Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC

Antonia, Scott; Balmanoukian, Ani Sarkis; Brahmer, Julie R.; Ou, Sai Hong Ignatius; Hellmann, Matthew D.; Kim, Sang We; Ahn, Myung Ju; Kim, Dong Wan; Gutierrez, Martin; Liu, Stephen V.; Schöffski, Patrick; Jäger, Dirk; Jamal, Rahima; Jérusalem, Guy; Lutzky, Jose; Nemunaitis, John; Calabrò, Luana; Weiss, Jared; Gadgeel, Shirish M.; Bhosle, Jaishree; Ascierto, Paolo A.; Rebelatto, Marlon C.; Narwal, Rajesh; Liang, Meina; Xiao, Feng; Antal, Joyce; Abdullah, Shaad E.; Angra, Natasha; Gupta, Ashok; Khleif, Samir N.; Segal, Neil H.

doi:10.1016/j.jtho.2019.06.010

Cited by 77 publications

(61 citation statements)

References 36 publications

(51 reference statements)

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“…In most cases, the cutoff value for PD-L1 positivity or negativity was that PD-L1 stained cells accounted for 1% of cancer cells, or cancer and immune cells, assayed by immunohistochemistry staining techniques. However, the thresholds were 5% in 17 studies, 10 , 17 – 20 , 24 , 26 , 35 , 40 , 47 , 56 , 61 , 69 , 78 , 88 , 96 , 168 10% in 3 articles, 31 , 127 , 159 25% in 5 studies, 43 – 45 , 48 , 49 and 50% in 3 records. 121 , 131 , 155 In addition, only PD-L1 positive cancer patients were recruited in 17 studies.…”

Section: Resultsmentioning

confidence: 96%

Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials

Zhao

2020

Ther Adv Med Oncol

100

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Background: Inhibitors targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have unprecedented effects in cancer treatment. However, the objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS) of PD-1/PD-L1 blockade monotherapy have not been systematically evaluated. Methods: We searched Embase, PubMed, and Cochrane database from inception to July 2019 for prospective clinical trials on single-agent PD-1/PD-L1 antibodies (avelumab, atezolizumab, durvalumab, cemiplimab, pembrolizumab, and nivolumab) with information regarding ORR, PFS, and OS. Results: Totally, 28,304 patients from 160 perspective trials were included. Overall, 4747 responses occurred in 22,165 patients treated with PD-1/PD-L1 monotherapy [ORR, 20.21%; 95% confidence interval (CI), 18.34–22.15%]. Compared with conventional therapy, PD-1/PD-L1 blockade immunotherapy was associated with more tumor responses (odds ratio, 1.98; 95% CI, 1.52–2.57) and better OS [hazard ratio (HR), 0.75; 95% CI, 0.67–0.83]. The ORRs varied significantly across cancer types and PD-L1 expression status. Line of treatment, clinical phase and drug target also impacted the response rates in some tumors. A total of 2313 of 9494 PD-L1 positive patients (ORR, 24.39%; 95% CI, 22.29–26.54%) and 456 of 4215 PD-L1 negative patients (ORR, 10.34%; 95% CI, 8.67–12.14%) achieved responses. For PD-L1 negative patients, the ORR (odds ratio, 0.92; 95% CI, 0.70–1.20) and PFS (HR, 1.15; 95% CI, 0.87–1.51) associated with immunotherapy and conventional treatment were similar. However, PD-1/PD-L1 blockade monotherapy decreased the risk of death in both PD-L1 positive (HR, 0.66; 95% CI, 0.60–0.72) and PD-L1 negative (HR, 0.86; 95% CI, 0.74–0.99) patients compared with conventional therapy. Conclusion: The efficacies associated with PD-1/PD-L1 monotherapy vary significantly across cancer types and PD-L1 expression. This comprehensive summary of clinical benefit from immunotherapy in cancer patients provides an important guide for clinicians.

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Section: Resultsmentioning

confidence: 96%

Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials

Zhao

2020

Ther Adv Med Oncol

100

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“…These findings confirm and further support results seen with durvalumab monotherapy in patients with mNSCLC. 3,13 In study B (PD-L1 TC <25%), while statistical significance was not achieved, durvalumab þ tremelimumab resulted in an OS HR versus SoC of 0.80 (P ¼ 0.109), with mOS of 11.5 and 8.7 months, respectively. These results are consistent with previous reports for combination therapies targeting the PD-1/PD-L1 and CTLA-4 pathways.…”

Section: Discussionmentioning

confidence: 94%

ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer

et al. 2020

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Background: Many patients with metastatic non-small-cell lung cancer (mNSCLC) experience disease progression after firstand second-line treatment; more treatment options are required for these patients. ARCTIC, a phase III, randomized, open-label study, assessed durvalumab AE tremelimumab versus standard of care (SoC) as ! third-line treatment of mNSCLC. Patients and methods: ARCTIC comprised two independent sub-studies. Study A: 126 patients with !25% of tumor cells (TCs) expressing programmed cell death ligand-1 (PD-L1) were randomized (1 : 1) to durvalumab [up to 12 months 10 mg/kg every 2 weeks (q2w)] or SoC. Study B: 469 patients with PD-L1 TC <25% were randomized (3 : 2 : 2 : 1) to durvalumab þ tremelimumab (12 weeks durvalumab 20 mg/kg þ tremelimumab 1 mg/kg q4w then 34 weeks durvalumab 10 mg/kg q2w), SoC, durvalumab (up to 12 months 10 mg/kg q2w), or tremelimumab (24 weeks 10 mg/ kg q4w then 24 weeks q12w). Primary end points: overall survival (OS) and progression-free survival (PFS) for durvalumab versus SoC (study A; descriptive only) and durvalumab þ tremelimumab versus SoC (study B). Results: Study A: median OS 11.7 (durvalumab) versus 6.8 (SoC) months {hazard ratio (HR) 0.63 [95% confidence interval (CI), 0.42e0.93]}; median PFS 3.8 (durvalumab) versus 2.2 (SoC) months [HR 0.71 (95% CI, 0.49e1.04)]. Study B: median OS 11.5 (durvalumab þ tremelimumab) versus 8.7 (SoC) months [HR 0.80 (95% CI, 0.61e1.05); P ¼ 0.109]. Median PFS of 3.5 months for both groups [HR 0.77 (95% CI, 0.59e1.01); P ¼ 0.056]. Treatment-related grade 3/4 adverse events: 9.7% (durvalumab) and 44.4% (SoC; study A) and 22.0% (durvalumab þ tremelimumab) and 36.4% (SoC; study B). Conclusions: 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 þ tremelimumab versus SoC were observed (patients with PD-L1 TC <25%). Safety profiles were consistent with previous studies. Trial registration: Clinicaltrials.gov identifier: NCT02352948.

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“…The study design and initial results of this multicenter, open-label study have been described previously. [11][12][13] This study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Council on Harmonization guidelines on Good Clinical Practice, any applicable laws and requirements, and any conditions required by a regulatory authority and/or Institutional Review Board/Independent Ethics Committee that has approved this study to be conducted in its territory. The study protocol was reviewed and approved by the Institutional Review Board or Ethics Committee of the participating centers, and informed consent was obtained.…”

Section: Methodsmentioning

confidence: 99%

Durvalumab activity in previously treated patients who stopped durvalumab without disease progression

Sheth

Gao

Mueller

et al. 2020

J Immunother Cancer

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BackgroundLimited data exist on potential clinical benefit with anti-programmed cell death ligand-1 (PD-L1) retreatment in patients who stop initial therapy for reasons other than disease progression or toxicity and develop disease progression while off treatment.Patients and methodsNCT01693562 was a phase I/II study evaluating durvalumab monotherapy in advanced solid tumors. Patients benefiting from treatment were taken off durvalumab at 1 year per protocol and prospectively followed. At disease progression, they were eligible for durvalumab retreatment. Outcomes evaluated during retreatment included best overall response (BOR2), duration of response (DoR2), disease control rate (DCR2), and progression-free survival (PFS2).ResultsOf 980 patients enrolled and treated with durvalumab 10 mg/kg every 2 weeks (Q2W) in the dose-expansion cohorts, 168 completed 1 year of initial durvalumab treatment with confirmed BOR1 of complete response in 20 (11.9%), partial response (PR) in 84 (50%), stable disease (SD) in 52 (31%), and disease progression in 12 (7.1%). All 168 patients stopped treatment and were eligible for retreatment at progression; 70 patients (41.7%) representing 14 primary tumor types were retreated and response evaluable. Confirmed BOR2 was PR in 8 patients (11.4%), SD in 42 (60.0%), disease progression in 16 (22.9%), and unevaluable in 4 (5.7%). Median DoR2 was 16.5 months. DCR2 ≥24 weeks (DCR2 24) was 47.1%. PFS2 rate at 12 months was 34.2%, and median PFS2 was 5.9 months. Median overall survival (OS2) was 23.8 months. Response rates, DCR2 24, and median DoR2 were generally greater in patients with high PD-L1 expression than those with low/negative expression. No new safety signals were observed during retreatment.ConclusionRetreatment restored antitumor activity, resulting in high rates of durable disease control with an acceptable safety profile. This evidence supports retreatment of patients who stop anti-PD-L1 therapy for reasons other than progression or toxicity, and supports further investigation.

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Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC

Cited by 77 publications

References 36 publications

Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials

Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials

ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer

Durvalumab activity in previously treated patients who stopped durvalumab without disease progression

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