Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M–Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report

Yang, James Chih‐Hsin; Shepherd, Frances A.; Kim, Dong Wan; Lee, Gyeong Won; Lee, Jong Seok; Chang, Gee Chen; Lee, Sung Sook; Wei, Yiqun; Lee, Yun Gyoo; Laus, G.; Collins, Barbara; Pisetzky, Francesca; Horn, Leora

doi:10.1016/j.jtho.2019.02.001

Cited by 148 publications

(108 citation statements)

References 16 publications

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“…The reason for the difference in reported ILD frequencies in the osimertinib plus durvalumab arm from CAURAL and our study remains unclear. 32 Data investigating EGFR-TKIs in combination with immunotherapy remain limited. Although preliminary phase I results suggest durvalumab plus gefitinib to be tolerable (NCT02088112), 33 PD-1/PD-L1 inhibitor efficacy in this setting has been limited, and the potential for added benefit in combination with EGFR-TKIs is not confirmed.…”

Section: Discussionmentioning

confidence: 99%

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

et al. 2020

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Background: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. Patients and methods: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25e75 mg p.o. twice a day; continuous or intermittent), savolitinib (600e800 mg p.o. once a day), or durvalumab (3e10 mg/kg intravenous every 2 weeks). Results: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n ¼ 36), savolitinib (n ¼ 18), or durvalumab (n ¼ 23). Most common adverse events (any grade), occurring in 20% of patients across dose groups, were: selumetinib armddiarrhea (75%), rash (58%), nausea (47%); savolitinib armdnausea (67%), rash (56%), vomiting (50%); durvalumab armdrash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n ¼ 1), 50 mg (n ¼ 1), and 75 mg (n ¼ 4) continuous-dose groups, savolitinib 600 mg (n ¼ 1) and 800 mg dose groups (n ¼ 2), and durvalumab 10 mg/kg (n ¼ 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. Conclusion: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. Clinical trials number: NCT02143466.

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Section: Discussionmentioning

confidence: 99%

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

et al. 2020

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“…Thus, EGFR-TKIs show promising efficacy for anti-PD-1/PD-L1 treatment. However, these possible mechanisms regarding the immunostimulatory effect of EGFR-TKIs do not fully explain the controversial results of the combination of ICIs and EGFR-TKIs in patients with EGFR mutations [27,28,30].…”

Section: Egfr-tkis Affect the Tme In Nsclcmentioning

confidence: 99%

“…The CAURAL trial is a multiphase III trial in which osimertinib is combined with durvalumab. Both EGFR-TKI-sensitizing-and EGFR T790 M mutation-positive advanced patients were included in the study, though the results did not show a benefit for the combination arms with regard to ORR (64% vs 80%), duration of response (DOR) (17.5 months vs 21.4 months) or disease control rate (DCR) (93% vs 100%), which was even lower than that of the osimertinib monotherapy treatment group [27]. In addition, the KEYNOTE-021 study [28] was conducted to test the efficacy of combination pembrolizumab with erlotinib in EGFR-mutant advanced NSCLC patients.…”

Section: Introductionmentioning

confidence: 94%

Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

et al. 2019

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Immunotherapy has been incorporated into the first- and second-line treatment strategies for non-small cell lung cancer (NSCLC), profoundly ushering in a new treatment landscape. However, both adaptive signaling and oncogenic (epidermal growth factor receptor (EGFR)-driven) signaling may induce PD-L1 upregulation in NSCLC. Nevertheless, the superiority of immune checkpoint inhibitors (ICIs) in advanced EGFR-mutant NSCLC is only moderate. ICIs appear to be well tolerated, but clinical activity for some advanced EGFR-mutant NSCLC patients has only been observed in a small proportion of trials. Hence, there are still several open questions about PD-L1 axis inhibitors in patients with NSCLC whose tumors harbor EGFR mutations, such as the effect of EGFR tyrosine kinase inhibitors (TKIs) or EGFR mutations in the tumor microenvironment (TME). Finding the answers to these questions requires ongoing trials and preclinical studies to identify the mechanisms explaining this possible increased susceptibility and to identify prognostic molecular and clinical markers that may predict benefits with PD-1 axis inhibition in this specific NSCLC subpopulation. The presence of multiple mechanisms, including dynamic immune TME profiles, changes in PD-L1 expression and low tumor mutational burdens, may explain the conflicting data regarding the correlation between PD-L1 axis inhibitors and EGFR mutation status. We conducted a review of this currently controversial topic in an attempt to aid in the decision-making process.

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“…In 2018, ASCO published the results of the NCT01693562 study, 59 in which durvalumab was used as monotherapy in patients with terminal stage SCLC brain metastasis. A total of 21 patients (20 treated) with extensive stage SCLC with metastatic brain tumors received treatment with durvalumab 10 mg/kg, once every two weeks.…”

Section: Sclcmentioning

confidence: 99%

<p>Use of Programmed Death Receptor-1 and/or Programmed Death Ligand 1 Inhibitors for the Treatment of Brain Metastasis of Lung Cancer</p>

Wang

Xie

et al. 2020

OTT

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The central nervous system (CNS) is regarded as an immune privileged environment; however, changes in the neuroimmunology paradigm have led to an increased interest in systematic immunotherapy in lung cancer therapy. The presence of the lymphatic system in the CNS as well as the physiological and biochemical changes in the blood-brain barrier in the tumor microenvironment suggests that immunocytes are fully capable of entering and exiting the CNS. Emerging clinical data suggest that inhibitors of programmed death receptor-1/programmed death ligand 1 (PD-1/PD-L1) can stimulate surrounding T cells and thus have antitumor effects in the CNS. For example, PD-1 antibody (pembrolizumab) monotherapy has displayed a 20-30% encephalic response rate in patients with brain metastases from malignant melanoma or non-small cell lung cancer. Combined application of nivolumab and ipilimumab anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 showed an encephalic response rate of 55% in patients with brain metastases of melanoma. Further evidence is required to verify these response rates and identify the mechanisms of curative effects and drug tolerance. While regional treatments such as whole-brain radiosurgery, stereotactic radiosurgery, and brain surgery remain the mainstream, PD-1/PD-L1 inhibitors display potential decreased neurotoxic effects. To date, five drugs have been approved for use in patients with encephalic metastases of lung carcinoma: the anti-PD-1 drugs, pembrolizumab and nivolumab, and the anti-PD-L1 agents, atezolizumab, durvalumab, and avelumab. In recent years, clinical trials of inhibitors in combination with other drugs to treat brain metastasis have also emerged. This review summarizes the biological principles of PD-1/PD-L1 immunotherapy for brain metastasis of lung cancer, as well as ongoing clinical trials to explore unmet needs.

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Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M–Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report

Cited by 148 publications

References 16 publications

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

<p>Use of Programmed Death Receptor-1 and/or Programmed Death Ligand 1 Inhibitors for the Treatment of Brain Metastasis of Lung Cancer</p>

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