Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Impact of the thyroid hormone T3 and its nuclear receptor TRα1 on colon cancer stem cell phenotypes and response to chemotherapies.

Colorectal cancers (CRCs) are highly heterogeneous and show a hierarchical organization, with cancer stem cells (CSCs) responsible for tumor development, maintenance, and drug resistance. Our previous studies showed the importance of thyroid hormone-dependent signaling on intestinal tumor development and progression through action on stem cells. These results have a translational value, given that the thyroid hormone nuclear receptor TRα1 is upregulated in human CRCs, including in the molecular subtypes associated with CSC features. We used an established spheroid model generated from the human colon adenocarcinoma cell line Caco2 to study the effects of T3 and TRα1 on spheroid formation, growth, and response to conventional chemotherapies. Our results show that T3 treatment and/or increased TRα1 expression in spheroids impaired the response to FOLFIRI and conferred a survival advantage. This was achieved by stimulating drug detoxification pathways and increasing ALDH1A1-expressing cells, including CSCs, within spheroids. These results suggest that clinical evaluation of the thyroid axis and assessing TRα1 levels in CRCs could help to select optimal therapeutic regimens for patients with CRC. Proposed mechanism of action of T3/TRα1 in colon cancer spheroids. In the control condition, TRα1 participates in maintaining homeostatic cell conditions. The presence of T3 in the culture medium activates TRα1 action on target genes, including the drug efflux pumps ABCG2 and ABCB1. In the case of chemotherapy FOLFIRI, the increased expression of ABC transcripts and proteins induced by T3 treatment is responsible for the augmented efflux of 5-FU and Irinotecan from the cancer cells. Taken together, these mechanisms contribute to the decreased efficacy of the chemotherapy and allow cells to escape the treatment. Created with BioRender.com .

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. METHODS: In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. INTERPRETATION: Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. FUNDING: Daiichi Sankyo and AstraZeneca.

Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer: Real-life data from the temporary use authorization program in France.

BACKGROUND: Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T-DXd) in France based on DESTINY-Breast01 trial which demonstrated its efficacy and safety in HER2-positive metastatic/unresectable breast cancer after ≥2 anti-HER2-based regimens received at metastatic stage. METHODS: This multicenter real-world early access program included HER2-positive metastatic/unresectable breast patients pretreated with at least two lines of anti-HER2 regimens who received T-DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks. RESULTS: Four hundred and fifty-nine patients (median age, 58 years; hormone receptor-positive, 67%; brain metastases, 28.1%) received T-DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2-22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow-up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T-DXd treatment was 3.4 (range, 0-7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD-related death. CONCLUSIONS: In this early access program in patients with heavily pretreated HER2-positive metastatic/unresectable breast cancer, T-DXd had antitumor activity with a similar response to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed.

[Chinese expert consensus on the management of clinical pathway and adverse events of trastuzumab deruxtecan (2024 edition)].

Trastuzumab deruxtecan (T-DXd) is one of the new generation antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER-2) with bystander effect. T-DXd can not only significantly improve the survival of HER-2-positive advanced breast cancer patients, but also enable advanced breast cancer patients with low HER-2 expression to benefit from HER-2-targeted therapy. T-DXd has been approved by the National Medical Products Administration (NMPA) for the treatment of HER-2-positive or HER-2-low breast cancer patients. It is foreseeable that T-DXd will be widely used in clinical practice in the future. However, T-DXd has also shown different safety characteristics compared to previous HER-2 targeted drugs in clinical trials. How to manage T-DXd adverse events more reasonably and fully utilize the efficacy of T-DXd is an urgent clinical problem. Based on the existing clinical evidence and guideline consensus, combined with clinical practice experience, the expert group finally reached the consensus of clinical care pathway and adverse reaction management of trastuzumab deruxtecan after many discussions. This consensus content includes the clinical use method of T-DXd, pre-treatment patient education, and management of common or noteworthy adverse events of T-DXd. The adverse events include infusion related adverse events, digestive system adverse events (nausea/vomiting, constipation, diarrhea, and decreased appetite), hematological adverse events (neutropenia, febrile neutropenia, anemia, thrombocytopenia), respiratory adverse events (interstitial lung disease/pneumonia), cardiovascular adverse events (decreased left ventricular ejection fraction), adverse events in liver function (elevated transaminases) and other common adverse events (alopecia, fatigue, etc). This consensus focuses on the prevention of adverse events, dose adjustment and treatment when adverse events occur, and recommendations for patients' lifestyle, aiming to improve clinicians' understanding of T-DXd and provide practical guidance for clinical oncologists on T-DXd clinical management.

Targeting Methionine Addiction Combined With Low-dose Irinotecan Arrested Colon Cancer in Contrast to High-dose Irinotecan Alone, Which Was Ineffective, in a Nude-mouse Model.

BACKGROUND/AIM: Colorectal cancer (CRC) is the third-leading cause of death in the world. Although the prognosis has improved due to improvement of chemotherapy, metastatic CRC is still a recalcitrant disease, with a 5-year survival of only 13%. Irinotecan (IRN) is used as first-line chemotherapy for patients with unresectable CRC. However, there are severe side effects, such as neutropenia and diarrhea, which are dose-limiting. We have previously shown that methionine restriction (MR), effected by recombinant methioninase (rMETase), lowered the effective dose of IRN of colon-cancer cells in vitro. The aim of the present study was to evaluate the efficacy of the combination of low-dose IRN and MR on colon-cancer in nude mice. MATERIALS AND METHODS: HCT-116 colon-cancer cells were cultured and subcutaneously injected into the flank of nude mice. After the tumor size reached approximately 100 mm3, 18 mice were randomized into three groups; Group 1: untreated control on a normal diet; Group 2: high-dose IRN on a normal diet (2 mg/kg, i.p.); Group 3: low-dose IRN (1 mg/kg i.p.) on MR effected by a methionine-depleted diet. RESULTS: There was no significant difference between the control mice and the mice treated with high-dose IRN, without MR. However, low-dose IRN combined with MR was significantly more effective than the control and arrested colon-cancer growth (p=0.03). Body weight loss was reversible in the mice treated by low-dose IRN combined with MR. CONCLUSION: The combination of low-dose IRN and MR acted synergistically in arresting HCT-116 colon-cancer grown in nude mice. The present study indicates the MR has the potential to reduce the effective dose of IRN in the clinic.

Trastuzumab deruxtecan for human epidermal growth factor receptor 2-low advanced or metastatic breast cancer: recommendations from the Japanese Breast Cancer Society Clinical Practice Guidelines.

The Japanese Breast Cancer Society Clinical Practice Guidelines are published as timely guidance on clinical issues in breast cancer treatment in Japan. In the recent edition of these guidelines, we addressed a new clinical question 34 (CQ 34, systemic treatment part) "Is trastuzumab deruxtecan recommended for patients with unresectable or metastatic HER2-low breast cancer?" and a new future research question 7 (FRQ 7, pathological diagnosis part) "How is HER2-low breast cancer diagnosed for the indication of trastuzumab deruxtecan?". These questions address use of trastuzumab deruxtecan in patients with unresectable or metastatic HER2-low breast cancer who have previously received chemotherapy for metastatic disease. The strengths of evidence and recommendation were determined through a quantitative and qualitative systematic review using multiple outcomes, including efficacy and safety. We conclude that trastuzumab deruxtecan is recommended for this patient population (strength of recommendation: 1; strength of evidence: moderate; CQ34) and that HER2-low expression for the indication of trastuzumab deruxtecan should be diagnosed using companion diagnostics based on appropriate criteria (FRQ7).

Innovative Nanoparticulate Strategies in Colon Cancer Treatment: A Paradigm Shift.

As a major public health issue, colorectal cancer causes 9.4% of total cancer-related deaths and comprises 10% of new cancer diagnoses worldwide. In the year 2023, an estimated 153,020 people are expected to receive an identification of colorectal cancer (CRC), resulting in roughly 52,550 fatalities anticipated as a result of this illness. Among those impacted, approximately 19,550 cases and 3750 deaths are projected to occur in individuals under the age of 50. Irinotecan (IRN) is a compound derived from the chemical structure of camptothecin, a compound known for its action in inhibiting DNA topoisomerase I. It is employed in the treatment strategy for CRC therapies. Comprehensive in vivo and in vitro studies have robustly substantiated the anticancer efficacy of these compounds against colon cancer cell lines. Blending irinotecan in conjunction with other therapeutic cancer agents such as oxaliplatin, imiquimod, and 5 fluorouracil enhanced cytotoxicity and improved chemotherapeutic efficacy. Nevertheless, it is linked to certain serious complications and side effects. Utilizing nano-formulated prodrugs within "all-in-one" carrier-free self-assemblies presents an effective method to modify the pharmacokinetics and safety portfolio of cytotoxic chemotherapeutics. This review focuses on elucidating the mechanism of action, exploring synergistic effects, and innovating novel delivery approaches to enhance the therapeutic efficacy of irinotecan.

Camptothecin enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma.

Apatinib has been shown to apply to a variety of solid tumors, including advanced hepatocellular carcinoma. Preclinical and preliminary clinical results confirmed the synergistic antitumor effects of apatinib in combination with anti-programmed death-1 (PD-1) inhibitors. In this study, we investigated camptothecin (CPT) enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma. CPT combined with a PD-1 inhibitor enhances the anti-tumor effects of low-dose apatinib in hepatocellular carcinoma which was evaluated in making use of the H22 mouse model (n = 32), which was divided into four groups. Immunohistochemical staining and western blotting were used to detect nuclear factor erythroid 2-related factor 2 (Nrf2) as well as sequestosome 1 (p62), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), PD-1, and programmed cell death ligand 1 (PD-L1). The results showed that the average size of the tumor of the combination group (Group D) was significantly less than that of the apatinib + PD-1 inhibitor group (Group C). The expression levels of Nrf2, p62, VEGFA, VEGFR2, PD-1, and PD-L1 in the apatinib + PD-1 inhibitor group(Group C) were lower than those in the control group (Group A) (P < 0.05). The expression levels of these genes in the apatinib + PD-1 inhibitor group (Group C) were significantly lower in the combination group (Group D) (P < 0.05). There was no obvious difference in body weight and liver and kidney functions between the four groups of mice. In conclusion, CPT improves the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma.

In vivo activation of FAP-cleavable small molecule-drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment.

Small molecule-drug conjugates (SMDCs) are increasingly considered as a therapeutic alternative to antibody-drug conjugates (ADCs) for cancer therapy. OncoFAP is an ultra-high affinity ligand of Fibroblast Activation Protein (FAP), a stromal tumor-associated antigen overexpressed in a wide variety of solid human malignancies. We have recently reported the development of non-internalizing OncoFAP-based SMDCs, which are activated by FAP thanks to selective proteolytic cleavage of the -GlyPro- linker with consequent release of monomethyl auristatin E (MMAE) in the tumor microenvironment. In this article, we describe the generation and the in vivo characterization of FAP-cleavable OncoFAP-drug conjugates based on potent topoisomerase I inhibitors (DXd, SN-38, and exatecan) and an anti-tubulin payload (MMAE), which are already exploited in clinical-stage and approved ADCs. The Glycine-Proline FAP-cleavable technology was directly benchmarked against linkers found in Adcetris™, Enhertu™, and Trodelvy™ structures by means of in vivo therapeutic experiments in mice bearing tumors with cellular or stromal FAP expression. OncoFAP-GlyPro-Exatecan and OncoFAP-GlyPro-MMAE emerged as the most efficacious anti-cancer therapeutics against FAP-positive cellular models. OncoFAP-GlyPro-MMAE exhibited a potent antitumor activity also against stromal models, and was therefore selected for clinical development.

Antibody-Drug Conjugates in Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) accounts for 15%-20% of all breast cancer. It is a heterogeneous breast cancer subtype with a poor prognosis. Given these negative features, there is a need for new treatment options beyond conventional chemotherapy in both the early stage and palliative setting. Impressive results have been reported with antibody-drug conjugates (ADCs) that link a cytotoxic payload to a monoclonal antibody, such as sacituzumab govitecan and trastuzumab deruxtecan, in the metastatic stage. The focus of this review is to discuss completed and ongoing trials involving ADCs in TNBC.

Glutathione - IR 797 coupled Casein Nano-Trojan for augmenting the therapeutic efficacy of camptothecin in highly invasive triple negative breast cancer.

The rapid metastasis & heterogenic constitution of triple negative breast cancer (TNBC) limits drug entry to the tumor, reducing treatment effectiveness. To address this, we have synthesized Casein nanoparticles (Cn NPs) with attached glutathione (GSH), a natural ligand for cancer cell overexpressed γ-glutamyl transpeptidase (GGT). Cn NPs encapsulated with Camptothecin and NIR dye IR 797 (CCN NPs) for combinatorial therapy of TNBC. The GSH-CCN nanoparticles (CCNG NPs) act as a Nano-Trojan to deceive the cancer cells by delivering therapeutic payloads directly to specific target cells. In this study, Casein Nano-Trojan is equipped with GSH as a targeting ligand for GGT. The binding of CCNG NPs with cell surface receptors switched the anionic charge to catanionic, prompting the target cell to engulf the nanoparticles. The Casein Nano-Trojan releases its therapeutic payload inside the target cell, potentially inhibiting proliferation & inducing a high percentage of cell death (85 ± 7 %). Disintegration of mitochondrial membrane potential, inhibition of both migration & re-growth were observed. Immunofluorescence, acridine orange/ethidium bromide stain, and nuclear fragmentation assay further confirmed the substantial DNA damage induced by the high expression of γH2AX and p53. Significant therapeutic efficacy was observed in the 3D spheroids of 4T1 cells and in vivo breast cancer mice model (BALB/c). These findings demonstrate that CCNG NPs could be an effective treatment approach for highly metastatic triple negative breast cancer.

Unleashing the Potential of Camptothecin: Exploring Innovative Strategies for Structural Modification and Therapeutic Advancements.

Camptothecin (CPT) is a potent anti-cancer agent targeting topoisomerase I (TOP1). However, CPT has poor pharmacokinetic properties, causes toxicities, and leads to drug resistance, which limit its clinical use. In this paper, to review the current state of CPT research. We first briefly explain CPT's TOP1 inhibition mechanism and the key hurdles in CPT drug development. Then we examine strategies to overcome CPT's limitations through structural modifications and advanced delivery systems. Though modifications alone seem insufficient to fully enhance CPT's therapeutic potential, structure-activity relationship analysis provides insights to guide optimization of CPT analogs. In comparison, advanced delivery systems integrating controlled release, imaging capabilities, and combination therapies via stimulus-responsive linkers and targeting moieties show great promise for improving CPT's pharmacological profile. Looking forward, multifaceted approaches combining selective CPT derivatives with advanced delivery systems, informed by emerging biological insights, hold promise for fully unleashing CPT's anti-cancer potential.

Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Phase Ib Clinical Study.

PURPOSE: Onvansertib is a highly specific inhibitor of polo-like kinase 1 (PLK1), with demonstrated safety in solid tumors. We evaluated, preclinically and clinically, the potential of onvansertib in combination with chemotherapy as a therapeutic option for KRAS-mutant colorectal cancer. PATIENTS AND METHODS: Preclinical activity of onvansertib was assessed (i) in vitro in KRAS wild-type and -mutant isogenic colorectal cancer cells and (ii) in vivo, in combination with irinotecan, in a KRAS-mutant xenograft model. Clinically, a phase Ib trial was conducted to investigate onvansertib at doses 12, 15, and 18 mg/m2 (days 1-5 and 14-19 of a 28-day cycle) in combination with FOLFIRI/bevacizumab (days 1 and 15) in patients with KRAS-mutant metastatic colorectal cancer who had prior oxaliplatin exposure. Safety, efficacy, and changes in circulating tumor DNA (ctDNA) were assessed. RESULTS: In preclinical models, onvansertib displayed superior activity in KRAS-mutant than wild-type isogenic colorectal cancer cells and demonstrated potent antitumor activity in combination with irinotecan in vivo. Eighteen patients enrolled in the phase Ib study. Onvansertib recommended phase II dose was established at 15 mg/m2. Grade 3 and 4 adverse events (AE) represented 15% of all treatment-related AEs, with neutropenia being the most common. Partial responses were observed in 44% of patients, with a median duration of response of 9.5 months. Early ctDNA dynamics were predictive of treatment efficacy. CONCLUSIONS: Onvansertib combined with FOLIFRI/bevacizumab exhibited manageable safety and promising efficacy in second-line treatment of patients with KRAS-mutant metastatic colorectal cancer. Further exploration of this combination therapy is ongoing. See related commentary by Stebbing and Bullock, p. 2005.

A plain language summary of the TROPiCS-02 study in patients with breast cancer (HR-positive/HER2-negative).

WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment for certain types of advanced or metastatic breast cancer. One common type of breast cancer has at least 1 of 2 hormone receptors (HR positive) and does not have human epidermal growth factor 2 (HER2 negative). The HR and HER2 receptors are known to influence how severe a case of breast cancer is. Certain treatments will only work if a specific receptor is present on breast cancer cells. HR-positive/HER2-negative advanced or metastatic breast cancer can be treated with sacituzumab govitecan. This is a summary of the results of the TROPiCS-02 study. This study compared sacituzumab govitecan with standard chemotherapy in participants with HR-positive/HER2-negative advanced or metastatic breast cancer. WHAT WERE THE RESULTS?: The study showed that participants treated with sacituzumab govitecan lived significantly longer without their cancer getting worse than participants treated with chemotherapy. Participants also survived significantly longer and their tumors became significantly smaller in more participants treated with sacituzumab govitecan than with chemotherapy. In general, participants treated with sacituzumab govitecan were more likely to have side effects and had more severe side effects. These side effects included low levels of a type of white blood cell known as neutrophils and diarrhea. Oncologists (doctors that treat cancer) know of these side effects as they are common among people being treated for cancer. Doctors can control these side effects by following standard treatment guidelines and the package insert for sacituzumab govitecan. Participants treated with sacituzumab govitecan maintained their sense of well-being and ability to do daily activities (quality of life) longer than participants treated with chemotherapy. It also took longer for fatigue and other symptoms of cancer to worsen in participants treated with sacituzumab govitecan compared with chemotherapy. WHAT DO THE RESULTS MEAN?: Sacituzumab govitecan is more effective than standard chemotherapies for people who have already received multiple treatments for HR-positive/ HER2-negative advanced breast cancer. The side effects from sacituzumab govitecan could generally be managed well by doctors. Although there were more side effects with sacituzumab govitecan than with chemotherapy, they were generally mild to moderate.

Trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2-expressing salivary gland carcinoma: a pooled analysis of two phase I studies.

BACKGROUND: HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed to present the efficacy and safety of T-DXd in patients with HER2-expressing SGC from a pooled analysis. METHODS: Patients with HER2-expressing SGC were pooled from two phase I, open-label studies of T-DXd: a two-phase, multiple-dose, first-in-human study (NCT02564900) and a single-sequence crossover drug-drug interaction study (NCT03383692). Endpoints included efficacy (objective response rate [ORR], duration of response [DoR] and progression-free survival [PFS]) and safety. RESULTS: This pooled analysis included 17 patients with SGC (median age: 57 years; male: 88.2%); median (range) follow-up duration was 12.0 (2.3-|34.8) months. Among these patients, 14 had received prior HER2-targeted agents and 13 had undergone prior radiotherapy. The investigator-assessed confirmed ORR was 58.8% (95% confidence interval [CI], 32.9-|81.6). The median (95% CI) DoR and PFS were 17.6 months (4.0 to not evaluable [NE]) and 20.5 months (11.1-NE), respectively. All 17 patients reported treatment-emergent adverse events (TEAEs); 76.5% reported TEAEs of grade ≥3. The most common TEAEs were decreased appetite (94.1%), nausea (88.2%) and neutrophil count decreased (76.5%). Of the 17 patients, five (29.4%) reported adjudicated drug-related interstitial lung disease (grade 1, n = 3; grade 2, n =1; grade 3, n = 1). CONCLUSION: The results of this pooled analysis provide evidence that clinical benefit is achievable with T-DXd in patients with HER2-expressing SGC. CLINICAL TRIAL INFORMATION: FIH study, NCT02564900; DDI study, NCT03383692.

Is switching intravesical chemotherapeutic agents beneficial in short-term recurrent high-risk non-muscle-invasive bladder tumors? A 5-year retrospective study.

OBJECTIVE: To explore if switching intravesical chemotherapeutic agents is beneficial in short-term recurrences of high-risk non-muscle-invasive bladder cancer (NMIBC) following the failure of preceding intravesical therapy. MATERIALS AND METHODS: From June 2010 to October 2015, 205 patients with NMIBC who experienced tumor recurrence within a year after receiving first-line intravesical chemotherapy (IVC) were classified into two groups. After a second complete transurethral resection (TUR) process, we immediately altered the intravesical instillation agent for 107 patients (group A). In contrast, the remaining 98 patients (group B) continued using their original intravesical instillation agent. After transurethral resection of the bladder tumor (TURBT), all patients received either an immediate instillation of epirubicin (EPI), gemcitabine (GEM), or hydroxycamptothecin (HCPT), followed by regular induction and maintenance instillations. Recurrence and progression rates were evaluated using the Chi-square test, and recurrence-free survival (RFS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. RESULTS: In this study, there was no significant difference in either the 5-year tumor recurrence or progression rates between the two groups (p > 0.05) The Kaplan-Meier plot showed no difference in progression-free or recurrence-free survival between the two groups. CONCLUSION: Switching IVC agents does not improve RFS and PFS for patients with short-term recurrent high-risk NMIBC.