Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Melanoma

A Phase 2, Multicenter, Randomized, Open-label Trial Assessing the Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Resectable, Stage IIIB to IVM1a Melanoma

This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.

Study Overview

• Status: Completed
• Conditions: Completely Resectable Stage IIIB, IIIC, or IVM1a Melanoma
• Intervention / Treatment: Procedure: Immediate surgical resection of melanoma lesion(s); Drug: Talimogene Laherparepvec

Detailed Description

This is a phase 2, multicenter, randomized, open-label study to estimate the efficacy of talimogene laherparepvec as a neoadjuvant treatment followed by surgery compared to surgery alone in subjects with completely resectable stage IIIB, IIIC, or IVM1a melanoma.

Arm 1: Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).

Arm 2: Immediate surgical resection of melanoma tumor lesion(s) Following surgery, adjuvant systemic therapy and/or radiotherapy may be administered at the investigator's discretion and per the institutional standard of care.

Subjects will be followed for safety approximately 30 (+15) days after surgery and for disease recurrence, subsequent anticancer therapy, and survival every 3 months (±30 days) for first 3 years after the end of the safety follow-up period and then every 6 months (±30 days) until death, subject withdraws full consent, or up to 5 years after the last subject is randomized.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • North Sydney, New South Wales, Australia, 2060
      • Research Site
  • South Australia
    • Woodville South, South Australia, Australia, 5011
      • Research Site
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Research Site
• Brazil
  • Rio de Janeiro, Brazil, 20220-410
    • Research Site
  • Santa Catarina
    • Florianopolis, Santa Catarina, Brazil, 88034-000
      • Research Site
  • São Paulo
    • Barretos, São Paulo, Brazil, 14784-400
      • Research Site
• France
  • Dijon, France, 21034
    • Research Site
  • Marseille cedex 05, France, 13385
    • Research Site
  • Paris, France, 75010
    • Research Site
  • Pierre Benite Cedex, France, 69495
    • Research Site
  • Toulouse cedex 9, France, 31059
    • Research Site
• Greece
  • Athens, Greece, 11527
    • Research Site
  • Heraklion - Crete, Greece, 71110
    • Research Site
• Poland
  • Poznan, Poland, 60-856
    • Research Site
  • Warszawa, Poland, 02-781
    • Research Site
  • Wroclaw, Poland, 50-368
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Research Site
  • Saint-Petersburg, Russian Federation, 197758
    • Research Site
  • Saint-Petersburg, Russian Federation, 197022
    • Research Site
• Spain
  • Madrid, Spain, 28009
    • Research Site
  • Andalucía
    • Malaga, Andalucía, Spain, 29010
      • Research Site
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Research Site
• Switzerland
  • Chur, Switzerland, 7000
    • Research Site
  • Zürich, Switzerland, 8091
    • Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • Research Site
  • California
    • Duarte, California, United States, 91010
      • Research Site
    • Orange, California, United States, 92868
      • Research Site
    • San Francisco, California, United States, 94115
      • Research Site
    • Santa Monica, California, United States, 90404
      • Research Site
  • Florida
    • Daytona Beach, Florida, United States, 32117
      • Research Site
    • Gainesville, Florida, United States, 32610
      • Research Site
    • Tampa, Florida, United States, 33612
      • Research Site
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Research Site
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Research Site
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Research Site
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Research Site
  • New York
    • New York, New York, United States, 10032
      • Research Site
    • New York, New York, United States, 10029
      • Research Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Research Site
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75390
      • Research Site
    • Dallas, Texas, United States, 75230
      • Research Site
    • Houston, Texas, United States, 77030
      • Research Site
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed diagnosis of stage IIIB, IIIC or IVM1a melanoma eligible for complete surgical resection.
• Prior systemic, regional and radiation anticancer therapies for melanoma must have been completed at least 3 months prior to randomization.
• Subject must have measurable disease and must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
• Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and must have a serum lactate dehydrogenase (LDH) ≤ 1.0 X upper limit of normal and adequate hematologic, hepatic, renal, and coagulation organ function- Other criteria may apply

Exclusion Criteria:

• Subject must not have primary ocular or mucosal melanoma, or history or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia).
• Subject must not have history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other symptomatic autoimmune disease.
• Subject must not have evidence of clinically significant immunosuppression or active herpetic skin lesions or prior complications of herpes simplex type 1 (HSV-1) infection (eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic systemic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
• Subject known to have acute or chronic active hepatitis B, hepatitis C, or human immunodeficiency virus infection will also be excluded.
• Subject must not have been treated previously with talimogene laherparepvec or tumor vaccine.

Other criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Surgery; Surgical resection of melanoma tumor lesion(s)	Procedure: Immediate surgical resection of melanoma lesion(s); Surgical resection of melanoma tumor lesion(s) will be performed after randomization any time during weeks 1 to 6.
Experimental: Talimogene Laherparepvec; Talimogene laherparepvec for 6 doses followed by surgical resection of melanoma tumor lesion(s).	Drug: Talimogene Laherparepvec; Talimogene laherparepvec will be administered by intralesional injection into the injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 10^6 plaque forming units (PFU)/mL at day 1 of week 1 followed by a dose of 10^8 PFU/mL at day 1 (±3 days) of week 4, 6, 8, 10 and 12 or until all injectable tumors have disappeared, or intolerance of study treatment or in the opinion of the investigator, immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence-Free Survival (RFS)	Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.	24 months after last participant was randomized (data cutoff date of 30 April 2019)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Histopathology Tumor-Free Margin (R0) Surgical Resection Rate	Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as absence of ink on the tumor for all disease. Rate is presented as the percentage of participants with histopathology tumor-free margin (R0) surgical resection.	18 weeks after last participant randomized (data cutoff date of 30 April 2019)
Pathological Complete Response (pCR) Rate	Pathological Complete Response (pCR) is defined as no evidence of viable tumor cells on complete pathological evaluation of the surgical specimen per institutional standards of care. Rate is presented as the percentage of participants with pCR.	18 weeks after last participant randomized (data cutoff date of 30 April 2019)
Best Overall Tumor Response Per Investigator Response Rate (Talimogene Laherparepvec Arm Only)	Response was assessed based on the response of the index lesions and nonindex lesions as described in protocol-defined World Health Organization (WHO) criteria (for complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), and presence or absence of new lesions. Best response for a participant is the best overall response observed across all time points. Response rate is reported as the percentage of participants with the best overall response (per investigator) of CR or PR. CR: complete disappearance of all index lesions, including any new measurable tumor lesions which might have appeared. PR: ≥ 50% reduction in the sum of the products of the 2 largest perpendicular diameters of all index lesions and new measurable lesions, if applicable, at the time of assessment as compared to the sum of the products of the perpendicular diameters of all index lesions at baseline.	18 months after last participant randomized (data cutoff date of 30 April 2019).
Lesion Objective Response Rate: Injected Lesions (Talimogene Laherparepvec Arm Only)	The investigator-assessed tumor response rate for injected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.	18 months after last participant randomized (data cutoff date of 30 April 2019).
Lesion Objective Response Rate: Uninjected Lesions (Talimogene Laherparepvec Arm Only)	The investigator-assessed tumor response rate for uninjected lesions, reported as the percentage of evaluable lesions in response. A lesion is in response if the decrease in tumor area is ≥ 50%.	18 months after last participant randomized (data cutoff date of 30 April 2019).
RFS	Recurrence free survival (RFS) is defined as the time from randomization to the date of event, and is presented as a Kaplan Meier estimate of time to events. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without a histopathology tumor-free margin (R0) surgical outcome or those who withdrew prior to surgery were considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment.	5 years after the last participant was randomized (last subject last visit occurred 28 April 2022)
Kaplan-Meier (K-M) Estimate of RFS Rate at 1 Year, 2 Years, 3 Years, and 5 Years	Kaplan-Meier estimates of the percentage of participants with RFS at 1 year, 2 years, 3 years, and 5 years from randomization. The event for RFS is defined as the first of local, regional, or distant recurrence of melanoma or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Participants without an event were censored at their last evaluable tumor assessment. Rate is presented as the percentage of participants with RFS at given time point.	5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Local Recurrence-Free Survival (LRFS)	Local recurrence-free survival (LRFS) is defined as the time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Local recurrence is defined as histologically or cytologically confirmed reappearance of melanoma in the area of up to 2 cm from the scar from the surgical excision or at the edge of the skin graft if that was used for closure.	5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Regional Recurrence-Free Survival (RRFS)	Regional recurrence-free survival (RRFS) is defined as the time from randomization to the date of the first of regional disease recurrence or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Regional recurrence excludes local recurrence and is defined as histologically, cytologically, or radiographically confirmed reappearance of melanoma in the regional lymph node basin.	5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Distant Metastases-Free Survival (DMFS)	Distant metastases-free survival (DMFS) is defined as the time from randomization to the date of the first of distant metastases or death due to any cause. Participants without an R0 surgical outcome or those who withdrew prior to surgery are considered an event at randomization. Distant metastases exclude local and regional recurrence and will include distant cutaneous/subcutaneous metastases, distant nodal metastases, or visceral, central nervous system, brain, or bone metastases.	5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Overall Survival (Kaplan-Meier)	Overall Survival (OS) is defined as the time from randomization to the date of death due to any cause.	5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Kaplan-Meier Estimate of OS at 1 Year, 2 Years, 3 Years, and 5 Years	Kaplan-Meier estimates of the percentage of participants alive at 1 year, 2 years, 3 years, and 5 years from randomization.	5 years after the last participant was randomized (last subject last visit occurred on 28 April 2022)
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Fatal Adverse Events (AEs), and TEAEs Leading to Discontinuations or Interruptions	Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.	Adverse Events are reported from first day of study drug or the surgery through 30 days after the last dose of study drug or 30 days after the surgery, whichever is later. Median duration of treatment was 11.14 weeks (range 0.1 to 12.3 weeks).
Number of Participants With Talimogene Laherparepvec-Related TEAEs, SAEs, Fatal AEs, and TEAEs Leading to Discontinuations or Interruptions	Adverse event (AE): any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. SAE: AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Event severity grades: 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). Treatment begins when the first dose of protocol-required therapies is administered to a participant (Talimogene Laherparepvec Arm) or the participant undergoes surgery (Surgery Arm). Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.	Adverse Events are reported from first day of study drug or the surgery through 30 days after the last administration of talimogene laherparepvec or 30 days after the surgical resection of melanoma tumor lesion(s), whichever is later.

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

General Publications

• Dummer R, Gyorki DE, Hyngstrom J, Berger AC, Conry R, Demidov L, Sharma A, Treichel SA, Radcliffe H, Gorski KS, Anderson A, Chan E, Faries M, Ross MI. Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial. Nat Med. 2021 Oct;27(10):1789-1796. doi: 10.1038/s41591-021-01510-7. Epub 2021 Oct 4.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2015
• Primary Completion (Actual): April 30, 2019
• Study Completion (Actual): April 28, 2022

Study Registration Dates

• First Submitted: August 5, 2014
• First Submitted That Met QC Criteria: August 5, 2014
• First Posted (Estimated): August 7, 2014

Study Record Updates

• Last Update Posted (Actual): June 5, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Talimogene laherparepvec
• Other Study ID Numbers: 20110266; 2014-001146-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR