Symptoms and General Pathology

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Neoplasms

Recurrence

Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Talimogene laherparepvec

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Talimogene laherparepvec is administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 3 weeks after the initial dose and every 3 weeks (Q3W) thereafter. Pembrolizumab is administered by intravenous infusion at a dose of 200 mg Q3W after the initial dose. Participants are treated until complete response, no injectable lesions, confirmed disease progression, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first.

The initial dose of talimogene laherparepvec is up to 8.0 mL of 10⁶ PFU/mL. Subsequent doses of talimogene laherparepvec are up to 8.0 mL of 10⁸ PFU/mL.

Talimogene Laherparepvec

Administered as a 30-minute intravenous infusion at a dose of 200 mg Q3W

The primary objective of this study was to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in adults with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).

This is a phase 1b/3, multicenter, clinical trial conducted in 2 parts (phase 1b and phase 3). In phase 1b talimogene laherparepvec is to be administered in combination with pembrolizumab to adults with recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). Dose limiting toxicity (DLT) is to be evaluated based on the first 18 DLT-evaluable participants. An expansion cohort of up to an additional 22 treated patients could be enrolled to further evaluate the safety and to estimate the efficacy of the combination of talimogene laherparepvec with pembrolizumab and to support a decision to initiate the phase 3 part of the study. The phase 3 part of the study was designed as a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, as assessed by overall survival, of treatment with talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab in adults with recurrent or metastatic SCCHN, however, a decision was made not to proceed to the phase 3 part of the study.

For Phase 1b there are no 'maskings' as it's open-label.

Talimogene Laherparepvec With Pembrolizumab for Recurrent Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY232 / KEYNOTE-137)

A Phase 1b/3 Multicenter, Randomized, Trial of Talimogene Laherparepvec in Combination With Pembrolizumab for the Treatment of Subjects With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

The following toxicities (graded per the Common Terminology Criteria for Adverse Events v 4.0) were considered DLTs if judged by the investigator to be related to either study drug:

* grade 4 non-hematologic (non-laboratory) toxicity
* ≥ grade 3 pneumonitis
* grade 3 non-hematologic toxicity for \> 3 days with optimal supportive care
* grade 3 fatigue was not classified as DLT, regardless of duration
* any ≥ grade 3 non-hematologic laboratory value if:

  * medical intervention was required,
  * the abnormality led to hospitalization, or
  * the abnormality persisted at ≥ grade 3 for \> 1 week unless deemed not clinically important by investigator and sponsor
* grade 3 or 4 febrile neutropenia
* thrombocytopenia \< 25 x 10⁹/L associated with bleeding event requiring intervention
* serious herpetic event: herpetic encephalitis, encephalomyelitis, or disseminated herpetic infection
* grade 5 toxicity
* other intolerable toxicity leading to permanent discontinuation of either study drug.

Objective response rate was defined as the percentage of participants with a best overall response of complete response or partial response assessed by the investigator using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Response was based on the size of tumors assessed by computed tomography (CT) or magnetic resonance imaging (MRI).

Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.

Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Confirmation by a consecutive assessment at least 4 weeks after first documentation required.

Analyses are presented below for both the unconfirmed and confirmed results.

Complete response rate (iCRR) was defined as the percentage of participants with a best overall response of complete response assessed by the investigator using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Response was based on the size of tumors assessed by computed tomography (CT) or magnetic resonance imaging (MRI).

Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.

Analyses are presented below for both the unconfirmed and confirmed results.

Best overall visit response of iCR, iPR, stable disease (iSD), progressive disease (iPD) or unevaluable (iUE) based on investigator assessment using irRECIST.

iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (target or non-target) must have reduction in short axis to \<10 mm.

iPR: Decrease in tumor size ≥ 30% relative to baseline. iPD: Increase in tumor size ≥ 20% and at least 5 mm absolute increase compared to nadir or qualitative worsening of non-target lesions or a new lesion.

iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD.

iUE: Any baseline lesion which was not assessed or was unable to be evaluated leading to an inability to determine the status of that particular tumor.

Not Done: Radiographic imaging was not performed to evaluate the response. iCR, iPR, and iPD required confirmation by a consecutive assessment at least 4 weeks after first documentation.

Duration of response (iDOR) per irRECIST was defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of a participant overall response of iPD or death. Participants who did not end their response at the time of analysis were censored at their last evaluable tumor assessment.

Disease control rate (iDCR) was defined as the percentage of participants with a best overall response of iCR or iPR or iSD assessed by the investigator using irRECIST.

Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.

Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Confirmation by a consecutive assessment at least 4 weeks after first documentation required.

Stable disease (iSD): Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD.

Analyses are presented below for both the unconfirmed and confirmed results.

Progression-free survival (iPFS) per irRECIST was defined as the interval from first dose to the earlier of a participant overall response of iPD or death from any cause; otherwise, iPFS was censored at the last evaluable tumor assessment. The initial date of an iPD that was consecutively confirmed was used.

Overall survival (OS) was defined as the interval from first dose to the event of death from any cause; otherwise, OS was censored at the date the participant was last known to be alive.

The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and based on the following scale:

Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death.

A serious adverse event is an AE that met at least 1 of the following serious criteria:

* fatal
* life threatening
* required in-patient hospitalization or prolongation of existing hospitalization
* resulted in persistent or significant disability/incapacity
* congenital anomaly/birth defect
* other medically important serious event.

Merck Sharp & Dohme LLC

Amgen

Serious adverse event and other adverse events are reported for all participants who received at least one dose of study drug.

Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL every 3 weeks (Q3W) thereafter. Pembrolizumab was administered by intravenous infusion at a dose of 200 mg Q3W.

Participants were treated until complete response, no injectable lesions, confirmed disease progression, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first.

Talimogene Laherparepvec + Pembrolizumab

Age, Continuous

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care, unable to carry out any work activities. Up and about \> 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair \> 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.

Eastern Cooperative Oncology Group (ECOG) Performance Status

Herpes Simplex Virus Status

Primary Tumor Site

Study Director

The DLT analysis set included DLT-evaluable participants who had the opportunity to be on treatment for at least 6 weeks and had received at least 2 doses of talimogene laherparepvec and 2 doses of pembrolizumab in combination, or who had a DLT during the DLT evaluation period after at least 1 dose of both study drugs in combination.

Number of Participants With a Dose Limiting Toxicity (DLT)

Confirmed Response

Unconfirmed Response

The efficacy analysis set included all enrolled participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab, excluding participants with locoregionally advanced disease with a recurrence \< 3 months after prior platinum-containing curatively intended multimodal therapy.

Objective Response Rate

Complete Response Rate

Best Overall Confirmed Response

Enrolled participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab, excluding participants with locoregionally advanced disease with a recurrence \< 3 months after prior platinum-containing curatively intended multimodal therapy, with a best response of iCR or iPR.

Duration of Confirmed Response

Disease Control Rate

Progression Free Survival

Overall Survival

All treatment-emergent adverse events

Treatment-emergent adverse events grade ≥ 2

Treatment-emergent adverse events grade ≥ 3

Treatment-emergent adverse events grade ≥ 4

Serious adverse events

AE leading to discontinuation of T-VEC

AE leading to discontinuation of pembrolizumab

Fatal adverse events

Talimogene laherparepvec-related AEs

Pembrolizumab-related AEs

Talimogene laherparepvec (T-VEC) was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL every 3 weeks (Q3W) thereafter. Pembrolizumab was administered by intravenous infusion at a dose of 200 mg Q3W.

Participants were treated until complete response, no injectable lesions, confirmed disease progression, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first.

All enrolled participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab.

Spots Global Cancer Trial Database for recurrent metastatic squamous cell carcinoma head and neck