A Phase I Study of the Pan-Notch Inhibitor CB-103 for Patients with Advanced Adenoid Cystic Carcinoma and Other Tumors.

PURPOSE: CB-103 selectively inhibits the CSL-NICD (Notch intracellular domain) interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This dose-escalation/expansion study aimed to determine safety, pharmacokinetics, and preliminary antitumor activity. EXPERIMENTAL DESIGN: Patients ≥18 years of age with selected advanced solid tumors [namely, adenoid cystic carcinoma (ACC)] and hematologic malignancies were eligible. CB-103 was dosed orally in cycles of 28 days at escalating doses until disease progression. Notch-activating mutations were required in a dose confirmatory cohort. Endpoints included dose-limiting toxicities (DLT), safety, tumor response, pharmacokinetics, and pharmacodynamics. Exploratory analyses focused on correlates of Notch and target gene expression. RESULTS: Seventy-nine patients (64, 12 dose-escalation cohorts; 15, confirmatory cohort) enrolled with 54% receiving two or more lines of prior therapy. ACC was the dominant tumor type (40, 51%). Two DLTs were observed [elevated gamma-glutamyl transferase (GGT), visual change]; recommended phase II dose was declared as 500 mg twice daily (5 days on, 2 days off weekly). Grade 3-4 treatment-related adverse events occurred in 15 patients (19%), including elevated liver function tests (LFTs), anemia, and visual changes. Five (6%) discontinued drug for toxicity; with no drug-related deaths. There were no objective responses, but 37 (49%) had stable disease; including 23 of 40 (58%) patients with ACC. In the ACC cohort, median progression-free survival was 2.5 months [95% confidence interval (CI), 1.5-3.7] and median overall survival was 18.4 months (95% CI, 6.3-not reached). CONCLUSIONS: CB-103 had a manageable safety profile and biological activity but limited clinical antitumor activity as monotherapy in this first-in-human study. SIGNIFICANCE: CB-103 is a novel oral pan-Notch inhibitor that selectively blocks the CSL-NICD interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This first-in-human dose-escalation and -confirmation study aimed to determine the safety, pharmacokinetics, and preliminary antitumor efficacy of CB-103. We observed a favorable safety profile with good tolerability and biological activity but limited clinical single-agent antitumor activity. Some disease stabilization was observed among an aggressive NOTCH-mutant ACC type-I subgroup where prognosis is poor and therapies are critically needed. Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs.

Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. METHODS: This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs, and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n = 8; cohort 1), asymptomatic untreated BMs (n = 4; cohort 2), or progressing BMs after local therapy (n = 9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial objective response rate (ORR-IC) for cohorts 2 and 3. RESULTS: As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P < .001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P < .001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade ≥3), nausea (42.9%; 0% grade ≥3), neutropenia (28.6%; 19% grade ≥3), and constipation (28.6%; 0% grade ≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd showed intracranial activity with manageable toxicity and maintained the quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.

SOLTI-1904 ACROPOLI TRIAL: efficacy of spartalizumab monotherapy across tumor-types expressing high levels of PD1 mRNA.

Improved selection of cancer patients who are most likely to respond to immune checkpoint inhibitors remains an unmet clinical need. Recently, a positive correlation between levels of PD1 mRNA and clinical outcome in response to PD1 blockade across diverse tumor histologies has been confirmed in several datasets. ACROPOLI is a parallel cohort, non-randomized, phase II study that aims to evaluate the efficacy of the anti-PD1 immune checkpoint inhibitor spartalizumab as monotherapy in metastatic patients with solid tumors that express high levels of PD1 (cohort 1; n = 111). An additional cohort of 30 patients with tumors expressing low levels of PD1, where PD1/PD-L1 antibodies in monotherapy are standard treatment, will also be included (cohort 2). Primary end point is overall response rate in cohort 1. Trial registration number: NCT04802876 (ClinicalTrials.gov).

Atezolizumab in the treatment of metastatic triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) accounts for approximately 10%-15% of all diagnosed breast cancers and is associated with an aggressive natural history and poor clinical outcomes. Immunotherapy using immune checkpoint inhibitors has emerged as an effective therapeutic option for TNBC. The results of the IMpassion130 trial have recently led to the approval of the combination of atezolizumab and nab-paclitaxel in the first-line treatment of patients with unresectable locally advanced or metastatic, PD-L1-positive TNBC. AREAS COVERED: This article summarizes the clinical development and ongoing research on atezolizumab in the treatment of metastatic TNBC. Results of atezolizumab monotherapy trials and data from combination studies with chemotherapy in the advanced setting are reviewed, with special focus on the design, methods, and key findings of the IMpassion130 trial. EXPERT OPINION: The approval of atezolizumab plus nab-paclitaxel represents an important advance in the treatment of metastatic TNBC. This combination has a favorable risk-benefit profile and is associated with clinically meaningful outcomes. However, further research is needed to identify better predictive biomarkers of response as well as novel immunotherapeutic strategies with atezolizumab and other anticancer drugs.

Clinical Implications of Extracellular HMGA1 in Breast Cancer.

The unconventional secretion of proteins is generally caused by cellular stress. During the tumorigenesis, tumor cells experience high levels of stress, and the secretion of some theoretically intracellular proteins is activated. Once in the extracellular space, these proteins play different paracrine and autocrine roles and could represent a vulnerability of cancer. One of these proteins is the high mobility group A1 (HMGA1), which is frequently overexpressed in tumors and presents a low expression in normal adult tissues. We have recently described that HMGA1 establishes an autocrine loop in invasive triple-negative breast cancer (TNBC) cells. The secretion of HMGA1 and its binding to the receptor for advanced glycation end products (RAGE) mediates the migration, invasion, and metastasis of TNBC cells and predicts the onset of metastasis in these patients. In this review, we summarized different strategies to exploit the novel tumorigenic phenotype mediated by extracellular HMGA1. We envisioned future clinical applications where the association between its change in subcellular localization and breast cancer progression could be used to predict tumor aggressiveness and guide treatment decisions. Furthermore, we proposed that targeting extracellular HMGA1 as monotherapy using monoclonal antibodies, or in combination with chemotherapy and other targeted therapies, could bring new therapeutic options for TNBC patients.

Concurrent palliative external radiotherapy with sorafenib or doxorubicin for bulky differentiated thyroid carcinoma: A case report.

Administration of external beam radiotherapy (EBRT) for a bulky recurrence or primary bulky tumor of differentiated thyroid carcinoma (DTC) is rare. No previous experience is available on the feasibility of administering EBRT simultaneously with systemic treatment with doxorubicin or sorafenib, or both. The present case study reported the results from two different institutions on 5 consecutive patients. Side effects and tolerance to radiotherapy plus systemic treatment with doxorubicin (20 mg/m2 intravenously weekly for 6/8 consecutive weeks) or sorafenib (400 mg/12 h orally for 8 weeks) or both, were analyzed in patients with DTC. The local response to radiotherapy and patient outcome was also analyzed. A total of 4 males and 1 female, aged 37-62 years with cervical bulky mass DTC were included. The pathological tumor types were papillary (2 patients), follicular (2 patients) and medullar thyroid carcinoma (1 patient). The radiated cervical mass was local recurrence in 3 cases and primary tumor in the other two. The total dose of radiotherapy ranged between 50 and 64.8 Gy. Three patients received sorafenib, 1 patient received doxorubicin and 1 patient received both treatments. The total planned dose of radiotherapy was administered to all patients. Grade 2 anemia and erythrodysesthesia was the most frequent toxicity. Only the patient who received doxorubicin plus sorafenib had grade 3 toxicity consisting of lymphopenia, folliculitis and mucositis. All but 1 patient had a good local response to radiotherapy. The administration of EBRT concurrently with sorafenib and doxorubicin to patients with DTC with a bulky cervical mass is feasible.

Targeting fibroblast growth factor receptors and immune checkpoint inhibitors for the treatment of advanced bladder cancer: New direction and New Hope.

Bladder cancer is one of the leading causes of death in Europe and the United States. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients with median overall survival of 15months and a 5-year survival rate of ⩽10%. Furthermore, unfit patients for cisplatin have no standard of care for first line therapy in advance disease Most second-line chemotherapeutic agents tested have been disappointing. Newer targeted drugs and immunotherapies are being studied in the metastatic setting, their usefulness in the neoadjuvant and adjuvant settings is also an intriguing area of ongoing research. Thus, new treatment strategies are clearly needed. The comprehensive evaluation of multiple molecular pathways characterized by The Cancer Genome Atlas project has shed light on potential therapeutic targets for bladder urothelial carcinomas. We have focused especially on emerging therapies in locally advanced and metastatic urothelial carcinoma with an emphasis on immune checkpoints inhibitors and FGFR targeted therapies, which have shown great promise in early clinical studies.