with (PD-1 exposed) and without (PD-1 naïve) prior exposure to PD-1-based immunotherapy. In the small cohort of patients who were PD-1 exposed (13 of 18 patients, 72%), the ORR was 56%, similar to the confirmatory (PD-1 naïve) cohort of patients, in whom the ORR was 63%, with a disease control rate (DCR) of 67%, as compared to 80% in the PD-1 naïve group. Efficacy was also seen in patients with poor prognostic factors such as liver metastasis, and was seen irrespective of LAG-3 or PD-1 ligand (PD-L1) expression in tumors. Dr Orloff also noted the ORR for the overall patient population of 61%, which compares favorably to the current ‘best available’ immunotherapy combination of Ipi/Nivo in advanced melanoma (58%); DCR and PFS rates were also comparable. She also noted the difference in adverse event (AE) profiles for the combination therapy relative to cemiplimab single agent therapy, with slightly higher incidence of the immune related AE of adrenal insufficiency. Owing to the favorable results seen in this trial, Dr Orloff noted that phase III clinical trials for the combination are ongoing for patients with advanced melanoma (NCT05352672) and as adjuvant treatment (NCT05608291).

Quick Summary

  • [Abstract 9510]: Targeted therapy with tunlametinib shows impressive response rates for advanced melanoma patients with NRAS-mutation and aggressive features, including those failing prior immunotherapy.

  • [Abstract 9507]: Pre-surgery (neoadjuvant) immunotherapy, either with nivolumab alone, or in combination with ipilimumab, shows efficacy for avoiding extensive and/or mutilating surgery in patients with advanced cutaneous squamous cell carcinoma. Results from the MATISSE Trial.

  • [Abstract 9509]: Intratumoral RP-1, an immune-stimulating protein, shows efficacy in combination with nivolumab immunotherapy in melanoma patients failing prior immunotherapy with PD-1 inhibitors. Results from the IGNYTE Trial.

  • [Abstract LBA9512]: Isolated hepatic perfusion (IHP) chemotherapy shows efficacy for treatment of liver metastases in patients with advanced uveal melanoma. Results from the SCANDIUM Trial.

  • [Abstract 9548]: Dual immunotherapy with fianlimab and cemiplimab shows efficacy in advanced/metastatic melanoma patients, both with and without prior exposure to PD-1-based immunotherapy.

Speaker Disclosure Information: Dr Orloff reported the following disclosures for this presentation: Consulting/Advisory: Immunocore, Ideaya, Delcath, Replimune; Speaker: Immunocore; Scientific Advisory Board: Trisalus.

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