Unresectable Stage IIIB-IV Melanoma Research Articles

Progression-free survival (PFS) in unresectable melanoma patients (pts) treated with talimogene laherparepvec (T-VEC) versus granulocyte macrophage colony-stimulating factor (GM-CSF) in OPTiM.

9524 Background: T-VEC is a modified oncolytic herpes virus designed as an intralesional therapy for unresectable advanced melanoma. OPTiM was a randomized, phase 3 trial that showed improved durable response rate (DRR) with T-VEC vs GM-CSF in pts with unresectable melanoma with regional or distant metastases (16.3% vs 2.1%, p < 0.001). Treatment benefit of T-VEC on DRR and overall survival (OS) was greater in stage IIIB-IVM1a vs IVM1b-IVM1c melanoma. This is the first report of PFS for T-VEC vs GM-CSF. Methods: OPTiM included pts ≥18 yrs with unresectable stage IIIB-IV melanoma; ≥1 injectable cutaneous, subcutaneous (SC), or nodal lesion; ECOG ≤1; LDH ≤1.5 ULN; ≤3 visceral metastases (excluding lung) with none > 3 cm. Pts were randomized 2:1 to receive intralesional T-VEC or SC GM-CSF. The primary endpoint was DRR (partial or complete response continuously for ≥6 mo starting within 12 mo) and reported previously. In this post hoc analysis, PFS was evaluated overall and by disease stage. Results: This analysis included 436 pts: 295 (68%) T-VEC, 141 (32%) GM-CSF; 57% men; 63 yr median age; 57% stage IIIB-IVM1a, 43% stage IVM1b-IVM1c. In the intention to treat set, T-VEC significantly improved PFS (HR: 0.68, 95% CI: 0.54, 0.85, unstratified log-rank p < 0.001). In stage IIIB-IVM1a, PFS favored the T-VEC arm vs the GM-CSF arm (HR: 0.60, 95% CI: 0.44, 0.80, unstratified log-rank p < 0.001). No treatment difference was seen in stage IVM1b-IVM1c (HR: 0.81, 95% CI: 0.57, 1.15, unstratified log-rank p = 0.199). Overall, the 12 mo PFS rate for T-VEC was 14.4% (95% CI: 10.5, 18.8) and GM -CSF was 4.6% (95% CI: 1.6, 10.2). In stage IIIB-IVM1a, the 12 mo PFS rate for T-VEC was 19.9% (95% CI: 14.0, 26.6) and GM-CSF was 3.2% (95% CI: 0.6, 9.9). In stage IVM1b-IVM1c, the 12 mo PFS rate for T-VEC was 7.4% (95% CI: 3.5, 13.2) and GM-CSF was 8.0% (95% CI: 1.9, 20.1). Conclusions: T-VEC demonstrated an improvement in PFS vs GM-CSF, driven primarily by pts with stage IIIB-IVM1a melanoma. This is consistent with previous data showing more pronounced OS benefit with T-VEC and greater efficacy with other immunotherapies in early metastatic disease. Clinical trial information: NCT00769704.

352P - Early safety from a phase I, multicenter, open-label, dose de-escalation study of talimogene laherparepvec (T-VEC) in Japanese patients (pts) with unresectable stage IIIB-IV melanoma (MEL)

352P - Early safety from a phase I, multicenter, open-label, dose de-escalation study of talimogene laherparepvec (T-VEC) in Japanese patients (pts) with unresectable stage IIIB-IV melanoma (MEL)

Primary results from a randomized (1:1), open-label phase II study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected stage IIIB- IV melanoma.

9509 Background: T is a HSV-1-based oncolytic virus designed to selectively replicate in tumors and produce GM-CSF to stimulate antitumor immune responses. I is an anti-CTLA-4 Ab that blocks inhibition of activated T cells. This is the first randomized study to evaluate the addition of an oncolytic virus to a checkpoint inhibitor. Methods: The 1o endpoint was ORR by immune-related response criteria. Key 2o endpoints: duration of response, disease control rate (DCR), PFS, OS, and safety. Prior treatment was allowed but not required. Pts had unresected stage IIIB-IV melanoma with measurable/injectable tumor(s) and no evidence of immunosuppression. T was given at approved dosing until no injectable tumors, disease progression (PD), or intolerance. I was started at w6 in T+I and at w1 in I at 3 mg/kg IV q3w x 4. Primary analysis occurred 6 m after last pt enrolled. Results: 198 pts were randomized: 98 T+I; 100 I. Characteristics were similar: 54% stage IIIB-IVM1a, 46% IVM1b/c. Median follow up time was 68 w (T+I) and 58 w (I). ORR was 38.8% (T+I) and 18.0% I, P = 0.002, Odds ratio (OR) 2.9. 89% T+I and 83% I pts remain in response. Unconfirmed visceral lesion response was 35.5% T+I vs 13.6% I. OS is immature. Of 190 pts (safety set: 95 T+I, 95 I), most common adverse events (AEs) for T+I, I (%) were fatigue (59, 42), chills (53, 3), and diarrhea (42, 35). 28% T+I and 18% I pts had gr ≥3 tx-related AE. There were 3 deaths (all unrelated) in T+I: 1 myocardial infarction and 2 PD. Conclusions: The study met the 1o endpoint. ORR was significantly higher for T+I vs I; responses were not limited to injected lesions. Toxicity of T+I combination was tolerable with no unexpected AEs. Clinical trial information: NCT01740297. [Table: see text]

Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma.

9568Background: T-VEC is a herpes simplex virus (HSV)-1 -based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF and stimulate antitumor immune responses in melanoma. T-VEC significantly improved durable response rate vs GM-CSF in stage IIIB-IV melanoma patients (pts) with injectable tumors. Pembro inhibits programmed cell death protein 1 and improves survival in advanced melanoma. The combination may further improve clinical benefit. Here we report phase 1b efficacy, safety and biomarker data from a phase 1b/3 study of T-VEC+pembro in unresectable stage IIIB-IV melanoma (NCT02263508) with all pts having started on T-VEC+pembro ≥ 6 mo prior. Methods: Key inclusion criteria: unresectable stage IIIB-IV melanoma, injectable lesions; no prior systemic tx; and ECOG PS 0-1. T-VEC: ≤ 4 mL in (sub)cutaneous/nodal lesions, 106 PFU/mL d1, 108PFU/mL d22 then Q2W; pembro: IV, 200 mg d36 then Q2W. Tx until first occurrence of: complete response (CR); no injectable tumors (for T-VEC); ...

A Phase I/III, multicenter, open-label trial of talimogene laherparepvec (T-VEC) in combination with pembrolizumab for the treatment of unresected, stage IIIb-IV melanoma (MASTERKEY-265)

Meeting abstracts T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF, and stimulate antitumor immune responses. OPTiM, a Phase III trial of T-VEC vs GM-CSF in unresectable stage IIIB-IV melanoma, improved the primary endpoint

Abstract B13: A phase 2, randomized, open-label trial assessing efficacy and safety of talimogene laherparepvec (T-VEC) neoadjuvant treatment (tx) plus surgery vs. surgery for resectable stage IIIB-IVM1a melanoma

Abstract Background: The risk of recurrence and death in patients (pts) with stages IIIB to IVM1a melanoma following resection is high. T-VEC is an HSV-1 derived oncolytic immunotherapy designed to selectively replicate in tumors and produce GM-CSF to enhance systemic antitumor immune responses. In OPTiM, a randomized phase 3 trial of intralesional T-VEC vs subcutaneous GM-CSF in pts with unresected Stage IIIB-IV melanoma, intralesional T-VEC improved durable response rate (DRR; partial response or complete response [CR] lasting continuously for ≥6 months [m]) from 2% to 16% (P<0.001) vs GM-CSF. In the primary overall survival (OS) analysis, median OS increased 4.4 m in the T-VEC arm (from 18.9 m to 23.3 m; HR=0.79, 95%CI: 0.62-1.00; P=0.051) (Kaufman et al, ASCO 2014). By lesion-level tumor response analysis, 64% of injected, 34% of uninjected non-visceral, and 15% of uninjected visceral lesions decreased in size by ≥ 50%, demonstrating systemic antitumor effects of T-VEC (Andtbacka et al, SSO 2014). Therefore, neoadjuvant T-VEC may help to decrease recurrence after resection of melanoma by improving local control through higher rates of tumor-free margin surgical (R0) resection, and decrease distant metastasis through systemic antitumor effects. Methods: This is a phase 2, multicenter, randomized, open-label study designed to estimate the efficacy of neoadjuvant T-VEC followed by surgery compared to surgery alone in pts with resectable stage IIIB, IIIC, or IVM1a melanoma. Key eligibility criteria are age ≥ 18 y old, melanoma stages IIIB/C or IVM1a with at least 1 injectable lesion, and Eastern Cooperative Oncology Group performance status 0 or 1. Prior systemic, regional, and radiation therapies for melanoma must have been completed ≥ 3 m prior to randomization. Primary ocular and mucosal melanoma is excluded. Pts with history or evidence of symptomatic autoimmune disease, immunodeficiency, clinically significant immunosuppression, active herpetic skin lesions or prior complications of HSV-1 infection, intermittent/chronic systemic tx with an antiherpetic drugs, and prior T-VEC or tumor vaccines are excluded. 150 pts are planned to be randomized 1:1 to receive either (A) 6 doses of T-VEC for 12 w followed by resection or (B) immediate resection. T-VEC will be administered intralesionally into injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 106 plaque forming units (PFU)/mL at d1 w1 followed by 108 PFU/mL at d1 of w4, 6, 8, 10, and 12, or until all injectable tumors have disappeared or intolerance to T-VEC, whichever is first. Pts experiencing growth in existing tumors or the appearance of new tumors can remain on T-VEC until w12 of therapy unless other tx, including immediate surgery, is warranted per investigator. The primary endpoint is recurrence-free survival (RFS). The primary analysis of the RFS will occur at the later timepoint of either 2 y after the end of randomization or 64 events of recurrence based on assumption of HR 0.6 benefiting T-VEC arm in RFS at 2 y. Additional and the final analyses will occur at 3 and 5 y after the randomization. Secondary endpoints are 2-y, 3-y, 5-y RFS, OS, overall tumor response and tumor response in injected and uninjected lesions (T-VEC arm only), rates of R0 resection and pathological CR, local recurrence and distant metastases-free survival, and safety. Tumors and blood samples will be collected before and after T-VEC tx to investigate the relationship between biomarkers of the immune system and response to tx. Citation Format: Robert HI Andtbacka, Mohamed Shabooti, Ai Li, Michael Chastain, Mark Shilkrut. A phase 2, randomized, open-label trial assessing efficacy and safety of talimogene laherparepvec (T-VEC) neoadjuvant treatment (tx) plus surgery vs. surgery for resectable stage IIIB-IVM1a melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B13.

Survival, safety, and response patterns in a phase 1b multicenter trial of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.

9063 Background: T-VEC is an HSV-derived oncolytic immunotherapy designed to induce systemic antitumor immunity. In a phase 3 melanoma study, T-VEC monotherapy significantly improved durable respon...

Association between durable response (DR) and overall survival (OS) in patients with unresected stage IIIb-IV melanoma treated with Talimogene Laherparepvec (T-VEC) in the Phase III OPTiM trial

Meeting abstracts T-VEC is an HSV-1-derived oncolytic immunotherapy designed to selectively replicate within tumors, produce GM-CSF and enhance systemic antitumor immune responses. In OPTiM ([NCT00769704][1]), a randomized Phase III trial of intralesional T-VEC vs subcutaneous GM-CSF for unresected

A Phase 1B/2, Multicenter, Open Label Trial to Evaluate the Safety and Efficacy of Talimogene Laherparepvec (T-Vec) and Ipilimumab (Ipi) Versus Ipi Alone in Previously Untreated, Unresected, Stage Iiib, Iiic, and Iv Melanoma

ABSTRACT Background: T-VEC is a herpes simplex virus-1 based oncolytic immunotherapy designed to selectively replicate in cancer cells and produce GM-CSF to initiate systemic antitumor immune responses. OPTiM, a phase 3 trial of T-VEC vs GM-CSF in unresected stage IIIB-IV melanoma, met its primary endpoint of higher durable response rate in favor of T-VEC. Objective response rate (ORR) was 26.4% vs 5.7%, with complete response (CR) 10.8% vs 0.7% in favor of T-VEC. Immune checkpoint blockade with ipi improves overall survival (OS) in advanced melanoma. Ipi has a 10-15% ORR with 1-2% CR by immune-related response criteria (irRC). A phase 1b/2 study was designed to evaluate safety and efficacy when T-VEC is added to ipi as a priming regimen (clinicaltrials.gov #NCT01740297). Phase 1b showed the combination was tolerable, and phase 2 opened in Aug 2013. Trial design: Phase 2 evaluates the efficacy and safety of T-VEC + ipi vs ipi alone in untreated, unresectable stage IIIB-IV melanoma. Approximately 140 patients will be randomized 1:1. The primary endpoint is OS. Secondary endpoints: safety, ORR, time to response, duration of response, progression-free survival, resection rate, 1- and 2-yr survival. Key eligibility criteria: unresectable stage IIIB-IV melanoma naive to systemic therapy (except adjuvant); ECOG performance status 0-1; measurable disease; ≥1 injectable cutaneous/ subcutaneous/ nodal tumor; no brain metastases; no symptomatic autoimmunity; no immunosuppression; no HIV/HBV/HCV; no antiherpetic therapy. T-VEC is injected into nonvisceral lesions up to 4 × 106 plaque forming units/mL (pfu/mL) on d1, wk 1; up to 4 × 108 pfu/mL d1, wk 4; then q2w. Ipi is dosed 3 mg/kg IV q3w × 4 starting wk 6 with the 3rd T-VEC dose. Treatment with T-VEC continues until all injectable tumors have disappeared, disease progression per irRC, or intolerance. Enrollment began in the USA and is expected to open in France/Germany by Dec 2014. Combining T-VEC and ipi represents a novel immunotherapeutic approach to promote the initiation of antitumor immunity and simultaneously enhance antitumor T-cell responses. Disclosure: F.A. Collichio: Dr. Collichio has served on an advisory board and received consultant fees from Amgen, Inc. She receives clinical trial research support from Amgen, Novartis, GlaxoSmithKline, Morphotec, and Bristol-Myers Squibb; M. Milhem: Dr. Milhem has participated on advisory boards for Genentech and Amgen, Inc.; R.H. Andtbacka: Dr. Andtbacka has participated in advisory boards for Amgen, Inc.; I. Puzanov: Dr. Puzanov has received honoraria for participation on advisory boards for Amgen, Inc. His institution receives research funding from Amgen, Inc.; Y. Saenger: Dr. Saenger has participated in advisory boards for Amgen, Inc.; J. Chesney: Dr. Chesney has served on an advisory board for Amgen, Inc. O. Hamid: Dr. Hamid has served as a consultant for Amgen, Inc. and has received clinical trials support from Amgen, Inc.; T. Logan: Dr. Logan's institution has received grant money, and writing assistance, medicines, equipment, or administrative support from Amgen, Inc.; J. Glaspy: Dr. Glaspy has served as a consultant to and received research support from Amgen, Inc.; C. Lebbe: Dr. Lebbe has participated in advisory boards for Roche, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, and Amgen, Inc.; J. Gansert: Dr. Gansert is a compensated employee and stockholder of Amgen, Inc.; A. Li: Ai Li is a compensated employee and stockholder of Amgen, Inc.; J. Chou: Dr. Chou is a compensated employee and stockholder of Amgen, Inc.; H. Kaufman: Dr. Kaufman has received honoraria from Amgen, Inc. for participation in advisory boards and has received research funding from Amgen, Inc. for conducting clinical trials. All other authors have declared no conflicts of interest.

Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.

9029^ Background: T-VEC, an HSV-1 derived oncolytic immunotherapy designed to induce systemic antitumor immunity, showed a ≥ 6 mos higher durable response rate vs GM-CSF in a phase 3 melanoma trial...

Phase 1 results of a phase 1b/2, multicenter, open-label trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) vs ipi alone in previously untreated, unresected stage IIIB-IV melanoma

Meeting abstracts T-VEC is a herpes simplex virus type-1-derived oncolytic immunotherapy designed to produce GM-CSF and to selectively replicate in and lyse tumors to induce a systemic anti-tumor immune response. A phase 3 study of T-VEC in Stage IIIB-IV melanoma demonstrated a significant

OPTiM Study Results

Results from the Efficacy and Safety Study of OncoVEX Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Compared to GM-CSF in Melanoma [OPTiM; NCT00769704; Andtbacka RHI et al. J Clin Oncol 2013 (suppl; abstr LBA9008)] showed that a genetically modified version of herpes simplex virus type 1 (talimogene laherparepvec), is safe and improves durable response rate in patients with unresectable stage IIIB-IV melanoma.

OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma.

LBA9008 Background: T-VEC is an oncolytic immunotherapy (OI) derived from herpes simplex virus type-1 designed to selectively replicate within tumors and to produce GM-CSF to enhance systemic antitumor immune responses. OPTiM is a randomized, phase III trial of T-VEC or GM-CSF in patients (pts) with unresected melanoma with regional or distant metastases. We report the primary results of the first phase III study of OI. Methods: Key criteria: age ≥18 yrs; ECOG ≤1; unresectable melanoma stage IIIB/C or IV; injectable cutaneous, SC, or nodal lesions; LDH ≤1.5X upper limit of normal; ≤3 visceral lesions (excluding lung), none >3 cm. Pts were randomized 2:1 to intralesional T-VEC (initially ≤ 4 mL x106 pfu/mL then after 3 wks, ≤ 4 mL x108 pfu/mL Q2W) or SC GM-CSF (125 µg/m2qd x 14 days q28d). The primary endpoint was durable response rate (DRR): partial or complete response (CR) continuously for ≥6 mos starting within 12 mos. Responses were per modified WHO by blinded central review. A planned interim analysis of overall survival (OS; key secondary endpoint) was performed. Results: 436 pts are in the ITT set: 295 (68%) T-VEC, 141 (32%) GM-CSF. 57% were men; median age was 63 yrs. Stage distribution was: IIIB/C 30%, IVM1a 27%, IVM1b 21%, IVM1c 22%. Objective response rate with T-VEC was 26% (95% CI: 21%, 32%) with 11% CR, and with GM-CSF was 6% (95% CI: 2%, 10%) with 1% CR. DRR for T-VEC was 16% (95% CI: 12%, 21%) and 2% for GM-CSF (95% CI: 0%, 5%), p<0.0001. DRR by stage (T-VEC, GM-CSF) was IIIB/C (33%, 0%), M1a (16%, 2%), M1b (3%, 4%), and M1c (8%, 3%). Interim OS showed a trend in favor of T-VEC; HR 0.79 (95% CI: 0.61, 1.02). Most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. Serious AEs occurred in 26% of T-VEC and 13% of GM-CSF pts. No ≥ grade 3 AE occurred in ≥ 3% of pts in either arm. Conclusions: T-VEC demonstrated both a statistically significant improvement in DRR over GM-CSF in pts with unresectable stage IIIB-IV melanoma and a tolerable safety profile; an interim analysis showed a trend toward improved OS. T-VEC represents a novel potential tx option for melanoma with regional or distant metastases. Clinical trial information: NCT00769704.