Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

All Drugs and Chemicals

Antineoplastic Agents

Micronutrients

Hematinics

Vitamins

Antibodies

Antibodies, Monoclonal

Gemcitabine

Paclitaxel

Carboplatin

Pemetrexed

Albumin-Bound Paclitaxel

Cisplatin

Durvalumab

Immunoglobulins

Tremelimumab

Tubulin Modulators

Antimitotic Agents

Antimetabolites

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Antineoplastic Agents, Immunological

Immunologic Factors

Folinic Acid

Folate

Vitamin B9

MEDI4736 (Durvalumab)

MEDI4736 (Durvalumab)+Tremelimumab

Paclitaxel + Carboplatin

Gemcitabine + Cisplatin

Gemcitabine + Carboplatin

Pemetrexed + Cisplatin

Pemetrexed + Carboplatin

Stuart McIntosh, MD

Naiyer Rizvi, MD

This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination therapy and MEDI4736 monotherapy versus platinum-based SoC chemotherapy in the first-line treatment of patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type locally advanced or metastatic NSCLC

Patients will be randomized in a 1:1:1 ratio to receive treatment with MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, or Standard of Care (SoC) therapy.

Phase III Open Label First Line Therapy Study of MEDI 4736 (Durvalumab) With or Without Tremelimumab Versus SOC in Non Small-Cell Lung Cancer (NSCLC)

A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 in Combination With Tremelimumab Therapy or MEDI4736 Monotherapy Versus Standard of Care Platinum-Based Chemotherapy in First Line Treatment of Patients With Advanced or Metastatic Non Small-Cell Lung Cancer (NSCLC)(MYSTIC).

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

The PFS per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) using blinded independent central review (BICR) assessments was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraw from randomized therapy or received another anti-cancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions (TLs) and an absolute increase of at least 5 millimeter (mm), taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Median PFS was calculated using the Kaplan-Meier technique.

The PFS per RECIST 1.1 using BICR assessments was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraw from randomized therapy or received another anti-cancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). The PD was defined as at least a 20% increase in the sum of diameters of TLs and an absolute increase of at least 5 mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Median PFS was calculated using the Kaplan-Meier technique.

The ORR per RECIST 1.1 using BICR assessments was defined as the percentage of participants with at least 1 visit response of Complete Response (CR) or Partial Response (PR). The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

The ORR per RECIST 1.1 using BICR assessments was defined as the percentage of participants with at least 1 visit response of CR or PR. The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

The DoR per RECIST 1.1 using BICR assessments was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (ie, date of PFS event or censoring - date of first response + 1). The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

The DoR per RECIST 1.1 using BICR assessments was defined as the time from the date of first documented response (CR or PR) until the first date of documented progression or death in the absence of disease progression (ie, date of PFS event or censoring - date of first response + 1). The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

The APF12 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 using BICR assessments at 12 months after randomization. The PFS was calculated using the Kaplan-Meier technique.

The PFS2 was defined as the time from the date of randomization to the earliest of the progression events (subsequent to that used for the primary variable PFS and excluding any confirmation of progression scans performed for first progression) or death (ie, date of PFS2 event or censoring - date of randomization + 1). The second progression event was determined by local standard clinical practice which may have included any of the following: objective radiological imaging, symptomatic progression, or death.

Patient reported outcomes for 5 disease related symptoms was assessed using the EORTC QLQ-Core 30 (C30) items questionnaire (fatigue and appetite loss) and the EORTC QLQ-Lung Cancer module 13 (LC13) (dysponea, cough and chest pain). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items with higher scores representing greater symptom severity. An improvement in symptoms were indicated by a negative change in score from baseline. A positive change in score from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change is defined as an absolute change in the score from baseline of \>=10.

Blood samples were collected to determine the serum concentration of durvalumab.

Blood samples were collected to determine the serum concentration of tremelimumab.

Blood samples were collected to determine the Cmax_ss of durvalumab. Steady state was defined as Cycle 4 (Week 12). PK parameters were determined using standard non-compartmental methods.

Blood samples were collected to determine the Cmax_ss of tremelimumab. Steady state was defined as Cycle 4 (Week 12). PK parameters were determined using standard non-compartmental methods.

Blood samples were collected to determine the Ctrough_ss of durvalumab. Steady state was defined as Cycle 4 (Week 12). PK parameters were determined using standard non-compartmental methods.

Blood samples were collected to determine the Ctrough_ss of tremelimumab. Steady state was defined as Cycle 4 (Week 12). PK parameters were determined using standard non-compartmental methods.

Blood samples were measured for the presence of ADAs and ADA-neutralizing antibodies (nAb) for durvalumab using validated assays. Tiered analysis was performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples were employed. Immunogenicity results were analyzed by summarizing the number of participants who developed detectable ADAs against durvalumab. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive.

Blood samples were measured for the presence of ADAs and ADA-nAb for tremelimumab using validated assays. Tiered analysis was performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples were employed. Immunogenicity results were analyzed by summarizing the number of participants who developed detectable ADAs against tremelimumab. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive.

AstraZeneca

Safety analysis set included all participants who received at least 1 dose of study treatment. All-cause mortality was determined for participants in FAS.

Participants received durvalumab 20 mg/kg IV infusion Q4W until worsening of the disease under investigation, unless specific treatment discontinuation criteria were met.

Durvalumab Monotherapy

Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued on durvalumab 20 mg/kg Q4W, starting on Week 16 until worsening of the disease under investigation, unless specific treatment discontinuation criteria were met.

Durvalumab + Tremelimumab

Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until worsening of disease under investigation, unless specific treatment discontinuation criteria were met.

1. Paclitaxel 200 mg/m\^2 and carboplatin AUC 5 or 6 mg\*min/mL.
2. Gemcitabine 1000 or 1250 mg/m\^2 and cisplatin 75 or 80 mg/m\^2. Additional dose of Gemcitabine 1000 or 1250 mg/m\^2 on Day 8 of each cycle (For squamous tumors only).
3. Gemcitabine 1000 or 1250 mg/m\^2 and carboplatin AUC 5 or 6 mg\*min/mL. Additional dose of Gemcitabine 1000 or 1250 mg/m\^2 on Day 8 of each cycle (For squamous tumors only).
4. Pemetrexed 500 mg/m\^2 and cisplatin 75 mg/m\^2 (For non-squamous tumors only; pemetrexed maintenance dose was permitted).
5. Pemetrexed 500 mg/m\^2 and carboplatin AUC 5 or 6 mg\*min/mL (For non-squamous tumors only; pemetrexed maintenance dose was permitted).

SoC Chemotherapy

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Full analysis set (FAS) included all randomized participants analyzed on an intent-to-treat (ITT) basis.

Global Clinical Lead

Durvalumab Monotherapy Vs SoC Chemotherapy

Durvalumab + Tremelimumab Vs SoC Chemotherapy

The PD-L1 (TC \>=25%) analysis set included subset of participants in the FAS whose PD-L1 status was PD-L1 (TC \>=25%) as defined by Ventana PD-L1 (SP263) assay (ie, \>=25% TCs expressing PD-L1 on the membrane). Comparison of durvalumab monotherapy Vs SoC and durvalumab + tremelimumab Vs SoC reporting groups were analysed for primary outcome measure.

Overall Survival (OS); PD-L1 (TC >=25%) Analysis Set Population, Durvalumab Monotherapy Vs SoC Chemotherapy and Durvalumab + Tremelimumab Vs SoC Chemotherapy

The PD-L1 (TC \>=25%) analysis set included the subset of participants in the FAS whose PD-L1 status was PD-L1 (TC \>=25%) as defined by the Ventana PD-L1 (SP263) assay (ie, \>=25% TCs expressing PD-L1 on the membrane). Comparison of durvalumab + tremelimumab Vs SoC chemotherapy reporting groups were analysed for the primary outcome measure.

Progression-Free Survival (PFS); PD-L1 (TC >=25%) Analysis Set Population, Durvalumab + Tremelimumab Vs SoC Chemotherapy

Durvalumab + Tremelimumab Vs Durvalumab Monotherapy

The PD-L1 (TC \>=25%) analysis set included the subset of participants in the FAS whose PD-L1 status was PD-L1 (TC \>=25%) as defined by the Ventana PD-L1 (SP263) assay (ie, \>=25% TCs expressing PD-L1 on the membrane). Comparison of durvalumab + tremelimumab Vs durvalumab monotherapy reporting groups were analysed for the secondary outcome measure.

OS; PD-L1 (TC >=25%) Analysis Set Population, Durvalumab + Tremelimumab Vs Durvalumab Monotherapy

The PD-L1 (TC \>=1%) analysis set included the subset of participants in the FAS whose PD-L1 status is PD-L1 (TC \>=1%) as defined by the Ventana PD-L1 (SP263) assay (ie, \>=1% TC expressing PD-L1 on the membrane).

OS; PD-L1 (TC >=1%) Analysis Set Population

The FAS included all randomized participants analyzed on an ITT basis.

OS; FAS Population

The PD-L1 (TC \>=25%) analysis set included subset of participants in the FAS whose PD-L1 status was PD-L1 (TC \>=25%) as defined by Ventana PD-L1 (SP263) assay (ie, \>=25% TCs expressing PD-L1 on the membrane). Comparison of durvalumab + tremelimumab Vs durvalumab and durvalumab Vs SoC reporting groups were analysed for secondary outcome measure.

PFS; PD-L1 (TC >=25%) Analysis Set Population, Durvalumab Monotherapy Vs SoC Chemotherapy and Durvalumab + Tremelimumab Vs Durvalumab Monotherapy

PFS; PD-L1 (TC >=1%) Analysis Set Population

PFS; FAS Population

The PD-L1 (TC \>=25%) analysis set included the subset of participants in the FAS whose PD-L1 status was PD-L1 (TC \>=25%) as defined by the Ventana PD-L1 (SP263) assay (ie, \>=25% TC expressing PD-L1 on the membrane).

Objective Response Rate (ORR); PD-L1 (TC >=25%) Analysis Set Population

ORR; PD-L1 (TC >=1%) Analysis Set Population

ORR; FAS Population

The PD-L1 (TC \>=25%) analysis set included the subset of participants in the FAS whose PD-L1 status was PD-L1 (TC \>=25%) as defined by the Ventana PD-L1 (SP263) assay (ie,\>=25% TC expressing PD-L1 on the membrane). DoR is only analyzed for those participants with a response (including unconfirmed responses).

Duration of Response (DoR); PD-L1 (TC >=25%) Analysis Set Population

The PD-L1 (TC \>=1%) analysis set included the subset of participants in the FAS whose PD-L1 status is PD-L1 (TC \>=1%) as defined by the Ventana PD-L1 (SP263) assay (ie, \>=1% TC expressing PD-L1 on the membrane). DoR is only analyzed for those participants with a response (including unconfirmed responses).

DoR; PD-L1 (TC >=1%) Analysis Set Population

The FAS included all randomized participants analyzed on an ITT basis. DoR is only analyzed for those participants with a response (including unconfirmed responses).

DoR; FAS Population

Percentage of Participants Alive and Progression Free at 12 Months (APF12); PD-L1 (TC >=25%) Analysis Set Population

Percentage of Participants APF12; PD-L1 (TC >=1%) Analysis Set Population

Percentage of Participants APF12; FAS Population

Time From Randomization to Second Progression (PFS2); PD-L1 (TC >=25%) Analysis Set Population

PFS2; PD-L1 (TC >=1%) Analysis Set Population

PFS2; FAS Population

EORTC QLQ-C30: Fatigue

EORTC QLQ-C30: Appetite loss

EORTC QLQ-LC13: Dyspnoea

EORTC QLQ-LC13: Cough

EORTC QLQ-LC13: Chest pain

Change From Baseline in Disease-Related Symptoms as Assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ) at 12 Months

At Week 0: Pre-infusion

At Week 0: End of infusion

At Week 12: Pre-infusion

At Week 12: End of infusion

At Week 24: Pre-infusion

At Week 24: End of infusion

At follow-up Month 3

Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of study treatment per the protocol for whom any post-dose data are available and who did not violate or deviate from the protocol in ways that would materially affect the PK analyses.

Serum Concentrations of Durvalumab

The PK analysis set included all participants who received at least 1 dose of study treatment per the protocol for whom any post-dose data are available and who did not violate or deviate from the protocol in ways that would materially affect the PK analyses.

Serum Concentrations of Tremelimumab

Maximum Serum Concentration at Steady State (Cmax_ss) of Durvalumab

Cmax_ss of Tremelimumab

Trough Serum Concentration at Steady State (Ctrough_ss) of Durvalumab

Ctrough_ss of Tremelimumab

ADA positive at any time

Treatment-emergent ADA positive

ADA positive at baseline and post-baseline

ADA positive at post-baseline only

ADA positive at baseline only

Treatment-boosted ADA

Persistent positive

Transient positive

nAb positive at any visit

Safety analysis set included all participants who received at least 1 dose of study treatment. ADA evaluable population included participants who have non-missing durvalumab baseline ADA and at least one non-missing post-baseline durvalumab ADA result.

Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab

Safety analysis set included all participants who received at least 1 dose of study treatment. ADA evaluable population included participants who have non-missing baseline tremelimumab ADA and at least one non-missing post-baseline tremelimumab ADA result.

Number of Participants With ADA Response to Tremelimumab

Participants received durvalumab 20 milligram per kilogram (mg/kg) intravenous (IV) infusion every 4 weeks (Q4W) until worsening of the disease under investigation, unless specific treatment discontinuation criteria were met.

Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until worsening of disease under investigation, unless specific treatment discontinuation criteria were met.

1. Paclitaxel 200 mg/square meter (m\^2) and carboplatin area under the plasma drug concentration-time curve (AUC) 5 or 6 mg\*minute per milliliter (mg\*min/mL).
2. Gemcitabine 1000 or 1250 mg/m\^2 and cisplatin 75 or 80 mg/m\^2. Additional dose of Gemcitabine 1000 or 1250 mg/m\^2 on Day 8 of each cycle (For squamous tumors only).
3. Gemcitabine 1000 or 1250 mg/m\^2 and carboplatin AUC 5 or 6 mg\*min/mL. Additional dose of Gemcitabine 1000 or 1250 mg/m\^2 on Day 8 of each cycle (For squamous tumors only).
4. Pemetrexed 500 mg/m\^2 and cisplatin 75 mg/m\^2 (For non-squamous tumors only; pemetrexed maintenance dose was permitted).
5. Pemetrexed 500 mg/m\^2 and carboplatin AUC 5 or 6 mg\*min/mL (For non-squamous tumors only; pemetrexed maintenance dose was permitted).

Spots Global Cancer Trial Database for medi4736 (durvalumab)+tremelimumab