A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors

Calvo, Emiliano; Soria, Jean Charles; Wee, Wen; Wang, Tao; Bahleda, Rastilav; Tolcher, Anthony W.; Gernhardt, Diana; O’Connell, Joseph; Millham, Robert; Giri, Nagdeep; Wick, Michael J.; Adjei, Alex A.; Hidalgo, Manuel

doi:10.1158/1078-0432.ccr-15-2301

Cited by 25 publications

(13 citation statements)

References 31 publications

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“…Likewise, a phase II randomized second-line study of linsitinib vs. topotecan in relapsed SCLC failed to show any clinical activity, with a PFS that significantly favored topotecan [87], see Table 3. Figitumumab, another monoclonal antibody associated with IGF-1R, failed to show efficacy in NSCLC [177,178] but clinical data for SCLC is rare [174]. A placebo-controlled study of platinum and etoposide plus figitumumab in SCLC was halted due to low accrual and discontinuation of further clinical investigation of figitumumab after enrolment of n = 9 patients (NCT00977561).…”

Section: Targeted Therapies In Sclc Treatmentmentioning

confidence: 99%

Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

Schulze

Evers

Kerkhoff

et al. 2019

Cancers

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Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13). Apart from these factors, the application of so-called ‘poly-(ADP)-ribose polymerases’ (PARP) inhibitors can influence tumor repair mechanisms and thus offer new perspectives for future treatment. Another promising therapeutic concept is the inhibition of ‘enhancer of zeste homolog 2’ (EZH2) in the loss of function of tumor suppressors or amplification of (proto-) oncogenes. Considering the poor prognosis of SCLC patients, new molecular pathways require further investigation to augment our therapeutic armamentarium in the future.

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Section: Targeted Therapies In Sclc Treatmentmentioning

confidence: 99%

Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

Schulze

Evers

Kerkhoff

et al. 2019

Cancers

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“…Dacomitinib also exhibited potent anticancer activity in many cancer types in vitro [ 16 – 18 ]. In addition, the combination of dacomitinib with other targeted therapies have been reported to overcome acquired or de novo resistance to cancer chemotherapy [ 19 ]. In this paper, we evaluated the effect of dacomitinib on the reversal of ABCG2-mediated MDR.…”

Section: Introductionmentioning

confidence: 99%

Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo

Guo¹,

To²,

Chen³

et al. 2018

J Exp Clin Cancer Res

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BackgroundATP-binding cassette subfamily G member 2 (ABCG2), a member of the ABC transporter superfamily proteins, mediates multidrug resistance (MDR) by transporting substrate anticancer drugs out of cancer cells and decreasing their intracellular accumulation. MDR is a major hurdle to successful chemotherapy. A logical approach to overcome MDR is to inhibit the transporter. However, no safe and effective MDR inhibitor has been approved in the clinic.MethodsThe MTT assay was used to evaluate cell cytotoxicity and MDR reversal effect. Drug efflux and intracellular drug accumulation were measured by flow cytometry. The H460/MX20 cell xenograft model was established to evaluate the enhancement of anticancer efficacy of topotecan by dacomitinib in vivo. To ascertain the interaction of dacomitinib with the substrate binding sites of ABCG2, the competition of dacomitinib for photolabeling of ABCG2 with [125I]- iodoarylazidoprazosin (IAAP) was performed. Vanadate-sensitive ATPase activity of ABCG2 was measured in the presence of a range of different concentrations of dacomitinib to evaluate the effect of dacomitinib on ATP hydrolysis as the energy source of the transporter. A flow cytometry-based assay and western blotting were employed to study whether dacomitininb could inhibit the expression level of ABCG2. The mRNA expression levels of ABCG2 were analyzed by real-time quantitative RT-PCR. The protein expression level of AKT, ERK and their phosphorylations were detected by Western blotting.ResultsHere, we found that dacomitinib, an irreversible pan-ErbB tyrosine kinase inhibitor (TKI) in phase III clinical trial, could enhance the efficacy of conventional chemotherapeutic agents specifically in ABCG2-overexpressing MDR cancer cells but not in the parental sensitive cells. Dacomitinib was found to significantly increase the accumulation of ABCG2 probe substrates [doxorubicin (DOX),Rhodamine 123 (Rho 123) and Hoechst 33342] by inhibiting the transporter efflux function. Moreover, dacomitinib stimulated ABCG2 ATPase activity and competed with [125I]-IAAP photolabeling of ABCG2 in a concentration-dependent manner. However, dacomitinib did not alter ABCG2 expression at protein and mRNA levels or inhibit ErbB downstream signaling of AKT and ERK. Importantly, dacomitinib significantly enhanced the efficacy of topotecan in ABCG2-overexpressing H460/MX20 cell xenografts in nude mice without incurring additional toxicity.ConclusionsThese results suggest that dacomitinib reverses ABCG2-mediated MDR by inhibiting ABCG2 efflux function and increasing intracellular accumulation of anticancer agents. Our findings advocate further clinical investigation of combinations of dacomitinib and conventional chemotherapy in cancer patients with ABCG2-overexpressing MDR tumors.

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“…Preliminary data on the efficacy of this treatment showed that 3 out of 61 (4.9%) patients had PR as the best overall response (BOR), and 22 (36%) had SD as BOR. The three patients with the PR had ovarian carcinoma, adenoid cystic carcinoma, and salivary gland carcinoma, while 8 of the 22 patients with SD had NSCLC [43].…”

Section: Other Combinations and Cancersmentioning

confidence: 99%

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

Bergonzini

Leonetti

Tiseo

et al. 2020

Expert Opinion on Pharmacotherapy

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2020): Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?, Expert Opinion on Pharmacotherapy, ABSTRACT Introduction: Non-small cell lung cancer (NSCLC) is a highly lethal disease. During the past 20 years, the epidermal growth factor receptor (EGFR) has been a relevant target for anticancer drug-design, and a large family of EGFR tyrosine kinase inhibitors (TKI) were designed, which improved therapeutic outcomes compared to conventional chemotherapy in NSCLC patients with specific EGFR mutations. However, resistance to these inhibitors occurs; therefore, the debate on which inhibitor should be used first is still open. Dacomitinib was approved in 2018 for the first-line treatment of NSCLC with EGFR activating mutations. Areas covered: This manuscript reviews the properties of dacomitinib, including the current information from clinical trials and its potential application as stand-alone therapy, or in combination. Expert opinion: Dacomitinib is a second-generation EGFR-TKI that has demonstrated significant improvement in overall survival in a phase III randomized study compared with gefitinib, a first-generation TKI. However, the rapid development and approval of a new generation of TKIs (osimertinib), with better clinical profiles, raises the question of which role can dacomitinib play in NSCLC. Further studies are required to evaluate the efficacy of this drug on brain metastases, as a second-line treatment after third-generation TKIs, or in combination with other types of treatments. ARTICLE HISTORY

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A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors

Cited by 25 publications

References 31 publications

Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

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