Neoadjuvant Dual vs Single Checkpoint Inhibitors in High-Risk Melanoma

1. The pathological response rate had an OR of 3.16 when comparing neoadjuvant dual vs single checkpoint inhibitors.

2. The grade 3-4 immune-related adverse event rate had an OR 3.75 when comparing neoadjuvant dual vs single checkpoint inhibitors.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Adjuvant therapy in resected advanced melanoma with immune checkpoint inhibitors (ICIs) aims to target micrometastases post-surgery, but relapse rates remain high, especially in stage III melanoma patients. Neoadjuvant therapy (NAT) with ICIs, initiated pre-surgery, is gaining traction for potentially enhancing immune response and improving treatment outcomes. This pooled analysis studied its safety and efficacy in high-risk resectable melanoma cases. Endpoints of interest included objective response rates (radiological and pathological; complete response [CR], partial response [PR], progressive disease [PD]), surgical resection rates, and safety. This analysis investigated 4 trials which used dual checkpoint inhibitors (DCPI, ipilimumab and nivolumab) and 2 trials which used anti-PD1 exclusively. The rCR rate was 10.29% in the DCPI group vs 5.63% in the anti-PD1 group with OR 1.93 (non-significant), the rPR rate was 39.71% vs 40%, and the rPD rate was 11.76% vs 15.63% with OR 0.72 (non-significant). The pCR rate was 45.36% in the DCPI group vs 20.81% in the anti-PD1 group with OR 3.16 (significant). In subgroup analysis, no statistically significant difference was found between the conventional dose DCPI (3-mg/kg IPI, 1-mg/kg NIVO) and alternative dose DCPI (1-mg/kg IPI and 3-mg/kg NIVO) regarding rCR, rPD, and pCR. The pCR OR for the conventional dose DCPI was 2.99 (significant) and for the alternate dose DCPI was 3.87 (significant) when compared to anti-PD1. The OR of surgical resection between DCPI and anti-PD1 was 1.56 (non-significant), and similarly, there was no statistical difference between the dosing of DCPI. With regards to safety, 33.82% of DCPI vs 12.09% of anti-PD1 patients experienced grade 3-4 immune-related adverse events, with OR 3.75 (significant). Conventional DCPI when compared to alternative DCPI had an OR of 4.76 (significant), and alternative DCPI when compared to anti-PD1 had an OR of 2.02 (significant). The OR for discontinuation was 10.27 (significant) when comparing DCPI vs anti-PD1 groups. The strengths of this study included its methodology and number of patients, and its limitations included the heterogeneity of studies. Overall, this analysis found that NAT with ICI yields significant endpoints, especially with DCPI-based regimens, though they carry a higher risk of severe adverse events.

Click to read the study in JAMA Oncology

Relevant Reading: Neoadjuvant checkpoint blockade for cancer immunotherapy

In-Depth [meta-analysis]: This pooled analysis investigated prospective NAT trials from the PudMed database between January 2018 to March 2023 which yielded 6 clinical trials with a total of 573 patients. 4 trials used DCPI and 2 trials used anti-PD1 exclusively. The rCR rate was 10.29% in the DCPI group vs 5.63% in the anti-PD1 group with OR 1.93 (95%CI, 0.86-4.33, p=0.11), the rPR rate was 39.71% vs 40%, and the rPD rate was 11.76% vs 15.63% with OR 0.72 (95%CI, 0.39-1.32, p=0.29). The pCR rate was 45.36% in the DCPI group vs 20.81% in the anti-PD1 group with OR 3.16 (95%CI, 1.99-4.99, p<0.001). In subgroup analysis, no statistically significant difference was found between the conventional dose DCPI and alternative dose DCPI regarding rCR, rPD, and pCR. The pCR OR for the conventional dose DCPI was 2.99 (95%CI, 1.53-5.83, p<0.001) and for the alternate dose DCPI was 3.87 (95%CI, 2.34-6.40, p<0.001) when compared to anti-PD1. The OR of surgical resection between DCPI and anti-PD1 was 1.56 (95%CI, 0.72-3.39, p=0.26), and similarly, there was no statistical difference between the dosing of DCPI. With regards to safety, 33.82% of DCPI vs 12.09% of anti-PD1 patients experienced grade 3-4 immune-related adverse events, with OR 3.75 (95%CI, 2.20-6.37, p<0.001). Conventional DCPI when compared to alternative DCPI had an OR 4.76 (95%CI, 2.38-9.52, p<0.001), and alternative DCPI when compared to anti-PD1 had an OR 2.02 (95%CI, 1.09-3.72, p=0.02). The OR for discontinuation was 10.27 (95%CI, 5.58-18.91, p<0.001) when comparing DCPI vs anti-PD1 groups. Overall, this analysis found that NAT with ICI yields significant endpoints, especially with DCPI-based regimens, though they carry a higher risk of severe adverse events.

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