Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial

Ahn, Myung‐Ju; Cho, Byoung Chul; Ou, Xiaoling; Walding, Andrew; Dymond, Angela W.; Ren, Song; Cantarini, Mireille

doi:10.1016/j.jtho.2022.01.012

Cited by 39 publications

(18 citation statements)

References 13 publications

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“…Several clinical trials also investigated the safety and efficacy of ICIs plus EGFR-TKIs. Jänne et al (17) revealed that in advanced EGFR-mutated NSCLC patients administered with first-line osimertinib plus durvalumab, ORR was 82% (48-98), the median duration of response (DOR) was 7.1 months and median progression-free survival (PFS) was 9.0 months. However, the enrollment in this patient cohort was terminated due to the potential risk of interstitial lung disease (ILD)-related AEs.…”

Section: Discussionmentioning

confidence: 99%

EGFR mutations and high PD-L1 expression of lung squamous cell carcinoma patients achieving pCR following neoadjuvant immuno-chemotherapy: Case report

Shi²,

Fu³

et al. 2022

Front. Oncol.

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The treatment of lung cancer has fully entered the era of immunotherapy, which has significantly elevated the survival rate of patients with advanced non-small cell lung cancer (NSCLC), thus shedding light on resectable NSCLC. Previous clinical trial data suggested that neoadjuvant immuno-chemotherapy obtained a significant objective response rate (ORR) and disease control rate (DCR). Here, a case that achieved an excellent outcome following neoadjuvant immuno-chemotherapy was reported. The patient admitted to our hospital was 58 years old, female, with a rare case of stage IB lung squamous cell carcinoma (LUSC) harboring both epidermal growth factor receptor (EGFR) p.L858R mutations and high expression of programmed death ligand-1 (PD-L1) (tumor proportion score (TPS)=80%). Her tumor substantially shrunk following two cycles of neoadjuvant immuno-chemotherapy. The patient successively received single-port right upper thoracoscopic lobectomy + mediastinal lymph node dissection, which attained pathologic complete response (pCR). Additionally, the patient had grade 2 myelosuppression during the two cycles, which was treated with polyethylene glycol recombinant human granulocyte colony-stimulating factor (rhG-CSF). The patient was discharged uneventfully without any procedure-related complications. Two courses of adjuvant immuno-chemotherapy were administered postoperatively, leaving the patient in good physical condition at the 5-month follow-up visit. This case provided evidence for the feasibility and effectiveness of neoadjuvant immuno-chemotherapy in treating early-stage LUSC with EGFR mutations and high expression of PD-L1. However, randomized and multi-center controlled trials are required to validate the findings.

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Section: Discussionmentioning

confidence: 99%

EGFR mutations and high PD-L1 expression of lung squamous cell carcinoma patients achieving pCR following neoadjuvant immuno-chemotherapy: Case report

Shi²,

Fu³

et al. 2022

Front. Oncol.

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“…Second-line treatment of T790M patients with bevacizumab in combination with osimertinib did not result in a prolonged progression-free survival (PFS) compared to osimertinib alone [60]; Nonetheless, other clinical trials of first-line treatment are ongoing (NCT02803203). In the TATTON trial, the combination of osimertinib and anti-PD-L1 durvalumab was associated with a significant number of immune-mediated adverse events, especially in interstitial lung disease (ILD) (NCT02143466) [61]. In the future, it is anticipated that more combination therapies based on osimertinib will be proposed.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Combination Therapy as First-Line Treatment for Patients with Advanced EGFR-Mutated, Non-Small Cell Lung Cancer: A Systematic Review and Bayesian Network Meta-Analysis

Wang

Huang

et al. 2022

Cancers

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(1) Background: Several randomized controlled trials (RCTs) have been conducted in combination with Efficacy and Safety of Epidermal Growth Factor Receptor(EGFR)-Tyrosine Kinase Inhibitor (TKI) for the first-line treatment of patients with advanced non-small cell lung cancer; however, head-to-head comparisons of combination therapies are still lacking. Therefore, this study aims to compare the efficacy and safety of various combination treatments. (2) Methods: We conducted a systematic review and Bayesian network meta-analysis by searching MEDLINE, EMBASE, and COCHRANE for relevant RCTs. (3) Results: TKI combined with antiangiogenic therapy, chemotherapy, or radiation achieved a significant benefit compared with TKI alone for progression free survival (PFS). A combination with radiation yielded better benefits in PFS than any other treatment. In terms of overall survival (OS), only the combination with pemetrexed and carboplatin (HR = 0.63, 95% credible interval 0.43–0.86)/radiation (0.44, 0.23–0.83) was superior to TKI alone. All of the combination therapies may increase the incidence of ≥Grade 3 AEs, as the pooled RRs are over 1; different toxicity spectrums were revealed for individual treatments. (4) Conclusions: The TKI combination of radiation/pemetrexed and carboplatin could provide the best antitumor effects among the first generation TKI-based treatments. Considering safety, ramucirumab and bevacizumab may be the ideal additions to TKIs (systematic review registration: PROSPERO CRD42022350474).

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“…Although the existence of DTPs in patients has yet to be established, several clinical strategies are currently being tested. Combination of EGFR-TKI with immune checkpoint inhibitors (ICIs), such as durvalumab or nivolumab, do not appear to be a good option for patients due to a high rate of toxicity [ 179 , 180 ]. Other attractive treatment strategies could include: (1) to maintain the tumour cells in a DTP state, (2) to eradicate the DTP population by targeting specific regulators, or (3) to prevent the establishment of DTPs ( Figure 5 ).…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer

Delahaye

Figarol

Pradines

et al. 2022

Cancers

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Lung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative due to the inevitable emergence of resistances. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant persister cells (DTP) through non-genetic reprogramming, by entering a reversible slow-to-non-proliferative state, before developing genetically derived resistances. Deciphering the molecular mechanisms governing the dynamics of the drug-tolerant state is therefore a priority to provide sustainable therapeutic solutions for patients. An increasing number of molecular mechanisms underlying DTP survival are being described, such as chromatin and epigenetic remodelling, the reactivation of anti-apoptotic/survival pathways, metabolic reprogramming, and interactions with their micro-environment. Here, we review and discuss the existing proposed mechanisms involved in the DTP state. We describe their biological features, molecular mechanisms of tolerance, and the therapeutic strategies that are tested to target the DTP.

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Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial

Cited by 39 publications

References 13 publications

EGFR mutations and high PD-L1 expression of lung squamous cell carcinoma patients achieving pCR following neoadjuvant immuno-chemotherapy: Case report

EGFR mutations and high PD-L1 expression of lung squamous cell carcinoma patients achieving pCR following neoadjuvant immuno-chemotherapy: Case report

Efficacy and Safety of Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Combination Therapy as First-Line Treatment for Patients with Advanced EGFR-Mutated, Non-Small Cell Lung Cancer: A Systematic Review and Bayesian Network Meta-Analysis

Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer

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