ABBV-399, a c-Met Antibody–Drug Conjugate that Targets Both <i>MET</i>–Amplified and c-Met–Overexpressing Tumors, Irrespective of <i>MET</i> Pathway Dependence

Wang, Jieyi; Anderson, Mark G.; Oleksijew, Anatol; Vaidya, Kedar S.; Boghaert, Erwin R.; Tucker, Lora; Zhang, Qian; Han, Edward K.; Palma, Joann P.; Naumovski, Louie; Reilly, Edward B.

doi:10.1158/1078-0432.ccr-16-1568

Cited by 98 publications

(122 citation statements)

References 37 publications

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“…Herein, we showed a novel strategy for overcoming AZD9291 resistance, providing the first account of the use of a c‐Met‐targeting ADC rather than a c‐Met‐inhibiting antibody. Based on the distinct antitumor mechanism of the ADC, SHR‐A1403, tumors could be screened for c‐Met expression as a biomarker, and having established c‐Met overexpression, treatment with SHR‐A1403 would be sufficient to overcome drug resistance . Thus, we believe that using a c‐Met ADC such as SHR‐A1403 is a more direct and feasible approach for overcoming resistance to EGFR‐TKI and warrants further clinical development.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the distinct antitumor mechanism of the ADC, SHR-A1403, tumors could be screened for c-Met expression as a biomarker, and having established c-Met overexpression, treatment with SHR-A1403 would be sufficient to overcome drug resistance. 27,33 Thus, we believe that using a c-Met ADC such as SHR-A1403 is a more direct and feasible approach for overcoming resistance to EGFR-TKI and warrants further clinical development. Previous studies have sought to overcome resistance to EGFR inhibitors by combining c-Met inhibitors with EGFR-TKI with the goal of causing resistant cells to become as sensitive to EGFR inhibitors as parental cells.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16][17][18][19] c-Met, encoded by the MET proto-oncogene, is the cell surface receptor for HGF, which is required for embryogenesis, cell proliferation, survival, and motility. 14,20,21 To date, inhibitors of HGF/c-Met signaling have been developed as monotherapies or combination therapies with EGFR-TKI for the treatment of NSCLC (eg cabozantinib, Exelixis; 22 crizotinib, Pfizer; 23 tivantinib, ArQule; 24 onartuzumab, Roche; rilotumumab; Amgen; [24][25][26] ABBV-399, AbbVie 27 ). In lung cancer cells with c-Met pathway-induced resistance to EGFR inhibitors, combination of a c-Met inhibitor and EGFR inhibitor has been shown to efficiently overcome such resistance.…”

Section: Introductionmentioning

confidence: 99%

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SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

Tong

Gao

et al. 2019

Cancer Science

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as the first‐line treatment of non‐small cell lung cancers (NSCLC) harboring EGFR‐activating mutations, but acquired resistance is ubiquitous and needs to be solved urgently. Here, we introduce an effective approach for overcoming resistance to the EGFR‐TKI, AZD9291, in NSCLC cells using SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met)‐targeting antibody‐drug conjugate (ADC) consisting of an anti‐c‐Met monoclonal antibody (c‐Met mAb) conjugated to a microtubule inhibitor. Resistant cells were established by exposing HCC827 to increasing concentrations of EGFR‐TKI. c‐Met was found to be overexpressed in most resistant cells. AZD9291 resistance was partially restored by combination of AZD9291 and crizotinib only in resistant cells overexpressing phospho‐c‐Met, which synergistically inhibited c‐Met‐mediated phosphorylation of the downstream targets ERK1/2 and AKT. In resistant cells overexpressing c‐Met, neither crizotinib nor c‐Met mAb was able to overcome AZD9291 resistance. In contrast, SHR‐A1403 strongly inhibited proliferation of AZD9291‐resistant HCC827 overexpressing c‐Met, regardless of the levels of c‐Met phosphorylation. SHR‐A1403 bound to resistant cells overexpressing c‐Met was internalized into cells and released associated microtubule inhibitor, resulting in cell‐killing activity that was dependent on c‐Met expression levels only, irrespective of the involvement of c‐Met or EGFR signaling in AZD9291 resistance. Consistent with its activity in vitro, SHR‐A1403 significantly inhibited the growth of AZD9291‐resistant HCC827 tumors and caused tumor regression in vivo. Thus, our findings show that SHR‐A1403 efficiently overcomes AZD9291 resistance in cells overexpressing c‐Met, and further indicate that c‐Met expression level is a biomarker predictive of SHR‐A1403 efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

Tong

Gao

et al. 2019

Cancer Science

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“…In our study we were not able to conduct c-met protein expression or gene amplification correlative studies due to lack of sufficient tumor tissue. A novel MET targeting antibody targeting both ligand-dependent and –independent MET signaling, ABT-700 was well tolerated in early clinical studies and demonstrated anti-tumor activity in select patients with MET amplified tumors (44). A multitude of small molecule MET inhibitors are also being evaluated in clinical trials in combination with EGFR TKIs, including cabozantinib, crizotinib, volitinib and tivantinib.…”

Section: Discussionmentioning

confidence: 99%

Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non–small cell lung cancer

Tarhini

Rafique

Floros

et al. 2017

Cancer

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Background Activation of MET and its ligand hepatocyte growth factor (HGF) are implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. This Phase I/II trial evaluated rilotumumab (anti-HGF antibody), combined with erlotinib, in patients with metastatic previously treated NSCLC. Methods Phase I adopted a dose de-escalation design with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and erlotinib 150 mg orally daily. Phase II evaluated the disease control rate (RECIST, DCR) of the combination using a Simon 2-stage design. Biomarkers examined included 10 plasma circulating molecules associated with EGFR and MET pathways. Results Without indications for de-escalation, the RP2D was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 squamous, 32 adenocarcinoma; 2 confirmed EGFR mutant, 33 confirmed EGFR wild-type (WT) and 7 KRAS mutant). DCR was 60% (90% CI, 47.1–71.3) in all patients. Median PFS was 2.6 months (90% CI, 1.4–2.7) and median OS was 6.6 months (90% CI, 5.6–8.9). Among EGFR WT patients, DCR was 60.6% (90% CI, 46.3–73.3), median PFS 2.6 months (90% CI, 1.4–2.7) and median OS 7.0 months (90% CI, 5.6–13.4). Elevated baseline levels of neuregulin 1 were associated with longer PFS (HR 0.41, 95% CI 0.19–0.87), while elevated amphiregulin was associated with more rapid progression (HR 2.14, 95% CI 1.48–3.08). Conclusion The combination had an acceptable safety profile and the DCR rate met the pre-specified criteria for success. In the EGFR WT group, DCR rate exceeded published reports for erlotinib alone. High circulating neuregulin 1 may indicate sensitivity to this combination.

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“…It is sponsored by AbbVie and, as with other agents, searches have to use ABBV-399 in the NCT data-tables. A report of early results from the Phase I study suggesting efficacy was published by Wang et al in 2017 [36].

NCT02099058: A Phase I/Ib Study with ABBV-399, an Antibody Drug Conjugate, in Subjects with Advanced Solid Cancer Tumors.

…”

Section: Auristatinsmentioning

confidence: 99%

Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates

Newman¹,

Cragg²

2017

Marine Drugs

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In this review, we have attempted to describe all of the antibody–drug conjugates using a marine-derived compound as the “warhead”, that are currently in clinical trials as listed in the current version of the NIH clinical trials database (clinicaltrials.gov). In searching this database, we used the beta-test version currently available, as it permitted more specific search parameters, since the regular version did not always find trials that had been completed in the past with some agents. We also added small discussion sections on candidates that are still at the preclinical stage, including a derivative of diazonamide that has an unusual interaction with tubulin (DZ-23840), which may also be a potential warhead in the future.

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ABBV-399, a c-Met Antibody–Drug Conjugate that Targets Both MET–Amplified and c-Met–Overexpressing Tumors, Irrespective of MET Pathway Dependence

Cited by 98 publications

References 37 publications

SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non–small cell lung cancer

Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates

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