Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial

Abstract

Purpose: Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In this study, we describe the patterns and time course of response to T-VEC from the phase III OPTiM trial of 436 patients with unresected stages IIIB-IV melanoma.

Methods: Lesion-level response analyses were performed based on the type of lesion (injected or uninjected cutaneous, subcutaneous, or nodal lesions; or visceral lesions [uninjected]), and the best percentage change from baseline of the sum of products of the longest diameters was calculated. Patients randomized to T-VEC (n = 295) who experienced a durable response (continuous partial or complete response for ≥6 months) were evaluated for progression prior to response (PPR), defined as the appearance of a new lesion or >25 % increase in total baseline tumor area.

Results: T-VEC resulted in a decrease in size by ≥50 % in 64 % of injected lesions (N = 2116), 34 % of uninjected non-visceral lesions (N = 981), and 15 % of visceral lesions (N = 177). Complete resolution of lesions occurred in 47 % of injected lesions, 22 % of uninjected non-visceral lesions, and 9 % of visceral lesions. Of 48 patients with durable responses, 23 (48 %) experienced PPR, including 14 who developed new lesions only. No difference in overall survival was observed, and median duration of response was not reached in patients with PPR versus those without PPR.

Conclusions: Responses in uninjected lesions provide validation of T-VEC-induced systemic immunotherapeutic effects against melanoma. PPR did not negatively impact the clinical effectiveness of T-VEC.

Figures

Fig. 1

T-VEC administration generated response in both injected and uninjected tumor lesions, including visceral lesions. Response of a individual injected lesions; b uninjected non-visceral lesions; and c visceral lesions (also uninjected). Vertical axis depicts maximal change in individual tumor lesion size (products of the two largest perpendicular diameters) from baseline

Fig. 2

Analysis of the patterns of response in T-VEC-treated patients in OPTiM. * Includes three patients with PPR in existing lesions who may have also developed new lesions. PPR progression prior to response, GM-CSF granulocyte–macrophage colony-stimulating factor, DR durable response

Fig. 3

Four distinct patterns of response in T-VEC-treated patients. a Without PPR and DR onset ≤6 months; b without PPR and DR onset >6 months; c with PPR due to new lesions only; and d with PPR due to existing lesions (with or without new lesions). The vertical axis depicts the change in tumor area from baseline, as assessed by the Endpoint Assessment Committee. PPR progression prior to response, DR durable response

Fig. 4

Examples of patients treated with T-VEC with a DR without PPR. a Patient without PPR and DR onset ≤6 months. The patient had recurrent stage IIIC melanoma with multiple in-transit tumor lesions on the leg. All lesions were injected with T-VEC and all resolved (CR) by 37 weeks after the start of treatment. The patient remained in CR until the end of the study, with DR duration of 60 weeks. b Patient without PPR and measurable response onset >6 months. The patient had recurrent stage IIIB (in-transit) melanoma of the scalp with 20 cutaneous lesions that were injected with T-VEC. Partial response was recorded on week 30 after the start of treatment. Lesions resolved completely by week 38 and the patient remained in CR until the end of the study, with DR duration of 48 weeks. Responses are reported per External Assessment Committee. Titles above each photography are weeks on study. DR durable response, PRR progression prior to response, CR complete response

Fig. 5

Example of a patient treated with T-VEC with a durable response and PPR due to enlargement of existing lesions. The patient had recurrent stage IVM1c melanoma of the right lower extremity with multiple regional and distant nodal metastases and elevated serum lactic dehydrogenase. Right inguinal and iliac lymph nodes were injected with T-VEC under ultrasound guidance (from week 14 for the iliac lymph node). PPR and increase in size in both injected and uninjected lesions were documented during the first 26 weeks of treatment. Responses are reported per External Assessment Committee. Titles above each photography are weeks on study. Partial response was recorded on week 40, and continued for 28 weeks. PPR progression prior to response