Chemo-immunotherapy combination after PD-1 inhibitor failure improves clinical outcomes in metastatic melanoma patients

Abstract

Management of PD-1 blockade resistance in metastatic melanoma (MM) remains challenging. Immunotherapy or chemotherapy alone provides limited benefit in this setting. Chemo-immunotherapy (CIT) has demonstrated favorable efficacy and safety profiles in lung cancer. Our pre-clinical study showed that in MM patients who have failed PD-1 blockade, the addition of chemotherapy increases CX3CR1+ therapy-responsive CD8+ T-cells with enhanced anti-tumor activity, resulting in improved clinical response. Here, we examined the clinical outcomes of CIT in MM patients after PD-1 blockade failure and the treatment-related changes in CX3CR1+ therapy-responsive CD8+ T-cells. We reviewed MM patients seen between January 2012 and June 2018 who failed anti-PD-1-based therapy and received subsequent CIT, immune checkpoint inhibitors (ICI) or chemotherapy alone. Overall survival (OS), objective response rate (ORR), event-free survival (EFS), and toxicities were assessed. Among 60 patients, 33 received CIT upon disease progression on PD-1 blockade. At a median follow-up of 3.9 years, the CIT group had a median OS of 3.5 years [95% confidence interval (CI) 1.7–NR] vs. 1.8 years (95% CI 0.9–2; P = 0.002) for those who received subsequent ICI (n = 9) or chemotherapy alone (n = 18), with ORR of 59% vs. 15% (P = 0.0003), respectively. The median EFS was 7.6 months (95% CI 6–10) following CIT vs. 3.4 months (95% CI 2.8–4.1; P = 0.0005) following ICI or chemotherapy alone. Therapy-responsive CX3CR1+CD8+ T-cells showed dynamic increase with successful CIT. CIT showed favorable clinical outcomes and acceptable safety profile in PD-1 blockade-resistant patients. CX3CR1+CD8+ therapy-responsive T-cells can be potentially used for monitoring disease response to CIT.

Thinking Outside the Field: Two Cases of RT+ICI Synergy in Melanoma

“…These T cells have the ability to withstand chemotherapy toxicity and are increased in patients with metastatic melanoma who respond to combination chemoimmunotherapy. 19,20 Clinical models suggest that these CX3CR1 + CD8 + T cells are PD-1 therapy-responsive effector CD8 + T cells capable of entering tumor tissues and exhibiting anti-tumor effects. 19 We also know CX3CR1 + CD8 + T cells increase after effective combined CIT and we wondered if we would see changes in the setting of NIVO/IPI + RT.…”

Multi-Omics and Informatics Analysis of FFPE Tissues Derived from Melanoma Patients with Long/Short Responses to Anti-PD1 Therapy Reveals Pathways of Response

“…In esophageal and other cancers, carboplatinum/paclitaxel chemotherapy was shown to increase PD-L1 expression [ 103 , 104 ]. Although there are some studies reviewing the potential synergistic effects of chemotherapy with anti-PD-1 [ 105 ], there is only one small case series to date suggesting the benefit of combination chemotherapy with PD-1 blockade after anti-PD-1 failure [ 106 ]. However, melanoma patients who received anti-PD-1 as a front-line therapy had increased responses compared to those patients who received prior therapies including chemotherapy in the original anti-PD1 trials [ 107 ].…”

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

“…Nevertheless, the majority of patients with metastatic melanoma do not respond to treatment or are prone to secondary resistance, with later disease progression. Therefore, the combination of these therapeutic modalities with chemotherapy has been explored as an advantageous strategy for melanoma management [311].…”