Complete clinical response to intralesional talimogene laherparepvec injection in a patient with recurrent, regionally advanced Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine malignancy that is highly aggressive and considered incurable upon distant metastasis. The incidence rate in the United States has significantly increased in the last 30 years and is estimated to be 0.79 per 100,000.1Fitzgerald T.L. Dennis S. Kachare S.D. Vohra N.A. Wong J.H. Zervos E.E. Dramatic increase in the incidence and mortality from Merkel cell carcinoma in the United States.Am Surg. 2015; 81: 802-806Crossref PubMed Google Scholar The prognosis for advanced MCC is poor, with a 5-year overall survival rate of 0% to 18%.2Lemos B.D. Storer B.E. Iyer J.G. et al.Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.J Am Acad Dermatol. 2010; 63: 751-761Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar Although MCC is chemotherapy sensitive, responses are not durable, and most patients with advanced MCC succumb to the disease. Avelumab and pembrolizumab are the only treatments approved by the US Food and Drug Administration for patients with MCC thus far. A phase II study found a 1-year progression-free survival rate of 30% compared with 0% with chemotherapy.3Iyer J.G. Blom A. Doumani R. et al.Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma.Cancer Med. 2016; 5: 2294-2301Crossref PubMed Scopus (141) Google Scholar, 4Cowey C.L. Mahnke L. Espirito J. Helwig C. Oksen D. Bharmal M. Real-world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA.Future Oncol. 2017; 13: 1699-1710Crossref PubMed Scopus (73) Google Scholar Talimogene laherparepvec (T-VEC) is a modified oncolytic herpes simplex virus that replicates in tumor cells and expresses granulocyte-macrophage colony-stimulating factor, promoting local and systemic antitumor response. T-VEC treatment was approved by the US Food and Drug Administration for treatment of advanced melanoma. In a phase III study, intralesional T-VEC injection had superior durable and overall response rates compared with subcutaneous granulocyte-macrophage colony-stimulating factor in patients with advanced melanoma.5Andtbacka R.H. Kaufman H.L. Collichio F. et al.Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.J Clin Oncol. 2015; 33: 2780-2788Crossref PubMed Scopus (1369) Google Scholar However, the clinical benefit of T-VEC in patients with advanced MCC is not known. Here we report on a patient with surgically incurable, recurrent MCC who had a complete response to intralesional T-VEC. A 66-year-old white man had a 6.5-cm MCC invading into the subcutaneous fat of his left buttock diagnosed in July 2014. He underwent wide local excision of the primary MCC, 2 adjacent satellite lesions, and left inguinal sentinel lymph node, which found one 13-mm positive node. Subsequently, he underwent complete left inguinofemoral lymph node dissection with negative nodes for metastasis. He received adjuvant radiotherapy to the primary site. Subsequently, he received 4 cycles of adjuvant cisplatin/etoposide. In March 2015, his MCC recurred with in-transit metastases in the left thigh and lower back. He then received pembrolizumab. After 1 dose, severe myocarditis developed, which resolved with high-dose prednisone treatment. He achieved nearly 2 years of a complete response after the 1 dose. In March 2017, the MCC recurred with 4 in-transit subcutaneous metastases in his left calf, which grew rapidly by June 2017 (Fig 1, A and B). Starting June 2017, he received T-VEC injection into 3 of the lesions at a dose of 2 mL of 106 plaque-forming units/mL followed by 4 mL of 108 plaque-forming units of T-VEC injected into the 3 lesions every 2 weeks. His disease regressed within 5 weeks. The only adverse events were grade 1 fever, chills, and fatigue. A positron emission tomogram (PET)/computed tomogram (CT) scan in September 2017 found reduction in size and metabolic activity of all 4 metastatic lesions, including the un-injected lesion. In February 2018, all 3 injected lesions became flat, without evidence of active metastases (Fig 1, C), and T-VEC was discontinued. A PET/CT scan performed in June 2019 found no areas of metastasis (Fig 1, D). This case report demonstrates a potential benefit of oncolytic virus therapy in MCC. When our patient had recurrence of MCC, he did not have effective treatment options given his severe myocarditis with pembrolizumab. Intralesional T-VEC resulted in a dramatic durable response for ≥2 years even in the uninjected metastatic lesion. Only 2 cases of intralesional T-VEC treatment in MCC exist in the literature.6Blackmon J.T. Dhawan R. Viator T.M. Terry N.L. Conry R.M. Talimogene laherparepvec for regionally advanced Merkel cell carcinoma: a report of 2 cases.JAAD Case Rep. 2017; 3: 185-189Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar As in our case, these patients had regionally advanced disease with surgically incurable MCC. Intralesional T-VEC injection was given to all metastatic lesions as first-line therapy. The patients had durable complete and partial responses, respectively. Unlike these 2 cases, our case also had a complete response in uninjected lesion with T-VEC, demonstrating both an oncolytic and systemic immune response. One disadvantage of intralesional T-VEC treatment is that it requires injectable lesions. It is also questionable whether the intralesional T-VEC treatment is superior to checkpoint inhibitors in patients with MCC. In patients with metastatic melanoma, intralesional T-VEC therapy has only shown a positive trend of overall survival benefit, whereas the checkpoint inhibitors lead to a significant survival benefit.5Andtbacka R.H. Kaufman H.L. Collichio F. et al.Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.J Clin Oncol. 2015; 33: 2780-2788Crossref PubMed Scopus (1369) Google Scholar Growing evidence suggests that intralesional T-VEC could synergize immune stimulation by checkpoint inhibitors. A phase II study in patients with metastatic melanoma compared a combination of T-VEC and ipilimumab to ipilimumab alone and found a higher response rate (39% vs 18%).7Chesney J. Puzanov I. Collichio F. et al.Randomized, open-label phase ii study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma.J Clin Oncol. 2018; 36: 1658-1667Crossref PubMed Scopus (311) Google Scholar Meanwhile, in a phase IB study, a combination of T-VEC and pembrolizumab versus pembrolizumab alone had a response rate of 62% versus 34%.8Long G.V. Dummer R. Ribas A. et al.Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma.J Clin Oncol. 2016; 34: 9568Crossref Google Scholar There are 3 clinical trials investigating intralesional T-VEC in patients with metastatic MCC (Table I). These include a phase II study of T-VEC with hypofractionated radiotherapy, a phase II study of T-VEC with nivolumab, and a phase I study of T-VEC with TTI-621 (a soluble recombinant fusion protein consisting of CD47 binding domain of human signal regulatory protein-α linked to the Fc region of human IgG1) in solid tumors, including MCC. With these investigations of intralesional T-VEC treatment, we will better understand its place in the treatment of advanced MCC in the future.Table ICurrently enrolling clinical trials of intralesional T-VEC therapy in patients with Merkel cell carcinomaClinical trialTreatmentPrimary endpointPhasePlanned no. of patientsNCT02819843•T-VEC with radiotherapy•TVEC without radiotherapyPR, CRII34NCT02978625•T-VEC + nivolumab•T-VEC + placeboORRII68NCT02890368•TI-621∗TTI-621 is a soluble recombinant fusion protein consisting of CD47 binding domain of human signal regulatory protein-α linked to the Fc region of human IgG1. monotherapy•TTI-621∗TTI-621 is a soluble recombinant fusion protein consisting of CD47 binding domain of human signal regulatory protein-α linked to the Fc region of human IgG1. + anti PD-1/PD-L1 antibody•TTI-621∗TTI-621 is a soluble recombinant fusion protein consisting of CD47 binding domain of human signal regulatory protein-α linked to the Fc region of human IgG1. + pegylated interferon-α2a•TTI-621∗TTI-621 is a soluble recombinant fusion protein consisting of CD47 binding domain of human signal regulatory protein-α linked to the Fc region of human IgG1. + T-VEC•TTI-621∗TTI-621 is a soluble recombinant fusion protein consisting of CD47 binding domain of human signal regulatory protein-α linked to the Fc region of human IgG1. + radiationOptimal dose findingI240CR, Complete response; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; ORR, overall response rate; PR, partial response.∗ TTI-621 is a soluble recombinant fusion protein consisting of CD47 binding domain of human signal regulatory protein-α linked to the Fc region of human IgG1. Open table in a new tab CR, Complete response; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; ORR, overall response rate; PR, partial response.