AstraZeneca’s Imfinzi (durvalumab) has been approved in the European Union and the UK for an additional dosing option, a 1,500mg fixed dose every four weeks, in locally advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on at least 1% of tumour cells...New option extends dosing from two to four weeks, reducing medical visits and improving patient convenience...

Imfinzi as monotherapy is indicated for the treatment of locally advanced, unresectable non‑small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on ≥ 1% of tumour cells and whose disease has not progressed following platinum‑based chemoradiation therapy.

The National Institute for Health and Care Excellence (NICE) on Friday recommended AstraZeneca's Imfinzi (durvalumab) for patients in England with PD-L1-positive locally advanced, unresectable, stage III non-small-cell lung cancer.

PD-L1≥1-49%....The following continuation maintenance regimens added...Durvalumab ± pemetrexed.

NON-SUPPORTIVE EVIDENCE: The PEARL Phase III trial for AstraZeneca’s Imfinzi (durvalumab) did not achieve statistical significance for the primary endpoints of improving overall survival (OS) versus platinum-based chemotherapy as a monotherapy treatment of patients with Stage IV (metastatic) non-small cell lung cancer (NSCLC) whose tumour cells express high levels (25% or more) of PD-L1, or in a subgroup of patients at low risk of early mortality. There was an improvement in OS with Imfinzi monotherapy, which was clinically meaningful in the subset of patients with PD-L1 tumour expression greater than 50%, a secondary endpoint.

The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non–small-cell lung cancer...updated OS (stratified HR, 0.72; 95% CI, 0.59 to 0.89; median, 47.5 v 29.1 months) and PFS (stratified HR, 0.55; 95% CI, 0.45 to 0.68; median, 16.9 v 5.6 months) remained consistent with the primary analyses....OS and PFS benefit favored durvalumab versus placebo across all PD-L1 subgroups....Kaplan-Meier curves for durvalumab versus placebo in PD-L1 subgroups are provided (Appendix Figs A2 and A3, online only).

AstraZeneca's Imfinzi (durvalumab) has been recommended for marketing authorisation in the European Union (EU) for an additional dosing option, 1,500mg fixed dose every four weeks, in the approved indication of locally advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on at least 1% of tumour cells and whose disease has not progressed following platinum-based chemoradiation therapy (CRT).

As of June 1, 2017, the objective response rate among patients with PD-L1 TC ≥25% was 35.6%, 34.4%, and 37.7% with durvalumab, durvalumab plus tremelimumab, and chemotherapy, respectively (eTable 7 in Supplement 1).

In heavily pretreated patients with mNSCLC, durvalumab demonstrated clinically meaningful improvements in OS and PFS versus SoC (patients with PD-L1 TC ≥25%); numerical improvements in OS and PFS for durvalumab + tremelimumab versus SoC were observed (patients with PD-L1 TC <25%).

This Phase 3 trial (NCT02352948) evaluated durvalumab (D) vs SoC and D plus anti-CTLA-4 tremelimumab (T) vs SoC in Stage IIIB/IV NSCLC….In SSA, median OS was 11.7 vs 6.8 mo with D vs SoC (HR 0.63 [0.42, 0.93]). 12-mo OS rates were 49.3% and 31.3%....D monotherapy provided a clinically meaningful improvement in OS vs SoC in PD-L1 TC ≥25% pts.

...DFS in FAS (using Investigator assessments according to RECIST 1.1)`PFS (using local standard practice)`Time to first subsequent therapy (TFST)`Time to second subsequent therapy (TSST)`Change from baseline in EORTC QLQ-C30`Change from baseline in EORTC QLQ-LC13`Time to deterioration in EORTC QLQ-C30`Time to deterioration in EORTC QLQ-LC13`IHC analysis of PD-L1 TC expression and spatial distribution within the tumor microenvironment relative to efficacy outcomes (ie, DFS, OS)The Ventana SP263 PD-L1 immunohistochemistry (IHC) assay will be used to determine PDL1 status in all specimens.`...

...PD-L1 expression ≥25% of tumor cells as assessed by the local pathology laboratory using protocols validated....

...EGFR mutant NSCLC with PD-L1 expression of 1% or higher is allowed if...

...• To study any correlations between baseline tumor PD-L1 expression (based on immunohistochemistry) and the baseline uptake and changes in 89Zr-durvalumab (89Zr-MEDI4736) uptake in tumor sites....

...Proportion of patients at time to death or distant metastasis (TTDM) assessed by BICR according to RECIST 1.1 in randomised patients`Peak Plasma Concentration (Cmax) in randomised patients`Trough Concentration (Ctrough) in randomised patients`Number of participants with treatment-related adverse events as assessed by CTCAE v5.0`Detection of ADA neutralising antibodies titres for all randomised patients`IHC analysis of tumoural PD-L1 expression and spatial distribution within the tumour microenvironment relative to efficacy outcome OS`IHC analysis of tumoural PD-L1 expression and spatial distribution within the tumour microenvironment relative to efficacy outcome PFS`IHC analysis of tumoural PD-L1 expression and spatial distribution within the tumour microenvironment relative to efficacy outcome ORR`Number of participants with abnormal findings with physical examination`vital sign (blood pressure [BP])`vital sign (pulse rate)`vital sign (temperature)`vital sign (respiration rate)`vital sign (12-lead electrocardiogram)`Change in Albumin (g/L)`Change in Alkaline phosphatase (U/L)`Change in Alanine aminotransferase (U/L)`Change in Aspartate aminotransferase (U/L)`Change in Amylase (U/L)`Change in Bicarbonate (mmol/L)`Change in Calcium (mmol/L)`Change in Chloride (mmol/L)`Change in Creatinine (μmol/L)`Change in Gamma glutamyltransferase (U/L)`Change in Glucose (mmol/L)`Change in Lactate dehydrogenase (U/L)`Change in Lipase (U/L)`Change in Magnesium (mmol/L)`Change in Potassium (mmol/L)`Change in Sodium (mmol/L)`Change in Total bilirubin (μmol/L)`Change in total protein (g/L)`Change in TSH (mIU/L)`Change in T3 free (reflex) (mIU/L)`Change in T4 free (reflex) (mIU/L)`Change in Urea or blood urea nitrogen, depending on the local practice (mmol/L)`Change in Uric acid (mmol/L)`Change in absolute neutrophil count (/L)`Change in absolute lymphocyte count (/L)`Change in haemoglobin (g/L)`Change in platelet count (/L)`Change in total white blood cell count (/L)`Change in activated partial thromboplastin time`Change in international normalised ratio`Urinalysis: Change in bilirubin (μmol/L)`Urinalysis: Change in blood`Urinalysis: Change in color and apprearance`Urinalysis: Change in ketones (mmol/L)`Urinalysis: Change in pH`Urinalysis: Change in protein (g/L)`Urinalysis: Change in specific gravity...

...- Any tumor PD-L1 expression is allowed (including 0% to 100%, or unknown at time of study enrollment)...

...Progression-Free Survival (PFS)`Progression-Free Survival (PFS) at 12 Months`Progression-Free Survival (PFS) at 24 Months`Progression-Free Survival (PFS) by PD-L1 Expression at 12 Months`Progression-Free Survival (PFS) by PD-L1 Expression Status at 24 Months`Overall Survival by PD-L1 Expression Status at 12 Months`Overall Survival by PD-L1 Expression Status at 24 Months`Overall Response Rate (ORR)`Overall Response Rate (ORR) in Patients With PD-L1 Expression Status = 0`Overall Response Rate (ORR) in Patients With PD-L1 Expression Status = 0%<PD-L1<50%.`...

...- Known PD-L1 TC expression status assayed by Ventana SP263....

...Compare Disease free survival (DFS) for patients with NSCLC that is PD-L1 expression TC ≥ 25% and patients without common activating EGFR mutations or ALK gene rearrangements...

...Complete pathologic response rates for PDL-1 negative and PDL-1 positive patients...

...Response Rate (recist 1.1)`Metabolic response rate on TEP-FDG`Delay between surgery and start of treatment`Number of participants with treatment-related adverse events as assessed by CTCAE v4.0`Disease-Free Survival (DFS)`Overall survival (OS)`Evaluation of predictive/prognostic value of PD-1/PD-L1 expression`Evaluation of changes in plasma/serum cytokines and other biomarkers`Major Pathological Response...

...Assess response rate by RECIST criteria 1.1 in Arm A and Arm B in advanced Kras mutation positive and PD-L1 high (≥50%) NSCLC patients.The objective response rate is the proportion of all subjects with confirmed PR or CR according to RECIST 1.1, from the start of treatment until disease progression/recurrence`Response Rate...

...Biomarkers include PD-L1 expression, tumor grading and tumor mutational burden (TMB). ...

...Histologically confirmed operable NSCLC (resectable stage IIA~IIIB) regardless of PD-L1 expression....

...Compare Disease free survival (DFS) for patients with NSCLC that is PD-L1 positive using the RECIST criteria...

...Quantitatively measure and describe changes in CD8 T-cell infiltration and interrogate whether radiotherapy causes changes in expression of PD-L1, a target for immunecheckpoint immunotherapy ...

...- Patient's tumour sample must be PD-L1 positive (≥25%of tumour cells with membrane staining (Cohort 1 and 2) or PD-L1 positive with ≥90% of tumour cells with membrane staining (Cohort 3))...

...- Histologically proven PD-L1-expression of ≥ 1% (tumor proportion score; TPS) in tumor sample as assessed in routine staging using a validated test such as Ventana SP236 assay...

...- PD-L1 expression of ≥ 25% of the tumor cells by local testing (Ventana SP142 excluded)...

...- Biopsy-proven NSCLC primary with PD-L1 expression ≥ 1%...

...Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR`Response Rate in MEDI4736-treated Participants`The percentage of PD-L1 positive participants with confirmed and unconfirmed, partial response and complete response to treatment with MEDI4736 per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1). ...

...DFS for patients with NSCLC that is PD-L1 positive. ...

...Histopathology with PD-L1 positive tumour cells >25%. ...

...TTP by PDL1 expression - TTP analysed according to PDL1 expression on biopsy taken before study entry. ...

...Histologically proven PD-L1-expression of ≥ 1% (tumor proportion score; TPS) in tumor sample as assessed in routine staging using a validated test such as Ventana SP236 assay7. ...

...To correlate the imaging data to immune and tissue characteristics, the imaging results will be related to multiple blood and tissue parameters, including tumor and TIL PD-1 and PD-L1 expression, as well as explorative markers; CD3, CD4, CD8, FOXP3, IL12R, IL7R, IL10 and MHC class I and II. ...

...• Occurence of treatment-related AEs and SAEs according to CTCAE V5.0• Abnormal values of laboratory parameters• PFS according to RECIST 1.1• Duration of Clinical Benefit (Duration of CR, PR, SD) according to RECIST 1.1• MFS• OS • QoL (FACT-L)• Descriptive sub-group analyses of efficacy in relation to PD-L1 expression levels (<°1% vs ≥°1%)Exploratory endpoints:• Vulnerability assessment based on the G8-screening questionnaire and its association to survival and outcome • Collection of blood- and stool based biomarker samples for future research...

...OS`LC`QoL`TTP by PDL1 expression...

This study demonstrates that single agent durvalumab is safe and well tolerated in the 1st line treatment of patients with advanced NSCLC and ECOG PS of 2, with an encouraging OS benefit in patients with PD-L1 positive tumors.

The multicenter, single-arm DOLPHIN (Phase II Study of Durvalumab [MEDI4736] Plus Concurrent Radiation Therapy in Advanced Localized NSCLC Patients) nonrandomized controlled trial was performed by 12 institutions in Japan from September 13, 2019, to May 31, 2022. Participants in the primary registration phase included 74 patients with programmed cell death ligand 1 (PD-L1)-positive, unresectable, locally advanced NSCLC....The 12-month PFS rate was 72.1% (90% CI, 59.1%-85.1%), and the median PFS was 25.6 months (95% CI, 13.1 months to not estimable) at a median follow-up of 22.8 months (range, 4.3-31.8 months).

This retrospective study demonstrates a statistically significant improvement in OS associated with durvalumab after CRT in PD-L1 ≥ 1%, but not PD-L1 < 1% NSCLC.

...58(42%) patients whose tumour expressed PDL1 received durvalumab….Multivariable Cox and Kaplan-Meier analyses demonstrated that patients treated with durvalumab experienced improved PFS and OS, adjusting for sex, age, performance status, and gross tumor volume (adjusted HR for OS:0.36, p=0.006 and for PFS:0.28,p=0.009; table1, figure1A and 1B).

This study demonstrated that single agent durvalumab is safe and well tolerated in the 1st line treatment of patients with advanced NSCLC and ECOG PS of 2, with an encouraging OS benefit in patients with PD-L1 positive tumors.

In this single-arm, multicenter, phase II trial pts with PD-L1 positive (tumor proportional score, TPS ≥25%), advanced NSCLC with PS2, unsuitable for combination chemotherapy determined by the investigators, in the absence of known contraindications for immunotherapy and sufficient organ function, received a fixed dose of 1500 mg durvalumab every four weeks....1L durvalumab in PS2 pts with advanced PD-L1 positive (TPS ≥25%) NSCLC is effective and led to a promising 6-month OS of 60%.

All patients were deemed unresectable by MTB and had PD-L1-positive (>1%) tumors, with at least stable disease, and receiving one durvalumab dose after CRT….At a median follow-up time of 18 months, the median PFS of the entire cohort was 23.2 months (2.10–47.63)....Ten pts are alive without progression, and 11 are alive with progressive disease. Median PFS2 was 7.23 months (1.03–42), and median OS was 15.5 months (1.07–46.17), respectively.

PACIFIC-R is an observational, retrospective study of a cohort of pts with unresectable Stage III NSCLC who received ≥1 dose of D (10 mg/kg IV Q2W)....OS rates were numerically higher in pts who received concurrent vs sequential CRT, pts with programmed cell death-ligand 1 (PD-L1) expression ≥1% vs <1%, and pts who started D ≤42 vs >42 days after finishing RT (Table)....PACIFIC-R data continue to provide evidence for the effectiveness of consolidation D after CRT in a large, diverse, real-world population, consistent with the PACIFIC trial. Favourable OS results were observed across subgroups, including pts who received sequential CRT and pts with PD-L1 <1%, with consistent rwPFS outcomes.

Patients received durvalumab for a median of 11.0 months. Median rwPFS was 21.7 months (95% CI: 19.1-24.5). RwPFS was numerically longer among patients who received concurrent versus sequential CRT (median, 23.7 vs. 19.3 months) and among patients with programmed cell death-ligand 1 (PD-L1) expression ≥1% versus <1% (22.4 vs. 15.6 months)....Consolidation durvalumab following definitive CRT was well tolerated and effective in this large, real-world cohort study of patients with unresectable, stage III NSCLC. As expected, rwPFS was higher among patients who received concurrent versus sequential CRT and patients with higher PD-L1 expression.

We conducted a retrospective review to assess the real-world impact of durvalumab on OS according to PD-L1 tumor proportion score (TPS)....This study demonstrates a significant improvement in OS associated with durvalumab after CRT in PD-L1 ≥ 1 %, but not in PD-L1 < 1% NSCLC.

The durvalumab effect was present in patients with PD-L1-positive tumors receiving durvalumab in comparison with other patients with known PD-L1 expression status without durvalumab (log-rank test: p = 0.0036)….An important finding was that survival of the entire group with PD-L1 expression as well as the subgroup of patients with PD-L1 expression who met the inclusion criteria of the PACIFIC trial was improved after the introduction of durvalumab consolidation.

Progression-free survival (PFS) and overall survival (OS) in PD-L1 expression subgroups (<1%, 1%-49%, and 50%-100%) were compared with 994 patients with stage III NSCLC treated without adjuvant durvalumab from 2015 to 2016....PFS was longer for PD-L1 50% to 100% (aHR, 0.44; 95% CI, 0.32-0.60; P < .001) and PD-L1 1% to 49% (aHR, 0.64; 95% CI, 0.47-0.86; P = .003) but not PD-L1 <1% (aHR, 0.84; 95% CI, 0.64-1.10; P = .19)....Increasing PD-L1 expression was associated with longer PFS (adjusted hazard ratio [aHR], 0.84 per 25% absolute increase in expression; 95% confidence interval [CI], 0.75-0.94; P = .003) and OS (aHR, 0.86 per 25% absolute increase in expression; 95% CI, 0.74-0.99; P = .036).

Progression-free survival (PFS) in the Durva group was significantly greater than that in the CRT alone group (not reached [NR] vs 12.9 months; p = 0.002)….In the CRT alone group, neither PD-L1 expression nor TIL status affected PFS; in contrast, in the Durva group, high density of CD8-positive TILs (TILHigh ≥100/mm2) and PD-L1-positive expression (tumour proportion score ≥1%; PD-L1+) was significantly associated with longer PFS (TIL: NR vs 9.5 months; p = 0.002; and PD-L1: NR vs 7.7 months; p = 0.003)....PD-L1+ and TILHigh at baseline could be predictive markers of the efficacy of CRT followed by durvalumab.

...maintenance therapy with durvalumab, for stage III unresectable NSCLC, PD-L1 >1%, responding to cCRT or sCRT, was associated with very promising short-term survival rates in a large multicenter, retrospective, real-world series.

Median follow-up for the entire cohort was 33.1 months (range: 6.3-111.8) and median overall survival was 27.2 (95% CI: 19.5-34.9) months....real-world analysis demonstrated that durvalumab after CRT led to significant improvement of local-regional control, PFS, and OS in PD-L1 expressing inoperable stage III NSCLC patients compared to a historical cohort.

In the immuno substudy, pan-negative NSCLC pts were randomized 2:1 either on D or SoC….In this population, maintenance D, vs SoC, did suggest a positive effect on PFS and OS in the PDL-1 positive subgroup but not in the overall population.

In a patient-level analysis, data were extracted from available trials of durvalumab...Moderate correlations were observed between ΔORR and OS HR: ITT, -0.63; PD-L1-enriched, -0.53. At the patient level, a positive association was observed between PFS and OS in non-small-cell lung cancer (Kendall's Tau=0.793; 95% confidence interval, 0.789-0.797), head-and-neck squamous-cell carcinoma (0.794; 0.789-0.798), and bladder cancer (0.872; 0.869-0.875).

CONTRADICTING EVIDENCE: 134 stage 3 NSCLC patients who received durvalumab had a median PFS was 15.4 months, with worse PFS in patients with PD-L1 1-49% (HR 2.4, p = 0.03) and PD-L1 < 1% (HR 2.6, p = 0.03)….Clonal expansion of T cells after CRT may influence the likelihood of an anti-tumor immune response following PD-L1 blockade in stage 3 NSCLC.