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

Jesus Vera Aguilera, Jonas Paludo, Robert R. McWilliams, Henan Zhang, Ying Li, Anagha B. Kumar, Jarrett Failing, Lisa A. Kottschade, Matthew S. Block, Svetomir N. Markovic, Haidong Dong, Roxana S. Dronca, Yiyi Yan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)364-375
Number of pages12
JournalMelanoma research
DOIs
StateAccepted/In press - 2020

Keywords

  • chemoimmunotherapy
  • chemotherapy
  • immunotherapy
  • therapy-responsive T-cells

ASJC Scopus subject areas

  • Oncology
  • Dermatology
  • Cancer Research

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