Epidermal Growth Factor Receptor Antibody Research Articles

Cutaneous Toxicities With Amivantamab for Non-Small Cell Lung Cancer: A Practical Guide and Best Practices.

Amivantamab is an epidermal growth factor receptor (EGFR) and MET bispecific antibody approved for certain patients with advanced non-small cell lung cancer with EGFR variant. Cutaneous toxicities are known on-target effects of EGFR inhibition. This article describes the occurrence and management of cutaneous toxicities in patients whose disease progressed on platinum chemotherapy treated with amivantamab. Post hoc analysis evaluated incidence, severity, and time to first onset of rash and paronychia. Five nurses and advanced practice providers were interviewed. Of 380 patients, 296 (78%) experienced treatment-related rash and/or paronychia. Paronychia (43%), rash (36%), and dermatitis acneiform (35%) were most frequent, with scalp rash reported by 17%. Treatment modifications because of rash and paronychia were infrequent. Nurses and advanced practice providers collaborate with physicians to manage cutaneous toxicities by administering comedications, modifying amivantamab dose, and educating patients.

Tislelizumab plus cetuximab and irinotecan in refractory microsatellite stable and RAS wild-type metastatic colorectal cancer: a single-arm phase 2 study

Immunotherapy confers little to no benefit in the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Mechanistic insights suggested that epidermal growth factor receptor (EGFR) antibody plus irinotecan might augment the tumor immune response in mCRC. Therefore, we conducted a proof-of-concept, single-arm, phase 2 study (ChiCTR identifier: ChiCTR2000035642) of a combination treatment regimen including tislelizumab (anti-PD-1), cetuximab (anti-EGFR) and irinotecan in 33 patients with MSS and RAS wild-type (WT) mCRC who were previously treated with ≥2 lines of therapy. The primary endpoint was met, with a confirmed objective response rate of 33%. As secondary endpoints, the disease control rate was 79%, and the median progression-free survival and overall survival were 7.3 and 17.4 months respectively. Among the 33 patients, 32 (97.0%) had treatment-related adverse events (AEs). Three (9.1%) reported grade ≥ 3 AEs, including rash (n = 1), neutropenia (n = 2). The post-hoc evaluation of dynamic circulating tumor DNA using next generation sequencing and the analysis of peripheral immune proteomics landscape using Olink revealed that lower variant allele frequency (VAF) at baseline, greater reduction in VAF on treatment, and a hot peripheral macroenvironment were associated with the treatment response independently. Our study showed the antitumor activity of tislelizumab, cetuximab, and irinotecan combination with a tolerable safety profile in previously treated MSS and RAS WT mCRC.

Prognostic and Predictive Significance of Primary Tumor Localization and HER2 Expression in the Treatment of Patients with KRAS Wild-Type Metastatic Colorectal Cancer: Single-Centre Experience from Serbia.

The treatment of patients with metastatic colorectal cancer (mCRC) is complex and is impacted by the location of the primary tumor (LPT). Our study aims to emphasize the importance of LPT as a prognostic and predictive marker as well as to examine the significance of HER2 overexpression in patients with mCRC, particularly in relation to the response to Epidermal Growth Factor Receptor Antibody treatment (anti-EGFR therapy). In this study, 181 patients with Kirsten RAS (KRAS) wild-type mCRC who received anti-EGFR therapy were included. Among them, 101 had left colon cancer (LCC) and 80 had right colon cancer (RCC). Results demonstrated that patients with KRAS wild-type LCC had better median overall survival (OS) (43 vs. 33 months, p = 0.005) and progression-free survival (PFS) (6 vs. 3 months, p < 0.001) compared to those with RCC. Multivariate analysis identified mucinous adenocarcinoma (p < 0.001), RCC location (p = 0.022), perineural invasion (p = 0.034), and tumors at the resection margin (p = 0.001) as independent predictors of OS, while mucinous adenocarcinoma (p = 0.001) and RCC location (p = 0.004) independently correlated with significantly shorter PFS. In addition, human epidermal growth factor receptor 2 (HER2) positive expression was significantly associated with worse PFS compared to HER2 negative results (p < 0.001). In conclusion, LPT is an important marker for predicting outcomes in the treatment of wild-type mCRC using anti-EGFR therapy, since patients with RCC have a statistically significantly shorter PFS and OS. Further investigation is needed to understand the role of HER2 overexpression in wild-type mCRC, as these patients also exhibit shorter survival.

Targeted polymer lipid hybrid nanoparticles for in-vitro siRNA therapy in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, characterised by a lack of hormone receptors and HER2 expression, resulting in limited treatment options and poor patient outcomes. This study explores a novel therapeutic approach using PLGA lipid nanoparticles loaded with siXBP1 and conjugated with an epidermal growth factor receptor (EGFR) antibody. This nanncarrier will silence the XBP1 gene, which is crucial for the progression and survival of TNBC, particularly in hypoxic conditions. The conjugation of nanoparticles with the EGFR antibody improves their targeting ability to TNBC cells, as confirmed by confocal microscopy and flow cytometry. The fluorescence intensity of the targeted nanoparticles was 1.45 times higher than that of the non-targeted counterparts. These nanoparticles efficiently delivered siRNA to TNBC cells, resulting in substantial XBP1 gene silencing efficacy of 75 %. Under hypoxic conditions, this gene silencing effect significantly promoted apoptosis by nearly threefold compared to normoxic conditions. These findings provide valuable insights into targeted therapies for TNBC and pave the way for further in vivo investigations to advance this approach toward clinical applications.

Abstract 1882: DXC024, a novel anti-TROP2/EGFR bispecific antibody and tubulysin conjugate, for targeted treatment of highly TROP2- or EGFR-expressing tumors

Abstract Antibody drug conjugates (ADCs) which combine the precision of targeted therapy with the cytotoxic effects of chemotherapy have become a promising drug class in cancer therapy. Epidermal growth factor receptor (EGFR) is overexpressed in a wide diversity of epithelial tumors, promoting cell proliferation and survival pathways. Tumor-associated calcium signal transducer 2 (Trop2) is also expressed in a wide range of solid tumors and has been used as a transport gate for cytotoxic agents into cells in antibody-drug conjugate constructions for clinic applications. However, the approved Trop2 ADC, sacituzumab govitecan, only showed an objective response rate (ORR) of 17% and median OS of 9.5 months for lung cancers. In addition, both EGFR-ADC and Trop2-ADC had exhibited strong side effects in clinical trials due to their expression on some normal tissues, such as skin, mouth, eyes, etc. We generated bispecific Fab/scFv antibodies targeting both TROP2 and EGFR using the knob-into-hole technology, which presumably have wider efficacy, less on-target toxicity in comparison to the ADCs constructed based on the fully individual EGFR and Trop2 IgG antibodies having strong affinity to either EGFR or Trop2 antigens. Indeed, many of generated anti-TROP2/EGFR BsAbs showed strong binding activity in TROP2highEGFRhigh cells and demonstrated over 60% internalization rate within 60 min in vitro. The selected BsAbs were subsequently conjugated with tubulysin B analogs with varieties of peptidyl linkers to generate bispecific ADC (DXC024) candidates, two of which exhibited strong killing activity in A431, MDA-MB-468, Calu3, MCF-7 cells with IC50 of single to ten digital pM. In vivo, they showed very good durable antitumor response at dose as low as 4.6 mg/Kg for one injection in Calu3 (TROP2highEGFRmoderate) xenograft model, and demonstrated enhanced anti-tumor efficacy in comparison to those of the same payload conjugated to the monoclonal TROP2 or EGFR ADCs. These results indicated that DXC024 would be a promising ADC candidate for targeted treatment of highly either TROP2- or EGFR-expressing tumors. Citation Format: Jingjing Zhu, Junxiang Jia, Huihui Guo, Xiangfei Kong, Yong Du, Zhicang Ye, Lingli Zhang, Yongxiang Chen, Lu Bai, Yunxia Zheng, Wei Zheng, Jun Zheng, Juan Wang, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Mengmeng Liu, Binbin Chen, Meng Dai, Fang Du, Miaomiao Chen, Zhixiang Guo, Qingliang Yang, Robert Y. Zhao. DXC024, a novel anti-TROP2/EGFR bispecific antibody and tubulysin conjugate, for targeted treatment of highly TROP2- or EGFR-expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1882.

Abstract 2724: BCG020, a novel bispecific antibody targeting EGFR and CD70, is effective against EGFR and CD70 high expressed tumors

Abstract The epidermal growth factor receptor (EGFR) is highly expressed across a wide range of different cancers, and is a known driver of cancer growth; EGFR upregulation is frequently associated with adverse prognosis. Many patients undergoing EGFR-TKI (tyrosine kinase inhibitors) treatment will acquire resistance, which can be accompanied by increased expression of CD70 in some cancers. Simultaneous engagement of both EGFR and CD70 with a bispecific antibody (bsAb) is a potential strategy to overcome such resistance and achieve greater efficacy. To explore this strategy, we developed a novel IgG1 bsAb, BCG020, targeting EGFR and CD70. The parental EGFR antibody and CD70 antibody were developed from fully human common light chain antibody mice (RenLite®). When compared to EGFR benchmarks, the parental EGFR antibody exhibits similar affinity to both human and cynomolgus monkey EGFR, similar internalization activity in EGFR+ tumor cell lines, and superior blocking activity of EGF to EGFR in vitro. Furthermore, the EGFR parental antibody demonstrates good stability. The parental CD70 antibody exhibits high affinity to both human and monkey CD70, with superior internalization activity to benchmark antibody in CD70+ tumor cell lines, as well as superior blockade of CD70-induced signaling of CD27-Luc when compared to benchmark antibodies. When assembled into a bsAb, BCG020 exhitibs the same high affinity as both parental antibodies, with higher internalization activity than parental antibodies and benchmark antibodies. To evaluate the efficacy of BCG020 in vivo, we established cell line-derived xenograft (CDX) models in immunodeficient (B-NDG) mice. We observed that BCG020 treatment (10 mg/kg) potently inhibited growth of EGFR+CD70+ tumors. Taken together, these data indicate that BCG020 is a first-in-class bispecific antibody with potential to treat solid tumors with high expression of EGFR and CD70. Citation Format: Yongfei Yang, Xiaoxia Sun, Ziyan Li, Yue Yan, Linpeng Xu, Xiaoxue Wu, Luheng Du, Ying Zhu, Chaoshe Guo, W. Frank An. BCG020, a novel bispecific antibody targeting EGFR and CD70, is effective against EGFR and CD70 high expressed tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2724.

Polyoxometalate-Nanozyme-Integrated Nanomotors (POMotors) for Self-Propulsion-Promoted Synergistic Photothermal-Catalytic Tumor Therapy.

Enzyme-powered nanomotors have demonstrated promising potential in biomedical applications, especially for catalytic tumor therapy, owing to their ability of self-propulsion and bio-catalysis. However, the fragility of natural enzymes limits their environmental adaptability and also therapeutic efficacy in catalysis-enabled tumor therapy. Herein, polyoxometalate-nanozyme-based light-driven nanomotors were designed and synthesized for targeted synergistic photothermal-catalytic tumor therapy. In this construct, the peroxidase-like activity of the P2 W18 Fe4 polyoxometalates-based nanomotors can provide self-propulsion and facilitate their production of reactive oxygen species thus killing tumor cells, even in the weakly acidic tumor microenvironment. Conjugated polydopamine endows the nanomotors with the capability of light-driven self-propulsion behavior. After 10 min of NIR (808 nm) irradiation, along with the help of epidermal growth factor receptor antibody, the targeted accumulation and penetration of nanomotors in the tumor enabled highly efficient synergistic photothermal-catalytic therapy. This approach overcomes the disadvantages of the intrinsically fragile nature of enzyme-powered nanomotors in physiological environments and, more importantly, provides a motility-behavior promoted synergistic anti-tumor strategy.

Polyoxometalate‐Nanozyme‐Integrated Nanomotors (POMotors) for Self‐Propulsion‐Promoted Synergistic Photothermal‐Catalytic Tumor Therapy

AbstractEnzyme‐powered nanomotors have demonstrated promising potential in biomedical applications, especially for catalytic tumor therapy, owing to their ability of self‐propulsion and bio‐catalysis. However, the fragility of natural enzymes limits their environmental adaptability and also therapeutic efficacy in catalysis‐enabled tumor therapy. Herein, polyoxometalate‐nanozyme‐based light‐driven nanomotors were designed and synthesized for targeted synergistic photothermal‐catalytic tumor therapy. In this construct, the peroxidase‐like activity of the P2W18Fe4 polyoxometalates‐based nanomotors can provide self‐propulsion and facilitate their production of reactive oxygen species thus killing tumor cells, even in the weakly acidic tumor microenvironment. Conjugated polydopamine endows the nanomotors with the capability of light‐driven self‐propulsion behavior. After 10 min of NIR (808 nm) irradiation, along with the help of epidermal growth factor receptor antibody, the targeted accumulation and penetration of nanomotors in the tumor enabled highly efficient synergistic photothermal‐catalytic therapy. This approach overcomes the disadvantages of the intrinsically fragile nature of enzyme‐powered nanomotors in physiological environments and, more importantly, provides a motility‐behavior promoted synergistic anti‐tumor strategy.

Engineering of cell-surface receptors for analysis of receptor internalization and detection of receptor-specific glycosylation.

The epidermal growth factor receptor (EGFR) is a cell-surface glycoprotein that is involved mainly in cell proliferation. Overexpression of this receptor is intimately related to the development of a broad spectrum of tumors. In addition, glycans linked to the EGFR are known to affect its EGF-induced activation. Because of the pathophysiological significance of the EGFR, we prepared a fluorescently labeled EGFR (EGFR128-AZDye 488) on the cell surface by employing the genetic code expansion technique and bioorthogonal chemistry. EGFR128-AZDye 488 was initially utilized to investigate time-dependent endocytosis of the EGFR in live cells. The results showed that an EGFR inhibitor and antibody suppress endocytosis of the EGFR promoted by the EGF, and that lectins recognizing glycans of the EGFR do not enhance EGFR internalization into cells. Observations made in studies of the effects of appended glycans on the entry of the EGFR into cells indicate that a de-sialylated or de-fucosylated EGFR is internalized into cells more efficiently than a wild-type EGFR. Furthermore, by using the FRET-based imaging method of cells which contain an EGFR linked to AZDye 488 (a FRET donor) and cellular glycans labeled with rhodamine (a FRET acceptor), sialic acid residues attached to the EGFR were specifically detected on the live cell surface. Taken together, the results suggest that a fluorescently labeled EGFR will be a valuable tool in studies aimed at gaining an understanding of cellular functions of the EGFR.

Lenvatinib-Loaded Poly(lactic-co-glycolic acid) Nanoparticles with Epidermal Growth Factor Receptor Antibody Conjugation as a Preclinical Approach to Therapeutically Improve Thyroid Cancer with Aggressive Behavior.

Lenvatinib, a tyrosine kinase inhibitor (TKI) approved for the treatment of progressive and radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), is associated with significant adverse effects that can be partially mitigated through the development of novel drug formulations. The utilization of nanoparticles presents a viable option, as it allows for targeted drug delivery, reducing certain side effects and enhancing the overall quality of life for patients. This study aimed to produce and assess, both in vitro and in vivo, the cytotoxicity, biodistribution, and therapeutic efficacy of lenvatinib-loaded PLGA nanoparticles (NPs), both with and without decoration using antibody conjugation (cetuximab), as a novel therapeutic approach for managing aggressive thyroid tumors. Poly(lactic-co-glycolic acid) nanoparticles (NPs), decorated with or without anti-EGFR, were employed as a lenvatinib delivery system. These NPs were characterized for size distribution, surface morphology, surface charge, and drug encapsulation efficiency. Cytotoxicity was evaluated through MTT assays using two cellular models, one representing normal thyroid cells (Nthy-ori 3-1) and the other representing anaplastic thyroid cells (CAL-62). Additionally, an in vivo xenograft mouse model was established to investigate biodistribution and therapeutic efficacy following intragastric administration. The NPs demonstrated success in terms of particle size, polydispersity index (PDI), zeta potential, morphology, encapsulation efficiency, and cetuximab distribution across the surface. In vitro analysis revealed cytotoxicity in both cellular models with both formulations, but only the decorated NPs achieved an ID50 value in CAL-62 cells. Biodistribution analysis following intragastric administration in xenografted thyroid mice demonstrated good stability in terms of intestinal barrier function and tumor accumulation. Both formulations were generally well tolerated without inducing pathological effects in the examined organs. Importantly, both formulations increased tumor necrosis; however, decorated NPs exhibited enhanced parameters related to apoptotic/karyolytic forms, mitotic index, and vascularization compared with NPs without decoration. These proof-of-concept findings suggest a promising strategy for administering TKIs in a more targeted and effective manner.

Intraocular cetuximab: Safety and effect on axial elongation in young Guinea pigs with lens-induced myopization

This study aimed to examine the intraocular tolerability of the epidermal growth factor receptor antibody cetuximab, when applied intravitreally, and its effect on axial elongation. Guinea pigs aged 2–3 weeks were subjected to bilateral plano glasses and bilateral lens-induced myopization (LIM) as a single procedure for group I (n = 8) and group II (n = 8), respectively. In the animals of group III (n = 8), group IV (n = 8), and group V (n = 8), the right eyes of the animals, in addition to LIM, received four weekly intravitreal injections of cetuximab (Erbitux®) in doses of 6.25 μg, 12.5 μg, and 25 μg, respectively. As controls, the left eyes, in addition to LIM, received corresponding intraocular injections of phosphate-buffered saline. The animals underwent regular ophthalmoscopic examinations and biometry for axial length measurements. With increasing doses of cetuximab, the inter-eye difference in axial elongation (at study end, left eyes minus right eyes) were significantly the smallest in group I (0.00 ± 0.02 mm) and group II (−0.01 ± 0.02 mm), they were larger in group III (0.04 ± 0.04 mm) and group IV (0.10 ± 0.03 mm), and they were the largest in group V (0.11 ± 0.01 mm). The inter-eye difference in axial elongation enlarged (P < 0.001) with the number of injections applied. Retinal thickness at the posterior pole (right eyes) was significantly thicker in group V than in group II (P < 0.01). The density of apoptotic cells (visualized by TUNEL-staining) did not vary significantly between any of the groups (all P > 0.05). The results suggest that intravitreal injections of cetuximab in young guinea pigs with LIM resulted in a reduction in axial elongation in a dose-dependent and number of treatment-dependent manner. Intraocular toxic effects, such as intraocular inflammation, retinal thinning, or an increased density of apoptotic cells in the retina, were not observed in association with the intravitreally applied cetuximab.

An Analysis of Risk Factors for the Development of Acneiform Eruptions in Patients on Monoclonal Antibody Epidermal Growth Factor Receptor Inhibitors

Acneiform eruptions occur frequently and early in patients on epidermal growth factor receptor inhibitors (EGFRi). Identification of baseline patient risk factors would prompt earlier referral to dermatology to optimize prevention and management. The primary objective of this retrospective study is to determine the association between clinical and demographic characteristics and the development of acneiform eruptions. A retrospective chart review was conducted on patients diagnosed with colon and head and neck cancers who started EGFRi between January 2017 and December 2021. Patients were followed until death or September 2022. Baseline demographic and clinical parameters were documented and patients were followed from the time of diagnosis to most recent visit for the development and management of an acneiform eruption. Regression analyses were performed to determine the association between baseline characteristics and the development of acneiform eruptions. A total of 66 patients were treated with cetuximab or panitumumab between 2017-2021 were included in the analysis. Forty-seven of the sixty-six patients developed an acneiform eruption while on EGFRi therapy (71.2%). Combination cancer therapy with another chemotherapeutic agent was associated with a lower risk of acneiform eruption (OR 0.03, P = .027). No other baseline features were statistically associated with a lower risk of acneiform eruption. Acneiform eruptions are a common cutaneous adverse event of EGFRi therapy. Ongoing research is required to elucidate risk factors for the development of acneiform eruptions, to improve the quality of life of oncology patients.

Nimotuzumab in combination with intensity modulated radiotherapy improve survival in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): A multicenter-based real-world study.

e18006 Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by the high expression of epidermal growth factor receptor (EGFR). Randomized study has demonstrated a survival advantage associated with the use of EGFR antibody (C225) in conjunction with radiation in locally advanced HNSCC (LA-HNSCC). However, the role of EGFR antibody plus concurrent chemoradiotherapy (CCRT), especially in the intensity-modulated radiotherapy (IMRT) era, is still controversial. Therefore, we conducted a multicenter, retrospective real-world study to investigate whether adding nimotuzumab, a humanized EGFR antibody, to IMRT-based treatment could improve survival in LA-HNSCC (NCT04949503). Methods: All HNSCC patients treated between January 2015 and December 2018 from 8 hospitals in China were screened. Eventually, patients who completed at least 5 course of nimotuzumab were identified as study group and those who did not receive nimotuzumab were considered controlled group. Propensity score matching (PSM) was utilized to balance known confounding factors, such as clinical stage (AJCC 7 ed.), primary location, and so on. Overall survival (OS) and progression-free survival (PFS) were compared between two groups. The Log-rank test was rendered to examine the overall difference of two survival curves and the Cloglog transformation test was performed to compare two survivals at a fixed timepoint. Results: A total of 25442 patients were screened, 1931 patients were eligible and 612 patients (306 patients in each group) were matched by PSM for final analysis. The percentage of stage IV disease was approximate 80% in both groups, and the use of CCRT was 62.4% in study group and 65.4% in controlled group. Totally 250 (81.7%) patients received IMRT in study group and 275 (89.8%) patients received IMRT in controlled group. The follow up was cut off on Jan 19, 2023 and the median follow up time was 54.2 (95%CI: 52.7-55.9) months. Among the entire cohort, the addition of nimotuzumab was associated with improved OS (HR = 0.75, 95% CI: 0.57-0.99, Log rank p = 0.038; 3y-OS: 74.6% vs 63.3%, Cloglog p = 0.004) as well as significantly advantageous PFS (HR = 0.74, 95% CI: 0.58-0.96, Log rank p = 0.020; 3y-PFS: 57.7% vs 44.3%, Cloglog p = 0.009). Subgroup analysis revealed that stage IV, T1, N2, radiotherapy duration ≥ 6 weeks, without previous surgery and CCRT sub-cohort could gained more OS benefit from the addition of nimotuzumab. Beneficial subgroup for PFS included stage IV, T2, N2, radiotherapy duration ≥ 6 weeks, without previous surgery and CCRT sub-cohort. Conclusions: The addition of nimotuzumab to IMRT-incorporated treatment may provide both OS and PFS benefit for LA-HNSCC, in particular those with stage IV or N2 diseases, without previous surgery, receiving radiotherapy ≥ 6 weeks and CCRT. Clinical trial information: NCT04949503 .

The Effect of Induction Chemotherapy with VEGF Inhibition on Tumor Response in Synchronously Metastasized Potentially Resectable Colorectal Cancer.

(1) Background: The pathological tumor response of the primary tumor to induction chemotherapy in synchronously metastasized colorectal cancer (mCRC) patients has not been investigated. The aim of this study was to compare patients treated with induction chemotherapy combined with vascular endothelial growth factor (VEGF) or with epidermal growth factor receptor (EGFR) antibodies. (2) Methods: We present a retrospective analysis, where we included 60 consecutive patients with potentially resectable synchronous mCRC who received induction chemotherapy combined with either VEGF or EGFR antibodies. The primary endpoint of this study was the regression of the primary tumor, which was assessed by the application of the histological regression score according to Rödel. The secondary endpoints were recurrence-free survival (RFS) and overall survival (OS). (3) Results: A significantly better pathological response and a longer RFS for patients treated with the VEGF antibody therapy compared to those treated with the EGFR antibodies was demonstrated (p = 0.005 for the primary tumor and log-rank = 0.047 for RFS). The overall survival did not differ. The trial was registered with clinicaltrial.gov, number NCT05172635. (4) Conclusion: Induction chemotherapy combined with a VEGF antibody revealed a better pathological response of the primary tumor, leading to a better RFS compared to that with EGFR therapy; this has clinical relevance in patients with potentially resectable synchronously mCRC.

Abstract IA07: Molecular characterization of acquired resistance to KRASG12C-EGFR inhibition in colorectal cancer

Abstract Until recently, efforts to pharmacologically target KRAS have been unsuccessful due to its small binding pocket, high affinity for GTP, and redundant mechanisms of posttranslational processing. The development of allele specific KRAS G12C inhibitors that trap KRAS in the inactive, GDP-bound, state led to a paradigm change and clinical responses in 30% of non-small cell lung cancer (NSCLC) patients harboring KRAS G12C mutations. KRAS G12C inhibitors, such as sotorasib and adagrasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular NSCLC. However, these agents are not as effective in colorectal cancers (CRC) with KRAS G12C mutation. We have previously shown that the activity of these drugs in KRAS G12C CRC is limited because activation of epidermal growth factor receptor (EGFR) reactivates ERK signaling therefore combinatorial KRAS G12C and EGFR inhibition more effectively targets KRAS G12C CRC. Early trial data provide clinical support for this observation as anti EGFR monoclonal antibodies combined with sotorasib or adagrasib double the overall response to single agents in KRAS G12C mutant CRC patients. Based on these data, these KRAS G12C and EGFR antibody combination treatments are being evaluated in registrational, phase 3 trials. Nonetheless, patients treated with these agents, alone or in combination, eventually acquire secondary resistance. Several studies have characterized resistance to KRAS G12C monotherapy, in this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS and EGFR inhibition in CRC. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drug can be detected at progression. Serial analysis of patient blood samples during treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumor marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification undergoes oncogene-induced senescence upon drug withdrawal. Senescence markers were detected in a tissue biopsy from a patient at relapse after treatment stop, and amplified KRAS G12C signal in circulating DNA from relapsed patients rapidly recedes after treatment interruption. These data indicate that while most resistance-associated alterations to KRAS-EGFR coinhibition remain subclonal, affecting a small population of cells, KRAS G12C amplification is a recurrent resistance mechanism that drives a higher portion of resistance over time and provides a potential therapeutic vulnerability, whereby therapies that target the senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition. Citation Format: Sandra Misale. Molecular characterization of acquired resistance to KRASG12C-EGFR inhibition in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA07.

A three-site recognition cytosensor based on multi-active AuIrPt polyhedral nanozymes for detection of CTCs

We developed a novel electrochemical cytosensor based on AuIrPt nanozymes and three-site recognition strategy for the detection of specific CTCs. Using pluronic F127 as the organic framework, new trimetallic AuIrPt nanozymes with exceptional multiple enzyme-like activities were synthesized, which could mimic the activities of three enzymes, SOD, POD, and CAT. Nanozymes linked with EpCAM (Epithelial cell adhesion molecule) aptamers served as signal tags to enhance sensitivity of the cytosensor, and anti-MUC1 (Mucin 1) and anti-EGFR (Epidermal growth factor receptor) antibodies for isolation and capture of the target CTCs, respectively. The AuIrPt nanozymes could approach the sensing interface and generate obvious currents through their exceptional catalytic activity only when all three proteins (MUC1, EpCAM, and EGFR) were simultaneously expressed on the cell membrane. Benefiting from the aforementioned advantages, our cytosensor could accurately distinguish between target cells and other cancer cells with a wide concentration range from 5 to 1 × 106 cells mL−1 and a low detection limit of 2 cells mL−1. Notably, the biosensor could assay target CTCs in complex whole blood matrixes, validating its resistance to interference and utility. By combining catalytic nanomaterials and three-site recognition strategy, a sensitive, accurate, and stable novel sensing platform has been developed, promising to facilitate the application of CTCs in early cancer screening.

An Adjusted Treatment Comparison Comparing Amivantamab Versus Real-World Clinical Practice in Europe and the United States for Patients with Advanced Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor Exon 20 Insertion Mutations.

Patients with advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (Exon20ins) have poor prognoses, exacerbated by a previous lack of specific treatment guidelines and unmet need for targeted therapies. Amivantamab, an EGFR and MET bispecific antibody, demonstrated efficacy and tolerability in patients with advanced EGFR-mutated NSCLC with Exon20ins following platinum-based therapy in CHRYSALIS (NCT02609776; Cohort D+). Since CHRYSALIS was single-arm, individual patient data (IPD)-based adjusted analyses versus similar patients in real-world clinical practice (RWCP) were conducted to generate comparative evidence. RWCP cohorts were derived from seven European and US real-world sources, comprising patients fulfilling CHRYSALIS Cohort D+eligibility criteria. Amivantamab was compared with a basket of RWCP treatments. Differences in prognostic characteristics were adjusted for using inverse probability weighting (IPW; average treatment effect among the treated [ATT]). Balance between cohorts was assessed using standardized mean differences (SMDs). Overall response rate (ORR; investigator- [INV] and independent review committee-assessed [IRC]), overall survival (OS), progression-free survival (PFS; INV and IRC) and time-to-next treatment (TTNT) were compared. Binary and time-to-event endpoints were analyzed using weighted logistic regression and proportional hazards regression, respectively. Pre-adjustment, baseline characteristics were comparable between cohorts. IPW ATT-adjustment improved comparability, giving closely matched characteristics. ORR (INV) was 36.8% for amivantamab versus 17.0% for the adjusted EU+US cohort (response rate ratio [RR]: 2.16). Median OS, PFS (INV) and TTNT were 22.77 versus 12.52months (hazard ratio [HR]: 0.47; p<0.0001), 6.93 versus 4.17months (HR: 0.55; p<0.0001) and 12.42 versus 5.36months (HR: 0.44; p<0.0001) for amivantamab versus the adjusted EU+US cohort, respectively. Results were consistent versus EU- and US-only cohorts, and when using IRC assessment. Adjusted comparisons demonstrated significantly improved outcomes for amivantamab versus RWCP, highlighting the value of amivantamab in addressing unmet need in patients with advanced EGFR Exon20ins NSCLC following platinum-based therapy. CHRYSALIS: NCT02609776.

HER2 positive breast cancer and its treatment with trastuzumab, where are we now?

HER2-positive breast cancer is one of the most common types of female breast cancer around the world. This review summarizes information and results of HER2 -positive breast cancer trials and compares their results with the standards in Bosnia and Herzegovina. It is done based on a literature search on PubMed and Google Scholar. This review analyzed trastuzumab as a golden treatment standard for HER2 -positive cancer treatments. Trastuzumab is a monoclonal anti-human epidermal growth factor receptor antibody and besides its effect in the treatment of breast cancer, suggests the treatment with trastuzumab within 1 year. Bosnia and Herzegovina have also accepted standards and guidelines for the treatment of HER2 -positive breast cancer and they are in step with the latest achievements worldwide.

Targeting EGFR and Monitoring Tumorigenesis of Human Lung Cancer Cells In Vitro and In Vivo Using Nanodiamond-Conjugated Specific EGFR Antibody.

Nanoprobes provide advantages for real-time monitoring of tumor markers and tumorigenesis during cancer progression and development. Epidermal growth factor receptor (EGFR) is a key protein that plays crucial roles for tumorigenesis and cancer therapy of lung cancers. Here, we show a carbon-based nanoprobe, nanodiamond (ND), which can be applied for targeting EGFR and monitoring tumorigenesis of human lung cancer cells in vitro and in vivo. The optimal fluorescent intensities of ND particles were observed in the human lung cancer cells and nude mice under in vivo imaging system. The fluorescence signal of ND particles can be real-time detected in the xenografted human lung tumor formation of nude mice. Moreover, the ND-conjugated specific EGFR antibody cetuximab (Cet) can track the location and distribution of EGFR proteins of lung cancer cells in vitro and in vivo. ND-Cet treatment increased cellular uptake ability of nanocomposites in the EGFR-expressed cells but not in the EGFR-negative lung cancer cells. Interestingly, single ND-Cet complex can be directly observed on the protein G bead by immunoprecipitation and confocal microscopy. Besides, the EGFR proteins were transported to lysosomes for degradation. Together, this study demonstrates that ND-conjugated Cet can apply for targeting EGFR and monitoring tumorigenesis during lung cancer progression and therapy.

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C

BackgroundAdagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.MethodsIn this phase 1–2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety.ResultsAs of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed.ConclusionsAdagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.)