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PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV.

Davar D, Wilson M, Pruckner C, Kirkwood JM - Case Rep Oncol Med (2015)

Bottom Line: Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response.HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels.In both patients, no significant toxicities were observed when pembrolizumab was initiated.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.

ABSTRACT
On the basis of remarkable antitumor activity, programmed death receptor-1 (PD-1) inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma in the second-line setting following progression on either CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for BRAF mutated melanoma). Given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections, clinical trials (including regulatory studies) evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV), and/or human immunodeficiency virus (HIV) infections. Herein, we describe two patients with advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response. HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels. Response is ongoing and HCV viral load remains undetectable. In both patients, no significant toxicities were observed when pembrolizumab was initiated. We argue for the further investigation of checkpoint inhibition in cancer patients with underlying chronic viral infections in the context of carefully designed clinical trials.

No MeSH data available.


Related in: MedlinePlus

Changes in tumor size and correlation with laboratory results in patient 1. After 3 cycles, index right breast lesion (A-B, lower panel) increased in size while index right pulmonary lesion decreased in size consistent with immune-related response pattern (A-B, upper panel). After 6 cycles, both lesions had decreased in size significantly (C, upper and lower panels). Although pembrolizumab treatment was associated with grade 1 leucopenia and grade 1 ALT/AST elevations initially, total white count and ALT/AST levels subsequently stabilized (graph). HCV viral load fluctuated between 3.36 IU/mL (6.53 log IU/mL) and 5.17 IU/mL (6.71 log IU/mL) before initiation of ledipasvir and sofosbuvir in April 2015. After 12-week course, HCV viral load became undetectable and remains so. To date, she has completed 15 cycles to date with ongoing excellent partial response.
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fig1: Changes in tumor size and correlation with laboratory results in patient 1. After 3 cycles, index right breast lesion (A-B, lower panel) increased in size while index right pulmonary lesion decreased in size consistent with immune-related response pattern (A-B, upper panel). After 6 cycles, both lesions had decreased in size significantly (C, upper and lower panels). Although pembrolizumab treatment was associated with grade 1 leucopenia and grade 1 ALT/AST elevations initially, total white count and ALT/AST levels subsequently stabilized (graph). HCV viral load fluctuated between 3.36 IU/mL (6.53 log IU/mL) and 5.17 IU/mL (6.71 log IU/mL) before initiation of ledipasvir and sofosbuvir in April 2015. After 12-week course, HCV viral load became undetectable and remains so. To date, she has completed 15 cycles to date with ongoing excellent partial response.

Mentions: Given the minimal disease burden, we encouraged her to pursue initial HCV therapy followed by therapy for advanced melanoma given the recent approval of antiviral agents with unprecedented levels of antiviral activity in HCV. However, she elected against this. In the setting of mild-moderate hepatitis with moderate fibrosis and mildly elevated ALT/AST, we were concerned about a heightened risk of ipilimumab-related hepatitis. Following an extensive discussion of the available options and carefully considering the respective risks of treatment, she commenced therapy with PD-1 inhibitor pembrolizumab at 2 mg/kg every three weeks. Restaging scans following 3 cycles showed a mixed response, slight increase in size of right breast lesion and new hilar and right axillary lymphadenopathy although pulmonary lesions were significantly decreased in size with an overall reduction in total tumor burden. Restaging scans following further 3 cycles of therapy showed significant reduction in size of both hilar/axillary lymphadenopathy and pulmonary nodules consistent with partial response (see Figure 1). After 9 cycles of pembrolizumab with ongoing response, she commenced a 12-week course of ledipasvir (NS5A inhibitor) and sofosbuvir (viral RNA polymerase inhibitor). During cycle 1–3 of pembrolizumab, ALT/AST levels and HCV viral loads remained stable. Following commencement of ledipasvir/sofosbuvir (after 9 cycles of pembrolizumab), HCV viral load declined to below detectable levels. At the time of reporting, she has an ongoing excellent partial response after 15 cycles of therapy with pembrolizumab with normal ALT/AST and undetectable HCV viral load.


PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV.

Davar D, Wilson M, Pruckner C, Kirkwood JM - Case Rep Oncol Med (2015)

Changes in tumor size and correlation with laboratory results in patient 1. After 3 cycles, index right breast lesion (A-B, lower panel) increased in size while index right pulmonary lesion decreased in size consistent with immune-related response pattern (A-B, upper panel). After 6 cycles, both lesions had decreased in size significantly (C, upper and lower panels). Although pembrolizumab treatment was associated with grade 1 leucopenia and grade 1 ALT/AST elevations initially, total white count and ALT/AST levels subsequently stabilized (graph). HCV viral load fluctuated between 3.36 IU/mL (6.53 log IU/mL) and 5.17 IU/mL (6.71 log IU/mL) before initiation of ledipasvir and sofosbuvir in April 2015. After 12-week course, HCV viral load became undetectable and remains so. To date, she has completed 15 cycles to date with ongoing excellent partial response.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581502&req=5

fig1: Changes in tumor size and correlation with laboratory results in patient 1. After 3 cycles, index right breast lesion (A-B, lower panel) increased in size while index right pulmonary lesion decreased in size consistent with immune-related response pattern (A-B, upper panel). After 6 cycles, both lesions had decreased in size significantly (C, upper and lower panels). Although pembrolizumab treatment was associated with grade 1 leucopenia and grade 1 ALT/AST elevations initially, total white count and ALT/AST levels subsequently stabilized (graph). HCV viral load fluctuated between 3.36 IU/mL (6.53 log IU/mL) and 5.17 IU/mL (6.71 log IU/mL) before initiation of ledipasvir and sofosbuvir in April 2015. After 12-week course, HCV viral load became undetectable and remains so. To date, she has completed 15 cycles to date with ongoing excellent partial response.
Mentions: Given the minimal disease burden, we encouraged her to pursue initial HCV therapy followed by therapy for advanced melanoma given the recent approval of antiviral agents with unprecedented levels of antiviral activity in HCV. However, she elected against this. In the setting of mild-moderate hepatitis with moderate fibrosis and mildly elevated ALT/AST, we were concerned about a heightened risk of ipilimumab-related hepatitis. Following an extensive discussion of the available options and carefully considering the respective risks of treatment, she commenced therapy with PD-1 inhibitor pembrolizumab at 2 mg/kg every three weeks. Restaging scans following 3 cycles showed a mixed response, slight increase in size of right breast lesion and new hilar and right axillary lymphadenopathy although pulmonary lesions were significantly decreased in size with an overall reduction in total tumor burden. Restaging scans following further 3 cycles of therapy showed significant reduction in size of both hilar/axillary lymphadenopathy and pulmonary nodules consistent with partial response (see Figure 1). After 9 cycles of pembrolizumab with ongoing response, she commenced a 12-week course of ledipasvir (NS5A inhibitor) and sofosbuvir (viral RNA polymerase inhibitor). During cycle 1–3 of pembrolizumab, ALT/AST levels and HCV viral loads remained stable. Following commencement of ledipasvir/sofosbuvir (after 9 cycles of pembrolizumab), HCV viral load declined to below detectable levels. At the time of reporting, she has an ongoing excellent partial response after 15 cycles of therapy with pembrolizumab with normal ALT/AST and undetectable HCV viral load.

Bottom Line: Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response.HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels.In both patients, no significant toxicities were observed when pembrolizumab was initiated.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.

ABSTRACT
On the basis of remarkable antitumor activity, programmed death receptor-1 (PD-1) inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma in the second-line setting following progression on either CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for BRAF mutated melanoma). Given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections, clinical trials (including regulatory studies) evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV), and/or human immunodeficiency virus (HIV) infections. Herein, we describe two patients with advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response. HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels. Response is ongoing and HCV viral load remains undetectable. In both patients, no significant toxicities were observed when pembrolizumab was initiated. We argue for the further investigation of checkpoint inhibition in cancer patients with underlying chronic viral infections in the context of carefully designed clinical trials.

No MeSH data available.


Related in: MedlinePlus