HER-2 amplification

The addition of durvalumab to a gemcitabine plus cisplatin regimen has significantly improved overall survival in the phase 3 TOPAZ-1 trial and is currently recommended as a standard first-line treatment. The phase 3 ABC-06 and phase 2b NIFTY trials have shown the benefit of second-line fluoropyrimidine plus oxaliplatin, and fluoropyrimidine plus nanoliposomal irinotecan, respectively...However, most patients eventually show resistance to the treatment, and tumor progression occurs within a year. Indeed, there should be further efforts to improve the outcomes of patients with advanced IHCCA.

P3, N=517, Completed, Qilu Pharmaceutical Co., Ltd. | Not yet recruiting --> Completed | Trial completion date: Dec 2022 --> Oct 2023

Our results demonstrate that Erbb2 ablation reveals a significant suppression of tumorigenesis on endometrial cancer of Ptend/d mice. Our results suggest that Erbb2 functions as an oncogene in endometrial cancer of Ptend/d mice implying that Erbb2 targeting can be used as an effective therapeutic approach for treatment of endometrial cancer with PTEN deficiency to hinder cancer development.

Fluorescence in situ hybridization was negative for HER2amplification in one case (International Federation of Gynecology and Obstetrics, grade 1) and positive in the other (International Federation of Gynecology and Obstetrics, grade 3). Our findings contribute to the growing evidence that HER2 is overexpressed in a small proportion of ovarian endometrioid carcinoma, and thus may serve as a potential therapeutic target in selected cases.

P1, N=63, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=185, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Feb 2025

P1/2, N=18, Recruiting, Jonsson Comprehensive Cancer Center | Phase classification: P1b --> P1/2 | Trial completion date: Apr 2025 --> Apr 2026 | Trial primary completion date: Apr 2024 --> Apr 2025

Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.

P1, N=63, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P4, N=51, Active, not recruiting, Zhongnan Hospital | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=27, Active, not recruiting, Washington University School of Medicine | Phase classification: P1b --> P1

Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.

Patients with HER2-overexpressing OC exhibited distinct histological, IHC, and genomic profiles. HER2-targeting agents are potential options for BRCA-wildtype patients, particularly as later lines of treatment.

The most frequently altered genes were: TP53 (8/19, 42%), RNF43 (7/19, 37%), ERBB2 (7/19, 37% [two amplified and five mutated cases]), ARID1A (6/19, 32%), and PIK3CA (4/19, 21%). In summary, AIG-associated GCs are often diagnosed at low stage in patients with long-standing misrecognized severe AIG; they often display a neuroendocrine component or differentiation, have relatively higher rates of MMR deficiency, and TMB-high.

In addition, the above clinicopathological characteristics and HER2 IHC results can be valuable determinants for identifying patients with HER2-altered NSCLC. These insights hold promise for the development of more effective diagnostic and therapeutic strategies for this complex subset of NSCLC patients.

P=N/A, N=1167, Recruiting, Breast Cancer Trials, Australia and New Zealand | Phase classification: P3 --> P=N/A | Trial completion date: Dec 2023 --> Apr 2026 | Trial primary completion date: Dec 2023 --> Oct 2025

P2, N=38, Active, not recruiting, National Cancer Institute (NCI)

It has been shown that STARD3 is correlated with human epidermal growth factor receptor 2 (HER2) amplification since it has the same localization as HER2 in the chromosome. In this review, we aimed to emphasize that investigating lipid metabolism together with the STARD3 biomarker has great potential not only for subtype-specific strategies but also for patient-specific strategies.

We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both...These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy...However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRASG12C or HER2 amplification) and in non-oncogenic driven patients.

P2, N=72, Not yet recruiting, The Netherlands Cancer Institute | Initiation date: Oct 2023 --> May 2024

Areas of tracer uptake showed varying levels of HER2 expression on IHC. The observed intra- and interindividual heterogeneity in [68Ga]Ga-ABY-025 uptake suggested that HER2 PET might be used as a tool for the noninvasive assessment of disease heterogeneity and has the potential to identify patients in whom HER2-targeted drugs can have a clinical benefit.

Lastly, a drug screening identified four candidate reagents commonly effective to all PDOs. Collectively, we showed that multiple PDOs could help reproduce the spatial diversity of a tumor and serve as a valuable resource in UCS research in many respects.

At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness...While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting...These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.

Compared to HER2 (3+) BC, the limited effectiveness of neoadjuvant trastuzumab and pertuzumab therapy for HER2 (2+)/ISH+ BC is due to subtype heterogeneity. Reassessment of targeted therapy efficacy in patients with HER2 (2+)/ISH+ BC is essential.

sWGS and targeted sequencing identified therapeutic opportunities in 75% of p53abn EC patients. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn ECs.

P2, N=51, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | N=112 --> 51 | Trial completion date: Mar 2027 --> Dec 2027 | Recruiting --> Suspended | Trial primary completion date: Mar 2024 --> Dec 2024

Thirty-eight HER2+ breast cancer patients who received neoadjuvant pyrotinib and trastuzumab plus chemotherapy (docetaxel and carboplatin) were retrospectively reviewed. The common adverse events included diarrhea (84.2%), anemia (73.7%), nausea and vomiting (63.2%), fatigue (50.0%), hypomagnesemia (44.7%), leukopenia (42.1%), thrombocytopenia (39.5%), elevated transaminase (36.8%), and pruritus (31.6%). Pyrotinib and trastuzumab plus chemotherapy serve as an acceptable neoadjuvant regimen exhibiting good efficacy and tolerance in HER2+ breast cancer patients, while further large-scale validation is warranted.

P2, N=1008, Recruiting, Fudan University | Not yet recruiting --> Recruiting

P2, N=356, Recruiting, Fudan University | Not yet recruiting --> Recruiting

Our study is an attempt to report such challenging FISH patterns and their work-up for a better understanding on the interpretation. Cumulative data along with follow-up in these cases would bring an insight into exact therapeutic outcome.

Our results suggest that in ERα+ BC cells, ZNF217 gene amplification could be indicative of a favorable response, while in ERα- BC cells, ZNF217 gene gain could be postulated as a potential predictor of treatment resistance. A broader understanding of the role of ZNF217 gene in treatment response, together with prospective studies in BC patients, could contribute to confirming our data, as well as optimizing existing treatments and exploring novel approaches to improve overall cancer treatment outcomes.

This study unravels the therapeutic vulnerability of trastuzumab-resistant HER2-positive BC and shows that an agent that targets the degradation of both HER2 and EGFR is highly effective in overcoming drug resistance in this disease. The findings provide new insights and innovations for advancing treatment of drug-resistant HER2-positive breast cancer that remains an unmet problem.

Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.

EGFR p.T790M is not only the major resistance mechanism to afatinib but also related to favourable survival outcomes. MET amplification and TP53 mutations were associated with poorer overall survival.

P3, N=347, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Mar 2025

Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.

P1, N=42, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team.

P2, N=63, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024

P2, N=88, Recruiting, Fudan University | N=66 --> 88

A recently published Phase III clinical trial (DESTINY-Breast04) has demonstrated that an antibody-drug conjugate (trastuzumab-deruxtecan) significantly reduced disease progression and death in patients with metastatic disease with IHC score 1+ or 2+ and without ISH amplification, defining a new category of cases known as HER2 low. At present, IHC scores 0, 1+ and 2+ show significant interobserver variability, and identifying HER2-low breast cancers may pose significant challenges with the current algorithms. More work is needed in this area to better define HER2-low breast cancers, target the appropriate group of patients and assess treatment efficacy.