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.

Fig. 1

Clinical benefits of chemoimmunotherapy (CIT) in metastatic melanoma patients after progressed on PD-1 blockade. (a and b) A patient with BRAF V600E mutation had symptomatic disease progression after receiving Dabrafenib plus Trematinib and Nivolumab plus Ipilimumab. He then received Pembrolizumab (200 mg Q 3 weeks) in combination with Carboplatin and Paclitaxel (AUC of 5 and 175 mg/m², respectively, Q 3 weeks). CT of the abdomen and pelvis obtained before (a) and after five cycles of CIT (b) are shown. Red arrows indicate large para-aortic and pelvic lesions. (c and d) A metastatic melanoma patient with BRAF V600E mutation was previously treated with targeted therapy and experienced significant disease progression after pembrolizumab therapy with peritoneal carcinomatosis. He subsequently received salvage CIT therapy with pembrolizumab (2 mg/kg Q 3 weeks) and carboplatin and paclitaxel (AUC of 5 and 175 mg/m², respectively). PET scans obtained before (c) and after two cycles of CIT (d) were shown. AUC, area under the curve.

Fig. 2

Clinical outcomes of chemo-immunotherapy (CIT), chemotherapy, or immune checkpoint inhibitors (ICI) in metastatic melanoma patients after disease progression on anti-PD1 therapy. EFS, event-free survival.

Fig. 3

Clinical outcomes of chemo-immunotherapy (CIT), chemotherapy, or immune checkpoint inhibitors (ICI) in metastatic melanoma patients after disease progression on anti-PD1 therapy according to BRAF status. (a) EFS in CIT cohort compared to ICI or chemotherapy alone cohort in BRAF wildtype MM patients. (b) EFS in CIT cohort compared to IC or chemotherapy alone cohort in BRAF mutant MM patients. (c) EFS in BRAF wild-type patients vs. BRAF mutant patients in CIT cohort. EFS, event-free survival; MM, metastatic melanoma.

Fig. 4

Frequency of CX3CR1+ therapy-responsive CD8+ T cells decreased after anti-PD1 therapy in non-responders. CD3+CD45+CD8+ cells were sorted and collected from PBMCs obtained from metastatic melanoma patients who have underwent subsequent anti-PD-1 therapy (BL: before anti-PD-1 therapy, PT: after anti-PD-1 therapy). Single cell RNAseq was performed and the frequencies of CX3CR1-expressing cells were compared before and after therapy in responders (a) and non-responders (b). BL, baseline; PBMCs, peripheral blood mononuclear cells; PT, post-therapy.

Fig. 5

Dynamic fluctuation of CX3CR1+ therapy-responsive CD8+ T-cells in peripheral blood upon anti-PD1 and subsequent CIT therapy in patients who responded to rescue CIT. (a) Percentage of CX3CR1⁺Granzyme B⁺ cells in CD11a^highCD8⁺ T-cell population isolated from the peripheral blood at multiple time points: prior to and after PD-1 therapy, the addition of chemotherapy and confirmed response to CIT (arrows indicate time points at treatment initiation and response assessment). (b) Percentage of Bim⁺ cells in CD11a^highCD8+ T cell population isolated from the peripheral blood obtained from the same patients at same time points as in (a). CIT, chemo-immunotherapy.