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. 2016 Aug;65(8):951-9.
doi: 10.1007/s00262-016-1856-z. Epub 2016 Jun 13.

Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis

Markus V Heppt  1 , Thomas K Eigentler  2 , Katharina C Kähler  3 , Rudolf A Herbst  4 , Daniela Göppner  5 , Thilo Gambichler  6 , Jens Ulrich  7 , Edgar Dippel  8 , Carmen Loquai  9 , Beatrice Schell  10 , Bastian Schilling  11   12 , Susanne G Schäd  13 , Erwin S Schultz  14 , Fanny Matheis  1 , Julia K Tietze  1 , Carola Berking  15
Affiliations

Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis

Markus V Heppt et al. Cancer Immunol Immunother. 2016 Aug.

Abstract

Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.

Keywords: Electrochemotherapy; Immune checkpoint blockade; Ipilimumab; Melanoma; Nivolumab; Pembrolizumab.

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Conflict of interest statement

Beatrice Schell, Edgar Dippel, Fanny Matheis, Markus V. Heppt, Susanne G. Schäd, and Thilo Gambichler declare no conflict of interest. Bastian Schilling: advisory for Roche, M.S.D. Sharp and Dohme, and Bristol-Myers Squibb, travel support from Roche, Bristol-Myers Squibb and Amgen, honoraria from Roche, M.S.D. Sharp and Dohme and Bristol-Myers Squibb. Carola Berking: advisory for Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, M.S.D. Sharp and Dohme, Novartis, Roche, speaker’s honoraria by Bristol-Myers Squibb, GlaxoSmithKline, M.S.D. Sharp and Dohme, Novartis, Roche. Carmen Loquai: advisory for Roche, Amgen, Novartis, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Ribological, speaker’s honoraria from Roche, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis, travel reimbursement from Roche, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis. Daniela Göppner: advisory for Roche, Amgen, Bristol-Myers Squibb and M.S.D. Sharp and Dohme, speaker’s honoraria from Roche and Bristol-Myers Squibb, travel reimbursement from Roche, Amgen and Novartis. Erwin S. Schultz: advisory for Bristol-Myers Squibb and Novartis, speaker’s honoraria for Novartis. Julia K. Tietze: speaker’s honoraria from Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis, Roche. Jens Ulrich: advisory for Roche, speaker’s honoraria from Bristol-Myers Squibb, M.S.D. Sharp and Dohme, GlaxoSmithKline, IGEA, Novartis, Roche, travel reimbursement from Bristol-Myers Squibb, IGEA, Medac, Roche. Katharina C. Kähler: advisory for Roche, Amgen, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, speaker’s honoraria from Roche, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis, travel reimbursement from Roche, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis. Rudolf A. Herbst: advisory for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Roche, speaker’s honoraria from Bristol-Myers Squibb, GlaxoSmithKline, M.S.D. Sharp and Dohme, Novartis, Roche. Thomas K. Eigentler: advisory for AMGEN, Roche, Bristol-Myers Squibb, travel support from Bristol-Myers Squibb and Novartis, speaker’s honoraria from Roche.

Figures

Fig. 1
Fig. 1
Complete local response before (a) and 3 months after (b) the combination therapy on the left upper arm. The patient received three cycles of ipilimumab along with ECT and experienced grade 3 autoimmune-related colitis
Fig. 2
Fig. 2
Kaplan–Meier estimates for progression-free (a) and overall survival (b) of the study population. The entire cohort comprised 33 patients receiving the combination therapy with n = 28 for ipilimumab and n = 5 for PD-1 inhibition with either pembrolizumab (n = 3) or nivolumab (n = 2). The median time to disease progression was 2.5 months (2 months for ipilimumab, 5 months for PD-1; p = 0.77). The median OS was 15 months (not reached for ipilimumab, 15 months for PD-1; p = 0.98)
Fig. 3
Fig. 3
Kaplan–Meier estimates of the study population according to therapy line (a) and elevation of serum LDH at baseline (b). Time to disease progression and overall survival are shown and did not show significant differences between therapy lines 1 and 2 (p = 0.95 for PFS; p = 0.21 for OS) nor LDH elevation (p = 0.14 for PFS; p = 0.21 for OS)
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