Melanoma
Conditions
Keywords
melanoma, talimogene laherparepvec, ipilimumab, immunotherapy
Brief summary
Phase 1b of the study will evaluate the safety of talimogene laherparepvec in combination with ipilimumab. Phase 2 is a randomized study that will evaluate the safety and efficacy of talimogene laherparepvec in combination with ipilimumab versus ipilumumab alone.
Detailed description
The phase 1b part is an open-label, multicenter, single-arm study where all participants will receive talimogene laherparepvec in combination with ipilimumab. The phase 2 part of the study is an open-label, multicenter, randomized study to further assess the safety and to evaluate the efficacy of talimogene laherparepvec in combination with ipilimumab. Participants will be randomized 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Participants randomized before amendment 2 will be stratified by stage of disease (stage IIIB/C, IVM1a, and stage IVM1b vs IVM1c) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E (a mutation resulting in a substitution of glutamic acid for valine at codon 600) (mutation vs mutation not present). Participants randomized after amendment 2 will be stratified by stage of disease (stage IIIB/C and IVM1a vs stage IVM1b and IVM1c) and prior therapy (treatment naïve vs previously treated with systemic anticancer immunotherapy vs previously treated with systemic anticancer treatment other than immunotherapy).
Interventions
DRUGTalimogene laherparepvec
Talimogene laherparepvec administered by intratumoral injection on Day 1 of Week 1, Day 1 of Week 4, then every two weeks thereafter.
DRUGIpilimumab
Ipilimumab administered intravenously every 3 weeks for a total of 4 infusions.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1b was an open-label, multicenter single-arm part of the study to evaluate safety of talimogene laherparepvec in combination with ipilimumab. Phase 2 was an open-label multicenter, randomized design to further assess safety and to evaluate efficacy of talimogene laherparepvec in combination with ipilimumab.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of malignant melanoma. * Stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c disease that is not suitable for surgical resection * Phase1: Treatment naïve: Must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy for unresected stage IIIB to IV melanoma. * Phase 2: * Either treatment naïve or received only one line of systemic anticancer therapy if v-raf murine sarcoma viral oncogene homolog B1 (BRAF) wild-type or up to two lines of systemic anticancer therapy including one BRAF inhibitor-containing regimen if BRAF mutant. Treatments given in an adjuvant setting (eg, interferon, radiotherapy, isolated limb perfusion, or investigational agents) are not considered as prior lines of therapy. No prior talimogene laherparepvec, other oncolytic virus therapies, or tumor vaccines are allowed, even if given in the adjuvant setting. * Subjects treated with prior ipilimumab must have had partial response (PR), complete response (CR), or at least 6 months of stable disease followed by disease progression. * Subjects previously treated with anti-program death-1 (PD1) or anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibodies must not have discontinued therapy due to any treatment-related adverse events including immune-related adverse events. Prior treatment-related adverse events should also be fully resolved and not requiring treatment for at least 28 days prior to randomization. * Measurable disease defined as one or both of the following * at least 1 melanoma lesion that can be accurately and serially measured in at least 2 dimensions and for which the longest diameter is ≥ 10 mm and with perpendicular diameter ≥ 5 mm as measured by contrast-enhanced or spiral computed tomography (CT) scan for visceral or nodal/soft tissue disease. Lymph nodes must measure \> 15 mm in their short axis to be considered measurable by CT scan. * at least 1 superficial cutaneous or subcutaneous melanoma lesion that can be accurately and serially measured in at least 2 dimensions and for which the short axis is ≥ 5 mm as measured by calipers * Injectable disease (ie, suitable for direct injection or through the use of ultrasound \[US\] guidance) defined as follows: * at least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion ≥ 5 mm in longest diameter * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Adequate hematologic, hepatic, renal, and coagulation functions
Exclusion criteria
* Primary uveal or mucosal melanoma * History or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia) * Phase 1b: History or evidence of central nervous system (CNS) metastases * Phase 2: Clinically active cerebral melanoma metastases. Subjects with up to 3 cerebral metastases, and neurological performance status of 0 may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or Gamma knife therapy, with no evidence of progression, and have not required steroids, for at least 2 months prior to enrollment. * History or evidence of symptomatic autoimmune disease (such as pneumonitis, glomerulonephritis, vasculitis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, scleroderma, or other), or history of autoimmune disease that required systemic treatment (ie, use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) in past 2 months prior to enrollment. Replacement therapy (eg, thyroxine for hypothyroidism, insulin for diabetes mellitus) is not considered a form of systemic treatment for autoimmune disease. * History of or plan for splenectomy or splenic irradiation * Active herpetic skin lesions or prior complications of herpes simplex type-1 virus (HSV-1) infection (eg, herpetic keratitis or encephalitis). * Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use * Known human immunodeficiency virus (HIV) disease * Known acute or chronic hepatitis B or hepatitis C infection * Phase 1b: Prior talimogene laherparepvec, ipilimumab, other CTLA-4 inhibitors, PD-1 inhibitors, or tumor vaccine * Phase 2: Prior talimogene laherparepvec, other oncolytic virus therapies, or tumor vaccines * Currently receiving or less than 28 days since ending systemic anticancer treatment for unresected stage IIIB to IV melanoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Dose-limiting Toxicities | The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12). | A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events version 3.0: * treatment-related non-laboratory adverse events (AE) ≥ grade 4 * ≥ grade 4 immune-mediated dermatitis * ≥ grade 4 immune-mediated endocrinopathy (except autoimmune thyroiditis) * ≥ grade 3 immune-mediated enterocolitis * ≥ grade 3 immune-mediated hepatitis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset) * ≥ grade 3 immune-mediated neuropathy * ≥ grade 3 other immune-mediated AEs including hemolytic anemia, angiopathy, myocarditis, pericarditis, temporal arteritis, or vasculitis, autoimmune thyroiditis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset), blepharitis, conjunctivitis, episcleritis, iritis, scleritis, or uveitis, pancreatitis, meningitis, arthritis or polymyalgia rheumatic, nephritis, pneumonitis, psoriasis or leukocytoclastic vasculitis. |
| Phase 2: Objective Response Rate | Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively. | Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI). CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to \<10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Progression-free Survival | From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively. | Progression-free survival was measured from the date of randomization to the date of disease progression (as measured by modified irRC) or death on or before the data cutoff date, whichever occurred first. Participants who had no disease progression and did not die while on study were censored at the last disease assessment date. |
| Phase 1b: Objective Response Rate | Tumor response was assesed every 12 weeks until disease progression; median follow-up time at the primary analysis was 148.4 weeks. | Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI). CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to \<10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders. |
| Phase 2: Best Overall Response | Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively. | Best overall response was categorized in descending order as a complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or unevaluable (UE) based on investigator assessment according to the modified irRC. CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to \<10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. PD: Increase in tumor burden ≥ 25% relative to nadir. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization. CR, PR and PD must have been confirmed at 2 consecutive assessment ≥ 4 weeks apart. Assessments occurring after the start of the first subsequent anticancer therapy or removal of a lesion were not included. |
| Phase 2: Disease Control Rate | Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively. | Disease control rate (DCR) was defined as the percentage of participants with a best overall response of CR, PR or SD based on investigator assessment according to the modified irRC. CR: Complete disappearance of all lesions and no new lesions; any pathological lymph nodes reduced in short axis to \<10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization. CR and PR must have been confirmed at 2 consecutive assessments ≥ 4 weeks apart. |
| Phase 2: Durable Response Rate | Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively. | Durable response rate (DRR) was defined as the percentage of participants with a duration of response (best response of CR or PR) per modified irRC of at least 6 months. Duration of response is the time from the first confirmed CR or PR to confirmed disease progression per the modified irRC or death, whichever occurs earlier. |
| Phase 2: Time to Response | Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively. | Time to confirmed response (TTR) was defined as the time from randomization to the date of the first confirmed CR or PR per modified irRC criteria. Participants who did not have a confirmed CR or PR were censored at their last evaluable tumor assessment date. |
| Phase 2: Duration of Response | Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively. | Duration of response was calculated only for participants with an objective response per modified irRC and was defined as the time from first confirmed objective response (CR or PR) to confirmed disease progression per the modified irRC or death, whichever was earlier. Responders who did not have an event of death or disease progression were censored at their last evaluable tumor assessment date. |
| Phase 2: Resection Rate | From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively. | Resection rate was defined as the percentage of participants who had surgical procedures for melanoma that resulted in a partial reduction or complete eradication of all previously unresectable cutaneous or visceral metastatic disease. Surgical procedures for melanoma with palliative intent (eg, for pain control) in the presence of disease progression were not considered resection. |
| Phase 2: Overall Survival | From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively. | Overall survival was defined as the time from the date of randomization to the date of death from any cause. Participants without an event were censored at the last date they were known to be alive. Participants with a vital status obtained after the data cut-off were censored at the date cut-off date. |
| Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 | Months 12 and 24; The median (Q1, Q3) follow-up time from randomization to the primary analysis data cutoff date was 80.6 (58.3, 106.3) weeks. | The overall survival estimates at month 24 data were not mature as most participants had not been followed for 24 months at the time of data cutoff. |
| Phase 2: Progression-free Survival - Final Analysis | From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group. | Progression-free survival was measured from the date of randomization to the date of disease progression (as measured by modified irRC) or death, whichever occurred first. Participants who had no disease progression and did not die while on study were censored at the last disease assessment date. |
| Phase 2: Overall Survival - Final Analysis | From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group. | Overall survival was defined as the time from the date of randomization to the date of death from any cause. Participants without an event were censored at the last date they were known to be alive. |
| Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis | Months 12 and 24 | — |
| Number of Participants With Adverse Events | From first dose of study drug to 30 days after last dose of T-VEC or 60 days after last dose of Ipi, whichever was later; median duration of treatment was 14.7 weeks in Phase 1b T-VEC + Ipi, 9.1 weeks in Phase 2 Ipi, and 21.1 weeks in Phase 2 T-VEC + Ipi. | Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, where grade 1 = mild AE, grade 2 = moderate AE, grade 3 = severe AE, grade 4 = life-threatening or disabling AE and grade 5 = death related to AE. The investigator assessed whether each AE was possibly related to talimogene laherparepvec (T-VEC) and/or ipilimumab (Ipi). |
Countries
France, Germany, United States
Participant flow
Recruitment details
This study was conducted at 33 centers in the United States of America, France, and Germany. Participants were enrolled in Phase 1b from 07 February 2013 to 08 July 2013 and in Phase 2 from 13 August 2013 to 25 February 2016.
Pre-assignment details
In Phase 1b all participants received talimogene laherparepvec in combination with ipilimumab. In Phase 2 participants were randomized in 1:1 ratio to receive talimogene laherparepvec plus ipilimumab or ipilimumab. Participants randomized prior to Protocol Amendment 2 were stratified by disease stage and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation V600E; participants randomized after Amendment 2 were stratified by disease stage and prior therapy.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab Participants received talimogene laherparepvec at an initial dose of 10⁶ plaque-forming units (PFU)/mL injected into 1 or more skin, nodal, or subcutaneous tumors with maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until complete response (CR), all injectable tumors had disappeared, confirmed disease progression per the modified immune-related response criteria (irRC), or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab administered intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). | 19 |
| Phase 2: Ipilimumab Participants received ipilimumab 3 mg/kg intravenously every 3 weeks for a total of 4 infusions starting at week 1. | 100 |
| Phase 2: Talimogene Laherparepvec + Ipilimumab Participants received talimogene laherparepvec at an initial dose of 10⁶ PFU/mL injected into 1 or more skin, nodal, or subcutaneous tumors with a maximum total volume of 4 mL. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL total) began 3 weeks after the first dose and were administered every 2 weeks until CR, all injectable tumors had disappeared, confirmed disease progression per the modified irRC, or intolerance of study treatment, whichever occurred first. Participants also received 3 mg/kg ipilimumab intravenously every 3 weeks for a total of 4 infusions starting at the time of the third dose of talimogene laherparepvec (week 6). | 98 |
| Total | 217 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 8 | 46 | 40 |
| Overall Study | Lost to Follow-up | 1 | 2 | 4 |
| Overall Study | Withdrawal by Subject | 4 | 16 | 17 |
Baseline characteristics
| Characteristic | Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Ipilimumab | Total | Phase 2: Talimogene Laherparepvec + Ipilimumab |
|---|---|---|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 12.1 | 64.2 years STANDARD_DEVIATION 13.3 | 63.6 years STANDARD_DEVIATION 13.5 | 63.6 years STANDARD_DEVIATION 14 |
| Age, Customized < 65 years | 11 Participants | 54 Participants | 111 Participants | 46 Participants |
| Age, Customized ≥ 65 years | 8 Participants | 46 Participants | 106 Participants | 52 Participants |
| BRAF V600 Mutation Status Missing/Unknown | 0 Participants | 6 Participants | 7 Participants | 1 Participants |
| BRAF V600 Mutation Status Mutation | 12 Participants | 34 Participants | 81 Participants | 35 Participants |
| BRAF V600 Mutation Status Wild-type | 7 Participants | 60 Participants | 129 Participants | 62 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 14 Participants | 73 Participants | 156 Participants | 69 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory) | 5 Participants | 27 Participants | 61 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 5 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 96 Participants | 212 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black (or African American) | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 18 Participants | 92 Participants | 207 Participants | 97 Participants |
| Sex: Female, Male Female | 11 Participants | 45 Participants | 92 Participants | 36 Participants |
| Sex: Female, Male Male | 8 Participants | 55 Participants | 125 Participants | 62 Participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IIIB - IVM1a | 8 Participants | 57 Participants | 115 Participants | 50 Participants |
| Tumor, Node, Metastasis (TNM) Disease Stage Stage IVM1b/c | 11 Participants | 43 Participants | 102 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 19 | 52 / 100 | 45 / 98 |
| other Total, other adverse events | 19 / 19 | 85 / 95 | 91 / 95 |
| serious Total, serious adverse events | 6 / 19 | 34 / 95 | 34 / 95 |
Outcome results
Primary
Phase 1b: Number of Participants With Dose-limiting Toxicities
A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events version 3.0: * treatment-related non-laboratory adverse events (AE) ≥ grade 4 * ≥ grade 4 immune-mediated dermatitis * ≥ grade 4 immune-mediated endocrinopathy (except autoimmune thyroiditis) * ≥ grade 3 immune-mediated enterocolitis * ≥ grade 3 immune-mediated hepatitis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset) * ≥ grade 3 immune-mediated neuropathy * ≥ grade 3 other immune-mediated AEs including hemolytic anemia, angiopathy, myocarditis, pericarditis, temporal arteritis, or vasculitis, autoimmune thyroiditis (except grade 3 that resolved to grade 1 or baseline within 28 days of onset), blepharitis, conjunctivitis, episcleritis, iritis, scleritis, or uveitis, pancreatitis, meningitis, arthritis or polymyalgia rheumatic, nephritis, pneumonitis, psoriasis or leukocytoclastic vasculitis.
Time frame: The DLT evaluation period was 6 weeks from the initial administration of ipilimumab (week 6 to 12).
Population: All phase 1b participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 1b: Number of Participants With Dose-limiting Toxicities | 0 Participants |
Primary
Phase 2: Objective Response Rate
Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI). CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to \<10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Population: All participants randomized in phase 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Objective Response Rate | 18.0 percentage of participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Objective Response Rate | 38.8 percentage of participants |
p-value: 0.00295% CI: [1.5, 5.5]Chi-squared, Corrected
Secondary
Number of Participants With Adverse Events
Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, where grade 1 = mild AE, grade 2 = moderate AE, grade 3 = severe AE, grade 4 = life-threatening or disabling AE and grade 5 = death related to AE. The investigator assessed whether each AE was possibly related to talimogene laherparepvec (T-VEC) and/or ipilimumab (Ipi).
Time frame: From first dose of study drug to 30 days after last dose of T-VEC or 60 days after last dose of Ipi, whichever was later; median duration of treatment was 14.7 weeks in Phase 1b T-VEC + Ipi, 9.1 weeks in Phase 2 Ipi, and 21.1 weeks in Phase 2 T-VEC + Ipi.
Population: All participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipi-related AEs leading to Ipi discontinuation | 0 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events AEs ≥ grade 3 | 3 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | AEs leading to discontinuation of T-VEC | 0 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related serious adverse events | 4 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events ≥ grade 4 | 0 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Fatal adverse events | 1 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events ≥ grade 3 | 4 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related serious adverse events | 1 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Adverse events ≥ grade 4 | 2 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events ≥ grade 2 | 8 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events | 15 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events AEs ≥ grade 2 | 12 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events | 17 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Adverse events ≥ grade 2 | 17 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related AEs leading to T-VEC discontinuation | 0 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Serious adverse events | 6 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | All adverse events | 19 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Fatal T-VEC-related adverse events | 0 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Adverse events ≥ grade 3 | 7 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events ≥ grade 4 | 1 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Fatal ipilimumab-related adverse events | 0 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | AEs leading to discontinuation of ipilimumab | 0 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | All adverse events | 90 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Adverse events ≥ grade 4 | 4 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Serious adverse events | 34 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | AEs leading to discontinuation of T-VEC | NA Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events AEs ≥ grade 2 | NA Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related AEs leading to T-VEC discontinuation | NA Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Fatal T-VEC-related adverse events | NA Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events ≥ grade 2 | 50 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events AEs ≥ grade 3 | NA Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events ≥ grade 4 | NA Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related serious adverse events | NA Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events | 78 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events ≥ grade 3 | 21 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events ≥ grade 4 | 2 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related serious adverse events | 19 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipi-related AEs leading to Ipi discontinuation | 12 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Fatal ipilimumab-related adverse events | 0 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Adverse events ≥ grade 3 | 41 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Adverse events ≥ grade 2 | 72 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | AEs leading to discontinuation of ipilimumab | 17 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Fatal adverse events | 1 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events | NA Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related serious adverse events | 14 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events AEs ≥ grade 2 | 44 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Fatal adverse events | 5 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipi-related AEs leading to Ipi discontinuation | 11 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Fatal ipilimumab-related adverse events | 1 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | AEs leading to discontinuation of ipilimumab | 13 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Adverse events ≥ grade 3 | 44 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related AEs leading to T-VEC discontinuation | 0 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | All adverse events | 92 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related serious adverse events | 10 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Adverse events ≥ grade 2 | 80 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events | 82 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events | 75 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Fatal T-VEC-related adverse events | 0 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events ≥ grade 2 | 48 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events ≥ grade 4 | 1 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Adverse events ≥ grade 4 | 6 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events ≥ grade 3 | 19 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | AEs leading to discontinuation of T-VEC | 6 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Ipilimumab-related adverse events ≥ grade 4 | 1 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | T-VEC-related adverse events AEs ≥ grade 3 | 15 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Number of Participants With Adverse Events | Serious adverse events | 34 Participants |
Secondary
Phase 1b: Objective Response Rate
Objective response rate is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) according to the modified immune-related response criteria (irRC) assessed by the investigator. Tumors were examined clinically and by computed tomography (CT) or magnetic resonance imaging (MRI). CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to \<10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. Response must have been confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date first documented. Participants who did not have any follow-up tumor assessments were regarded as non-responders.
Time frame: Tumor response was assesed every 12 weeks until disease progression; median follow-up time at the primary analysis was 148.4 weeks.
Population: All phase 1b participants who received ≥ 1 dose of investigational product (talimogene laherparepvec or ipilimumab).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 1b: Objective Response Rate | 52.6 percentage of participants |
Secondary
Phase 2: Best Overall Response
Best overall response was categorized in descending order as a complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or unevaluable (UE) based on investigator assessment according to the modified irRC. CR: Complete disappearance of all lesions and no new lesions; Any pathological lymph nodes reduced in short axis to \<10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. PD: Increase in tumor burden ≥ 25% relative to nadir. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization. CR, PR and PD must have been confirmed at 2 consecutive assessment ≥ 4 weeks apart. Assessments occurring after the start of the first subsequent anticancer therapy or removal of a lesion were not included.
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Population: All participants randomized in phase 2
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Progressive Disease (PD) | 33 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Stable Disease (SD) | 24 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Complete Response (CR) | 7 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Partial Response (PR) | 11 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Unevaluable (UE) | 17 Participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Not Done (ND) | 8 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Unevaluable (UE) | 4 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Partial Response (PR) | 25 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Stable Disease (SD) | 19 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Progressive Disease (PD) | 31 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Not Done (ND) | 6 Participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Best Overall Response | Complete Response (CR) | 13 Participants |
Secondary
Phase 2: Disease Control Rate
Disease control rate (DCR) was defined as the percentage of participants with a best overall response of CR, PR or SD based on investigator assessment according to the modified irRC. CR: Complete disappearance of all lesions and no new lesions; any pathological lymph nodes reduced in short axis to \<10 mm. PR: Decrease in tumor burden ≥ 50% relative to baseline. SD: Not meeting criteria for CR or PR, in absence of PD and no earlier than 77 days after the date of enrollment/randomization. CR and PR must have been confirmed at 2 consecutive assessments ≥ 4 weeks apart.
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Population: All participants randomized in phase 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Disease Control Rate | 42.0 percentage of participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Disease Control Rate | 58.2 percentage of participants |
p-value: 0.03395% CI: [1.1, 3.4]Chi-squared, Corrected
Secondary
Phase 2: Durable Response Rate
Durable response rate (DRR) was defined as the percentage of participants with a duration of response (best response of CR or PR) per modified irRC of at least 6 months. Duration of response is the time from the first confirmed CR or PR to confirmed disease progression per the modified irRC or death, whichever occurs earlier.
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Population: All participants randomized in phase 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Durable Response Rate | 13.0 percentage of participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Durable Response Rate | 29.6 percentage of participants |
p-value: 0.00795% CI: [1.4, 5.8]Chi-squared, Corrected
Secondary
Phase 2: Duration of Response
Duration of response was calculated only for participants with an objective response per modified irRC and was defined as the time from first confirmed objective response (CR or PR) to confirmed disease progression per the modified irRC or death, whichever was earlier. Responders who did not have an event of death or disease progression were censored at their last evaluable tumor assessment date.
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Population: Participants randomized in phase 2 with a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Duration of Response | NA months |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Duration of Response | NA months |
Secondary
Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24
The overall survival estimates at month 24 data were not mature as most participants had not been followed for 24 months at the time of data cutoff.
Time frame: Months 12 and 24; The median (Q1, Q3) follow-up time from randomization to the primary analysis data cutoff date was 80.6 (58.3, 106.3) weeks.
Population: All participants randomized in phase 2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 | Month 24 | 67.7 percentage of participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 | Month 12 | 81.4 percentage of participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 | Month 12 | 86.9 percentage of participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 | Month 24 | 76.6 percentage of participants |
Secondary
Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis
Time frame: Months 12 and 24
Population: All participants randomized in phase 2
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis | Month 12 | 79.9 percentage of participants |
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis | Month 24 | 69.3 percentage of participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis | Month 12 | 83.3 percentage of participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Kaplan-Meier Estimate of Percentage of Participants Alive at Month 12 and 24 - Final Analysis | Month 24 | 72.7 percentage of participants |
Secondary
Phase 2: Overall Survival
Overall survival was defined as the time from the date of randomization to the date of death from any cause. Participants without an event were censored at the last date they were known to be alive. Participants with a vital status obtained after the data cut-off were censored at the date cut-off date.
Time frame: From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Population: All participants randomized in phase 2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Overall Survival | NA months |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Overall Survival | NA months |
p-value: 0.47495% CI: [0.44, 1.46]Log Rank
Secondary
Phase 2: Overall Survival - Final Analysis
Overall survival was defined as the time from the date of randomization to the date of death from any cause. Participants without an event were censored at the last date they were known to be alive.
Time frame: From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group.
Population: All participants randomized in phase 2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Overall Survival - Final Analysis | 50.1 months |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Overall Survival - Final Analysis | 84.9 months |
p-value: 0.3795% CI: [0.56, 1.24]Log Rank
Secondary
Phase 2: Progression-free Survival
Progression-free survival was measured from the date of randomization to the date of disease progression (as measured by modified irRC) or death on or before the data cutoff date, whichever occurred first. Participants who had no disease progression and did not die while on study were censored at the last disease assessment date.
Time frame: From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Population: All participants randomized in phase 2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Progression-free Survival | 6.4 months |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Progression-free Survival | 8.2 months |
p-value: 0.34895% CI: [0.56, 1.23]Log Rank
Secondary
Phase 2: Progression-free Survival - Final Analysis
Progression-free survival was measured from the date of randomization to the date of disease progression (as measured by modified irRC) or death, whichever occurred first. Participants who had no disease progression and did not die while on study were censored at the last disease assessment date.
Time frame: From randomization until the end of study (09 March 2021); median follow-up time was 155 weeks in the Ipilimumab group and 214 weeks in the Talimogene Laherparepvec + Ipilimumab group.
Population: All participants randomized in phase 2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Progression-free Survival - Final Analysis | 6.4 months |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Progression-free Survival - Final Analysis | 13.5 months |
p-value: 0.1495% CI: [0.55, 1.09]Log Rank
Secondary
Phase 2: Resection Rate
Resection rate was defined as the percentage of participants who had surgical procedures for melanoma that resulted in a partial reduction or complete eradication of all previously unresectable cutaneous or visceral metastatic disease. Surgical procedures for melanoma with palliative intent (eg, for pain control) in the presence of disease progression were not considered resection.
Time frame: From randomization until the primary analysis data cut-off date of 23 August 2016; median follow-up time was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Population: All participants randomized in phase 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Resection Rate | 3.0 percentage of participants |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Resection Rate | 5.1 percentage of participants |
p-value: 0.696Chi-squared, Corrected
Secondary
Phase 2: Time to Response
Time to confirmed response (TTR) was defined as the time from randomization to the date of the first confirmed CR or PR per modified irRC criteria. Participants who did not have a confirmed CR or PR were censored at their last evaluable tumor assessment date.
Time frame: Tumor response was assessed every 12 weeks until disease progression; median follow-up time at the primary analysis was 57.7 weeks and 68.1 weeks in each treatment group respectively.
Population: All participants randomized in phase 2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Talimogene Laherparepvec + Ipilimumab | Phase 2: Time to Response | NA months |
| Phase 2: Talimogene Laherparepvec + Ipilimumab | Phase 2: Time to Response | 5.8 months |
p-value: 0.22895% CI: [0.8, 2.49]Log Rank