Randomized phase II study of fulvestrant and erlotinib compared with erlotinib alone in patients with advanced or metastatic non-small cell lung cancer

Garon, Edward B.; Siegfried, Jill M.; Stabile, Laura P.; Young, Patricia A.; Márquez-Garbán, Diana C.; Park, David J.; Patel, Ravi; Hu, Eddie; Sadeghi, Saeed; Parikh, Rupesh J.; Reckamp, Karen L.; Adams, Brad; Elashoff, Robert M.; Elashoff, David; Grogan, Tristan; Wang, He Jing; Đačić, Sanja; Brennan, Meghan B.; Valdes, Yacgley; Davenport, Simon; Dubinett, Steven M.; Press, Michael F.; Slamon, Dennis J.; Pietras, Richard J.

doi:10.1016/j.lungcan.2018.06.013

Cited by 39 publications

(38 citation statements)

References 56 publications

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“…Several clinical trials have evaluated fulvestrant treatment in combination with EGFR TKIs in NSCLC based on the preclinical discovery of crosstalk between these two pathways. These combination treatments were shown to be well-tolerated by NSCLC patients and demonstrated a moderate increase in responsiveness and OS compared to the single treatment arm alone (90,91). A component of the Phase I study of gefitinib combined with fulvestrant evaluated the correlative relationship between tumoral ERα and ERβ protein expression and response to treatment.…”

Section: Clinical Studiesmentioning

confidence: 99%

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

2020

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Lung cancer mortality represents the leading cause of cancer related deaths in the United States and worldwide. Almost half of these deaths occur in female patients, making lung cancer the most common cause of cancer mortality in women with a higher annual mortality rate than breast, uterine, and ovarian cancers combined. The distinct epidemiological, histological and biological presentation of non-small cell lung cancer (NSCLC) in women combined with extensive preclinical data have demonstrated that the female sex hormone β-estradiol (E2) plays an important role in NSCLC tumorigenesis, prognosis, and treatment response. Estrogen receptors are widely expressed on stromal and immune cells, and estrogen-linked signaling pathways are known to be involved in regulating the response of both the innate and adaptive immune system. Immune evasion has been recognized as a "hallmark" of cancer and immunotherapy has re-defined standard of care treatment for NSCLC. Despite these advancements, the low response rates observed in patients treated with immune checkpoint inhibitors has led to a search for mediators of immunosuppression and ways to augment the action of these agents. We focus on emerging data describing sex differences that modulate immunotherapy efficacy in NSCLC, immunosuppressive properties of E2 that lead to a pro-tumor microenvironment (TME), and the translational potential of altering the immune microenvironment by targeting the estrogen signaling pathway. E2-induced modulation affects multiple cell types within the TME, including cancer-associated fibroblasts, tumor infiltrating myeloid cells, and tumor infiltrating lymphocytes, all of which interplay with lung tumor cells via E2 and estrogen receptor engagement, ultimately shaping the TME that may, in part, be responsible for the sex-based disparities observed in NSCLC. An improved understanding of the role of the estrogen pathway in NSCLC anti-cancer immunity may lead to novel therapeutic approaches for altering the TME to improve the efficacy of immunotherapy agents.

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Section: Clinical Studiesmentioning

confidence: 99%

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

2020

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“…An improvement in median overall survival was seen among all patients who received the dual therapy. 26 The improvement when combining erlotinib (which only targets EGFR) with fulvestrant was modest, and our results here indicate that clinical effects might be further improved if HER2/HER3 signaling was also suppressed. Our preclinical evidence shows synergy using the combination of the antiestrogen fulvestrant with dacomitinib, a pan-HER TKI recently FDA approved in EGFRmutant lung cancer.…”

Section: Discussionmentioning

confidence: 62%

Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC

Almotlak

Farooqui

Siegfried

2020

Journal of Thoracic Oncology

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Introduction: Mounting evidence supports a role for estrogen signaling in NSCLC progression. We previously reported a seven-gene signature that predicts prognosis in estrogen receptor b positive (ERbþ) NSCLC. The signature defines a network comprised of ER and human EGFR-2/3 (HER2/HER3) signaling. Methods: We tested the efficacy of combining the pan-HER inhibitor, dacomitinib, with the estrogen antagonist, fulvestrant, in ERbþ NSCLC models with differing genotypes. We assessed the potency of this combination on xenograft growth and survival of host mice, and the ability to reverse the gene signature associated with poor outcome. Results: Synergy was observed between dacomitinib and fulvestrant in three human ERbþ NSCLC models: 201T (wild-type EGFR), A549 (KRAS mutant), and HCC827 (EGFR 19 deletion) with combination indices of 0.1-0.6. The combination, but not single agents, completely reversed the gene signature associated with poor prognosis in a mechanism that is largely mediated by activator protein 1 downregulation. In vivo, the combination also induced tumor regression and reversed the gene signature. In HCC827 xenografts treated with the combination, survival of mice was prolonged after therapy discontinuation, tumors that recurred were less aggressive, and two mechanisms of HER inhibitor resistance involving c-Met activation and PTEN loss were blocked. Conclusions: The combination of an ER blocker and a pan-HER inhibitor provides synergistic efficacy in different models of ERbþ NSCLC. Our data support the use of this combination clinically, considering its ability to induce potent antitumor effects and produce a gene signature that predicts better clinical outcomes.

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“…EGFR‐TKIs show a clinical benefit for patients with NSCLC harbouring EGFR‐activating mutations; however, NSCLC with wild‐type EGFR unfortunately has a minimal activity to EGFR‐TKIs and chemotherapy remains an important component of treatment . Meanwhile, the majority of patients with NSCLC worldwide are EGFR wild‐type; thus, novel therapeutic strategies are urgently required for treating EGFR wild‐type NSCLC patients . The combination of EGFR‐TKI with other agent is effective to treat EGFR wild‐type NSCLC patients .…”

Section: Discussionmentioning

confidence: 99%

“…33,34 Meanwhile, the majority of patients with NSCLC worldwide are EGFR wild-type; thus, novel therapeutic strategies are urgently required for treating EGFR wild-type NSCLC patients. 35 The combination of EGFR-TKI with other agent is effective to treat EGFR wild-type NSCLC patients. 36,37 In our study, DYRK1A inhibitor harmine plus AZD9291 showed synergistic anti-cancer activity in EGFR wild-type NSCLC cell lines, including A549, NCI-H1299 and NCI-H460 cells.…”

Section: Egfr-tkis Show a Clinical Benefit For Patients With Nsclc Har-mentioning

confidence: 99%

DYRK1A inhibition suppresses STAT3/EGFR/Met signalling and sensitizes EGFR wild‐type NSCLC cells to AZD9291

Ding

et al. 2019

J Cellular Molecular Medi

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DYRK1A is considered a potential cancer therapeutic target, but the role of DYRK1A in NSCLC oncogenesis and treatment requires further investigation. In our study, high DYRK1A expression was observed in tumour samples from patients with lung cancer compared with normal lung tissues, and the high levels of DYRK1A were related to a reduced survival time in patients with lung cancer. Meanwhile, the DYRK1A inhibitor harmine could suppress the proliferation of NSCLC cells compared to that of the control. As DYRK1A suppression might be effective in treating NSCLC, we next explored the possible specific molecular mechanisms that were involved. We showed that DYRK1A suppression by siRNA could suppress the levels of EGFR and Met in NSCLC cells. Furthermore, DYRK1A siRNA could inhibit the expression and nuclear translocation of STAT3. Meanwhile, harmine could also regulate the STAT3/EGFR/Met signalling pathway in human NSCLC cells. AZD9291 is effective to treat NSCLC patients with EGFR‐sensitivity mutation and T790 M resistance mutation, but the clinical efficacy in patients with wild‐type EGFR remains modest. We showed that DYRK1A repression could enhance the anti‐cancer effect of AZD9291 by inducing apoptosis and suppressing cell proliferation in EGFR wild‐type NSCLC cells. In addition, harmine could enhance the anti‐NSCLC activity of AZD9291 by modulating STAT3 pathway. Finally, harmine could enhance the anti‐cancer activity of AZD9291 in primary NSCLC cells. Collectively, targeting DYRK1A might be an attractive target for AZD9291 sensitization in EGFR wild‐type NSCLC patients.

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Randomized phase II study of fulvestrant and erlotinib compared with erlotinib alone in patients with advanced or metastatic non-small cell lung cancer

Abstract: Addition of fulvestrant to erlotinib was well tolerated, with increased activity noted among EGFR wild type patients compared to erlotinib alone, albeit in an unplanned subset analysis.

Cited by 39 publications

References 56 publications

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC

DYRK1A inhibition suppresses STAT3/EGFR/Met signalling and sensitizes EGFR wild‐type NSCLC cells to AZD9291

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