Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study.

BACKGROUND: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations. METHODS: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting. FINDINGS: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis. INTERPRETATION: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting. FUNDING: AstraZeneca and Daiichi Sankyo.

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

Modeling the novel SERD elacestrant in cultured fulvestrant-refractory HR-positive breast circulating tumor cells.

PURPOSE: Metastatic hormone receptor-positive (HR+) breast cancer initially responds to serial courses of endocrine therapy, but ultimately becomes refractory. Elacestrant, a new generation FDA-approved oral selective estrogen receptor degrader (SERD) and antagonist, has demonstrated efficacy in a subset of women with advanced HR+breast cancer, but there are few patient-derived models to characterize its effect in advanced cancers with diverse treatment histories and acquired mutations. METHODS: We analyzed clinical outcomes with elacestrant, compared with endocrine therapy, among women who had previously been treated with a fulvestrant-containing regimen from the recent phase 3 EMERALD Study. We further modeled sensitivity to elacestrant, compared with the currently approved SERD, fulvestrant in patient-derived xenograft (PDX) models and cultured circulating tumor cells (CTCs). RESULTS: Analysis of the subset of breast cancer patients enrolled in the EMERALD study who had previously received a fulvestrant-containing regimen indicates that they had better progression-free survival with elacestrant than with standard-of-care endocrine therapy, a finding that was independent estrogen receptor (ESR1) gene mutations. We modeled elacestrant responsiveness using patient-derived xenograft (PDX) models and in ex vivo cultured CTCs derived from patients with HR+breast cancer extensively treated with multiple endocrine therapies, including fulvestrant. Both CTCs and PDX models are refractory to fulvestrant but sensitive to elacestrant, independent of mutations in ESR1 and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) genes. CONCLUSION: Elacestrant retains efficacy in breast cancer cells that have acquired resistance to currently available ER targeting therapies. Elacestrant may be an option for patients with HR+/HER2- breast cancer whose disease progressed on fulvestrant in the metastatic setting. TRANSLATIONAL RELEVANCE: Serial endocrine therapy is the mainstay of management for metastatic HR+breast cancer, but acquisition of drug resistance highlights the need for better therapies. Elacestrant is a recently FDA-approved novel oral selective estrogen receptor degrader (SERD), with demonstrated efficacy in the EMERALD phase 3 clinical trial of refractory HR+breast cancer. Subgroup analysis of the EMERALD clinical trial identifies clinical benefit with elacestrant in patients who had received prior fulvestrant independent of the mutational status of the ESR1 gene, supporting its potential utility in treating refractory HR+breast cancer. Here, we use pre-clinical models, including ex vivo cultures of circulating tumor cells and patient-derived xenografts, to demonstrate the efficacy of elacestrant in breast cancer cells with acquired resistance to fulvestrant.

First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours.

BACKGROUND: Interleukin-1 (IL-1) signalling is involved in various protumoural processes including proliferation, immune evasion, metastasis and chemoresistance. CAN04 is a first-in-class monoclonal antibody that binds IL-1 receptor accessory protein (IL1RAP), required for IL-1 signalling. In this first-in-human phase 1 study, we assessed safety, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of CAN04 monotherapy. METHODS: Patients with advanced solid tumours known to express IL1RAP and refractory to standard treatments were enrolled in a dose-escalation study with 5 dose levels (1.0-10.0 mg/kg) of weekly CAN04. RESULTS: Twenty-two patients were enrolled. Most common adverse events were infusion-related reactions (41%), fatigue (32%), constipation (27%), diarrhoea (27%), decreased appetite (23%), nausea (23%) and vomiting (23%). One dose limiting toxicity was reported. No maximum tolerated dose was identified. Pharmacokinetics analyses indicate higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and CRP were observed in most patients. Twenty-one patients were evaluable for response, 43% had stable disease per immune-related response criteria with no partial/complete responses. CONCLUSIONS: The IL1RAP targeting antibody CAN04 can be safely administered to patients up to 10.0 mg/kg weekly, which was defined as the RP2D. Serum biomarkers supported target engagement and IL-1 pathway inhibition. CLINICAL TRIAL REGISTRATION: NCT03267316.

Trilaciclib prior to gemcitabine plus carboplatin for metastatic triple-negative breast cancer: phase III PRESERVE 2.

Triple-negative breast cancer (TNBC) is an aggressive malignancy for which cytotoxic chemotherapy remains the backbone of treatment. Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor that induces transient cell cycle arrest of hematopoietic stem and progenitor cells and immune cells during chemotherapy exposure, protecting them from chemotherapy-induced damage and enhancing immune activity. Administration of trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly improved overall survival (OS) compared with GCb alone in an open-label phase II trial in patients with metastatic TNBC, potentially through protection and direct activation of immune function. The randomized, double-blind, placebo-controlled, phase III PRESERVE 2 trial will evaluate the efficacy and safety of trilaciclib administered prior to GCb in patients with locally advanced unresectable or metastatic TNBC. Clinical Trial Registration: NCT04799249 (ClinicalTrials.gov).

ROSALINE: a phase II, neoadjuvant study targeting ROS1 in combination with endocrine therapy in invasive lobular carcinoma of the breast.

Invasive lobular carcinoma (ILC) is the most common histologic subtype of breast cancer after invasive ductal carcinoma (i.e., no special type [NST]). ILC differs from NST in clinical presentation, site-specific metastases and response to conventional therapies. Loss of E-cadherin protein expression, due to alterations in its encoding gene CDH1, is the most frequent oncogenic event in ILC. Synthetic lethality approaches have shown promising antitumor effects of ROS1 inhibitors in models of E-cadherin-defective breast cancer in in vivo studies and provide the rationale for testing their clinical activity in patients with ILC. Entrectinib is a tyrosine kinase inhibitor targeting TRK, ROS1 and ALK tyrosine kinases. Here, the authors present ROSALINE (NCT04551495), a phase II study testing neoadjuvant entrectinib and endocrine therapy in women with estrogen receptor-positive, HER2-negative early ILC.

Breast cancer is the most common cancer among women worldwide. Breast cancer is not a unique disease, but rather a heterogeneous disease, with different subtypes. Lobular breast cancer is the second most common histologic subtype of breast cancer after ductal breast cancer. Lobular breast cancer has some peculiar characteristics that make it a distinct entity in the context of breast cancer. Nevertheless, few clinical studies so far have focused specifically on this subtype. ROSALINE is a clinical study aimed to test entrectinib, a new drug that showed promising activity in preliminary research studies, in combination with endocrine therapy in women with lobular breast cancer before surgery. Trial Registration Number: NCT04551495 (ClinicalTrials.gov).

Analyses of the Rationale and Implementation of Research Biopsies in Oncology Clinical Trials at a Tertiary Cancer Center.

BACKGROUND: Biomarkers in clinical trials have led to massive incorporation of research biopsies, with potentially risks and no direct benefit for patients. In 2018, the American Society of Clinical Oncology (ASCO) released an ethical framework to provide guidance on incorporating research biopsies in cancer clinical trials. MATERIALS AND METHODS: We collected biopsy requirements of cancer clinical trials conducted at Institut Jules Bordet (IJB) between 2015 and 2019 to examine adherence with the ASCO Ethical Framework. We used logistic regression models to test the association between the request for biopsy, the request for tissue, and the adherence to the ASCO framework as well as some trial characteristics. RESULTS: Between January 2015 and December 2019, 178 oncological studies were conducted at IJB. Of these, 138 (78%) were sponsored by industry, 132 (74%) were phase II and III studies, and 141 (79%) concerned metastatic disease. Tissue was required for inclusion for 119 (67%) studies, among which 59 required at least one new biopsy. Adherence to ASCO's Ethical Framework was 67% for studies requiring tissue and went down to 39% for studies requiring at least one new biopsy. In multivariate analysis, requests for tissue or new biopsies increased in early-phase studies (p < .001, p < .001, respectively) and in studies investigating innovative treatments (immunotherapy or targeted therapies; p < .01, p = .02). Compliance to the ASCO framework significantly decreased with time (p < .001) and in early-phase studies (p < .001). CONCLUSION: Numerous studies required tissue or new biopsies for exploratory objectives of unknown clinical utility. Requests for tissue increased over the years, whereas compliance to ASCO's Ethical Framework decreased. IMPLICATIONS FOR PRACTICE: In 2019, the American Society of Clinical Oncology (ASCO) developed an ethical framework to provide guidance on incorporating research biopsies in clinical trials. This study underlines the growing request for tissue in clinical trials with potentially no impact on drug development and no benefit to actual or future patients. Adherence to ASCO's Ethical Framework decreases through time. These results highlight the importance of improving the ethics of research biopsies. ASCO's Ethical Framework offers an opportunity to improve quality of care in clinical research by maximizing scientific utility and allowing for clinically meaningful correlative science and safe access to innovative treatments for a maximum number of patients.

Factors associated with SARS-CoV-2 infection and outcome in patients with solid tumors or hematological malignancies: a single-center study.

BACKGROUND: Immunocompromised cancer patients are presumed to be at high risk of developing COVID-19 infection. Predisposing factors to contracting COVID-19 and to severe outcomes have been described in registries but were not compared between solid tumors and hematological malignancies. METHOD: This retrospective single oncologic center study included adults with solid tumors or hematological malignancies referred to testing by naso-pharyngeal swab for a SARS-CoV-2 RT-PCR from March 10 to May 18, 2020. RESULTS: A total of 212 patients were included in the study. Forty-five (21%) were tested positive with SARS-CoV-2. The univariate analysis with positive SARS-CoV-2 PCR as a dependent variable reveals significant odds ratios (ORs) for age-with a mean of 62.5 years-(OR: 1.05, 95% CI: 1.02-1.08), performance status ≥2 (OR: 2.38, 95% CI: 1.22-4.70), inpatient status (OR: 2.36, 95%CI: 1.11-4.91), and hematological malignancies (OR: 2.48, 95% CI: 1.23-4.96). In contrast, OR for solid tumors reveals a negative association (OR: 0.40, 95% CI: 0.20-0.81). When integrating severe outcome (ICU admission or COVID-19-related death) as a dependent variable, the univariate logistic regression model shows significant ORs for pre-existing lymphopenia (OR: 4.0, 95% CI: 1.17-15.04), hematological malignancies (OR: 3.73, 95% CI: 1.09-13.80), and a negative association for solid tumors (OR: 0.27; 95% CI: 0.07-0.92). CONCLUSION: In patients referred for SARS-CoV-2 testing, hematological malignancies were associated with a higher risk of COVID-19 infection and severe outcomes. Other factors were age and inpatient status.

A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging.

BACKGROUND: Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17ß-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). METHODS: Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. RESULTS: Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. CONCLUSION: Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02650817 . Registered on 08 January 2016.

First-in-human, dose-escalation, phase 1 study of anti-angiopoietin-2 LY3127804 as monotherapy and in combination with ramucirumab in patients with advanced solid tumours.

BACKGROUND: This is the first-in-human study of novel anti-angiopoietin-2 (Ang-2) monoclonal antibody LY3127804 as monotherapy and in combination with ramucirumab in advanced solid tumours. METHODS: Patients received intravenous LY3127804 monotherapy (4, 8, 12, 16, 20 and 27 mg/kg) in part A; LY3127804 (8, 12, 16, 20 and 27 mg/kg) with 8 mg/kg ramucirumab in part B; and LY3127804 (20 mg/kg) with 12 mg/kg ramucirumab in part C. Treatments were administered every 2 weeks (Q2W) during 28-day cycles. Dose-escalation was based on cycle 1 dose-limiting toxicities (DLTs). RESULTS: Sixty-two patients were treated in part A (n = 20), part B (n = 35) and part C (n = 7). Constipation, diarrhoea and fatigue were the most common treatment-emergent adverse events (TEAEs) in part A; hypertension and peripheral oedema were the most frequent TEAE in parts B and C. No DLT was observed and maximum tolerated dose for LY3127804 was not reached. Four patients achieved partial response with combination therapy (clear cell endometrial carcinoma, cervix squamous cell carcinoma, carcinoma of unknown primary and gastroesophageal junction carcinoma), 29 achieved stable disease, and 24 had progressive disease. CONCLUSIONS: LY3127804 monotherapy and its combination with ramucirumab are well tolerated. LY3127804 20 mg/kg was the recommended Phase 2 dose.

Feasibility and clinical impact of routine molecular testing of gastrointestinal cancers at a tertiary centre with a multi-gene, tumor-agnostic, next generation sequencing panel.

BACKGROUND: High-throughput sequencing technologies are increasingly used in research but limited data are available on the feasibility and value of these when routinely adopted in clinical practice. MATERIAL AND METHODS: We analyzed all consecutive cancer patients for whom genomic testing by a 48-gene next-generation sequencing (NGS) panel (Truseq Amplicon Cancer Panel, Illumina) was requested as part of standard care in one of the largest Belgian cancer networks between 2014 and 2019. Feasibility of NGS was assessed in all study patients, while the impact of NGS on the decision making was analyzed in the group of gastrointestinal cancer patients. RESULTS: Tumor samples from 1064 patients with varying tumor types were tested, the number of NGS requests increasing over time (p < .0001). Success rate and median turnaround time were 91.4% and 12.5 days, respectively, both significantly decreasing over time (p ≤ .0002). Non-surgical sampling procedure (OR 7.97, p < .0001), tissue from metastatic site (OR 2.35, p = .0006) and more recent year of testing (OR 1.79, p = .0258) were independently associated with NGS failure. Excluding well-known actionable or clinically relevant mutations which are recommended by international guidelines and commonly tested by targeted sequencing, 57/279 (20.4%) assessable gastrointestinal cancer patients were found to have tumors harboring at least one actionable altered gene according to the OncoKB database. NGS results, however, had a direct impact on management decisions by the treating physician in only 3 cases (1.1%). CONCLUSIONS: Our findings confirm that NGS is feasible in the clinical setting with acceptably low failure rates and rapid turnaround time. In gastrointestinal cancers, however, NGS-based multiple-gene testing adds very little to standard targeted sequencing, and in routine practice the clinical impact of NGS panels including genes which are not routinely recommended by international guidelines remains limited.

Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study.

BACKGROUND: Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. METHODS: We did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0·3 mg/kg to 2·4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. FINDINGS: Between Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2·4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1·5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3-4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1·2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two [1%]) and dyspnoea (two [1%]). The most common treatment-related adverse events (grades 1-4) were fatigue (48 [33%] of 146 patients), conjunctivitis (45 [31%]), and dry eye (45 [31%]). Most patients (104 [71%] of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20·4-48·4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13·8-46·8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16·3-67·6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0·2-30·2) of 16 patients with gastric cancer, four (25%, 7·3-52·4) of 16 patients with urothelial cancer, and five (39%, 13·9-68·4) of 13 patients with endometrial cancer. INTERPRETATION: Trastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. FUNDING: Synthon Biopharmaceuticals.

Network science in clinical trials: A patient-centered approach.

There has been a paradigm shift in translational oncology with the advent of novel molecular diagnostic tools in the clinic. However, several challenges are associated with the integration of these sophisticated tools into clinical oncology and daily practice. High-throughput profiling at the DNA, RNA and protein levels (omics) generate a massive amount of data. The analysis and interpretation of these is non-trivial but will allow a more thorough understanding of cancer. Linear modelling of the data as it is often used today is likely to limit our understanding of cancer as a complex disease, and at times under-performs to capture a phenotype of interest. Network science and systems biology-based approaches, using machine learning and network science principles, that integrate multiple data sources, can uncover complex changes in a biological system. This approach will integrate a large number of potential biomarkers in preclinical studies to better inform therapeutic decisions and ultimately make substantial progress towards precision medicine. It will however require development of a new generation of clinical trials. Beyond discussing the challenges of high-throughput technologies, this review will develop a framework on how to implement a network science approach in new clinical trial designs in order to advance cancer care.

Antibody-Drug Conjugates in Breast Cancer: a Comprehensive Review.

OPINION STATEMENT: Antibody-drug conjugates are an elegant approach to cancer treatment that couples the specificity of monoclonal antibodies to the cytotoxicity of classic chemotherapy agents, permitting, at least in theory, increased activity and reduced toxicity. In breast cancer, the early success of trastuzumab-emtansine (T-DM1) in the HER2-positive metastatic setting led to great hopes, later dashed by results in the early setting (KRISTINE trial) and in combination with pertuzumab (MARIANNE trial). Parallel to this, development of ADCs in breast cancer has suffered other setbacks, including the recent failure of other agents (MM-302) as well as the suspension of a few programs (XMT-1522, ADCT-502) with the overall effect of dampening the impetus of this concept and halting/delaying the progress of drugs associated with it, particularly when immunotherapy is at the center of so many efforts. Numerous antibody-drug conjugates remain, however, in development, and could prove successful. Critically, ADCs could permit the introduction of novel concepts such as the expansion of potent anti-HER2 therapy to HER2-low breast cancer, treatment beyond resistance to T-DM1, and synergy in combination with immune checkpoint blockade. In the early setting, the ATEMPT trial may show that T-DM1 reduces toxicity while maintaining good outcomes for lower risk HER2+ patients. ADCs based on bispecific antibodies are also in development. Finally, breakthroughs are occurring in the orphan triple-negative breast cancer subtype with agents targeting surface proteins. The recent results of Sacituzumab govitecan suggest substantial activity in heavily pre-treated patients and underscore the enduring relevance of antibody drug conjugates as a path towards better outcomes.

EMERALD: Phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer.

Elacestrant is a novel, nonsteroidal, orally bioavailable selective estrogen receptor degrader (SERD) that has demonstrated activity in patients with estrogen receptor (ER)-positive/HER2-negative breast cancer previously treated with endocrine therapies including fulvestrant and/or CDK 4/6 inhibitor therapy, and in those with ESR1 mutations (ESR1-mut) known to confer endocrine resistance. Herein, we describe the design and methodology of EMERALD, an international, multicenter, randomized, open-label, active-controlled, Phase III clinical study comparing the efficacy and safety of elacestrant to standard-of-care endocrine monotherapy treatment (fulvestrant or an aromatase inhibitor, per investigator's choice) in patients with ER-positive/HER2-negative advanced breast cancer. Primary end points are progression-free survival in ESR1-mut patients and in all patients (NCT03778931; EudraCT 2018-002990-24).

Evolving paradigms in multifocal breast cancer.

The 7th edition of the TNM defines multifocal breast cancer as multiple simultaneous ipsilateral and synchronous breast cancer lesions, provided they are macroscopically distinct and measurable using current traditional pathological and clinical tools. According to the College of American Pathologists (CAP), the characterization of only the largest lesion is considered sufficient, unless the grade and/or histology are different between the lesions. Here, we review three potentially clinically relevant aspects of multifocal breast cancers: first, the importance of a different intrinsic breast cancer subtype of the various lesions; second, the emerging awareness of inter-lesion heterogeneity; and last but not least, the potential introduction of bias in clinical trials due to the unrecognized biological diversity of these cancers. Although the current strategy to assess the lesion with the largest diameter has clearly its advantages in terms of costs and feasibility, this recommendation may not be sustainable in time and might need to be adapted to be compliant with new evolving paradigms in breast cancer.

Current-day precision oncology: from cancer prevention, screening, drug development, and treatment - have we fallen short of the promise?

PURPOSE OF REVIEW: Precision oncology has been a strategy of prevention, screening, and treatment. Although much has been invested, have the results fallen so far short of the promise? The advancement of technology and research has opened new doors, yet a variety of pitfalls are present. This review presents the successes, failures, and opportunities of precision oncology in the current landscape. RECENT FINDINGS: The use of targeted gene sequencing and the overwhelming results of superresponders have generated much excitement and support for precision oncology from the medical community. Despite notable successes, many challenges still pave the way of precision oncology: intratumoral heterogeneity, the need for serial biopsies, availability of treatments, target prioritization, ethical issues with germline incidental findings, medical education, clinical trial design, and costs. SUMMARY: Precision oncology shows much potential through the use of next-generation sequencing and molecular advances, but does this potential warrant the investment? There are many obstacles on the way of this technology that should make us question if the investment (both monetary and man-hours) will live up to the promise. The review aims to not criticize this technology, but to give a realistic view of where we are, especially regarding cancer treatment and prevention.

Phase I dose-escalation study of plitidepsin in combination with bevacizumab in patients with refractory solid tumors.

This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m, n=3; 3.8 mg/m, n=4; and 4.8 mg/m, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained.

An open-label, dose-escalation study to evaluate the safety and pharmacokinetics of CEP-9722 (a PARP-1 and PARP-2 inhibitor) in combination with gemcitabine and cisplatin in patients with advanced solid tumors.

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors may potentiate chemotherapy by hindering DNA damage repair pathways. CEP-9722 is the prodrug of CEP-8983, a selective inhibitor of PARP-1 and PARP-2. Preclinical studies and a prior phase 1 study suggested that CEP-9722 may cause less myelosuppression than has been observed with other oral PARP inhibitors. The primary objective of this study was to determine the maximum-tolerated dose of CEP-9722 in combination with gemcitabine and cisplatin in patients with advanced solid tumors. All patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. Patients who completed one cycle of chemotherapy alone continued chemotherapy in combination with CEP-9722 150, 200, 300, or 400 mg orally twice daily on days 2-7, with dose-limiting toxicity assessed in cycle 2. Patients experiencing clinical benefit could continue treatment until disease progression or unacceptable toxicity. Thirty-two patients enrolled; 18 patients completed cycle 1 and received chemotherapy plus CEP-9722. The median (range) treatment administration with CEP-9722 was five (1-12) cycles. No patient experienced dose-limiting toxicity with CEP-9722 treatment. Grade 3/4 hematologic adverse events included neutropenia (28%) and leukopenia (11%); adverse events led to discontinuation in 33% of patients. One patient achieved complete response, three had partial responses, and 11 had stable disease; however, the relative contribution of CEP-9722 and/or the chemotherapeutic agents cannot be determined from this single-arm design. This study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression.