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Background: Metastatic triple-negative breast cancer (mTNBC) is the most aggressive and heterogeneous breast cancer subtype, with limited therapeutic options. Immune-checkpoint inhibitors (ICI) with chemotherapy are approved as first-line therapy in mTNBC for patients with PD-L1+tumors. The generation of immunosuppressive extracellular adenosine in the tumor microenvironment by the overexpression of ectoenzyme CD73 is a mechanism that could impair ICI and chemotherapy activity. The SYNERGY trial investigates if the addition of an anti-CD73 monoclonal antibody, oleclumab, increases the clinical benefit (CB) to the combination of chemotherapy with an anti-PD-L1 antibody, durvalumab, in previously untreated patients with advanced or mTNBC. Here we present data from a primary analysis including the first 68 evaluable patients. Methods: Patients with previously untreated inoperable locally advanced or mTNBC were randomized between carboplatin AUC 1.5 and paclitaxel 80 mg/m2 q1w x 12 in combination with durvalumab 1500 mg q4w with (Arm A) or without (Arm B) oleclumab 3000 mg q2w x5 followed by 3000 mg q4w according to the recommended phase 2 dose. Maintenance with immunotherapy was continued after chemotherapy. The primary hypothesis is that the addition of oleclumab increases the clinical benefit rate (CBR) at week 24 defined as complete response, partial response or stable disease according to RECIST 1.1. by 20% (1-sided α=0.1 and 80% power with 68 pts/arm; 150 pts to be enrolled). Patients were stratified by PD-L1 status and CD73 immunohistochemistry (IHC) expression assessed on baseline tumor tissue by a central lab. Using the Lan-Demets approach, the stopping boundary was z test < 0.074, p=0.464. Data from this primary analysis for safety and futility were reviewed by an independent data monitoring committee ( IDMC). Results: The 68th evaluable patient reached week 24 on the 2nd Apr 2021. Patients’ baseline characteristics were well balanced between both arms. Grade 3-4 adverse events (AE) occurred in 28/33 patients (84.9%) in Arm A and 21/35 patients (60.0%) in Arm B (p=0.03). Most common grade 3-4 AE were hematological toxicities with neutropenia (Arm A 17/33 [51.5%]; Arm B 12/35 [34.3%], and anemia (Arm A 5/33 [15.2%]; 1/35 [2.9%] in Arm B). There was no increase of immune-related AEs in the arm A with oleclumab. In Arm A, 15/33 patients (45%) met the CB criterion vs. 17/35 patients (49%) in Arm B. The futility boundary was crossed with z-value = -0.2574, p=0.69 (one-sided Fisher's exact). No significant difference in CBR was observed when patients were stratified according to PD-L1 status or CD73 IHC expression. Based on these results, the IDMC recommended to stop further recruitment. Patients under treatment are allowed to continue with durvalumab and oleclumab after being informed of these preliminary results. Of note, at the moment of interim analysis, long-lasting responses were observed with immunotherapy maintenance in both arms. Conclusion: The addition of oleclumab to the combination of chemotherapy by carboplatin and paclitaxel with durvalumab as first-line therapy for advanced or mTNBC did not significantly increase CBR at 6 months. Thus, in arm A the CBR was 45% in the overall population with long-lasting responses and an acceptable toxicity profile. Longer follow-up to evaluate the survival benefit is required. Further investigations evaluating the heterogeneity of this disease using blood and tissue samples collected during trial will shed light on the mechanisms associated with response and resistance to the trial regimens and help to define specific subgroups of patients with TNBC who could benefit from ICI and adenosine targeting agents. Citation Format: Veronique Debien, Christian Maurer, Philippe Aftimos, Florian Clatot, Delphine Loirat, Kevin Punie, François Ghiringhelli, Anhony Gonçalves, Donatienne Taylor, Tom Van den Mooter, Jean-Marc Ferrero, Hervé Bonnefoi, Jean-Luc Canon, François Duhoux, Renaud Poncin, Fernando Bazan, Nicolas Isambert, Philippe Barthelemy, Mariana Brandão, Paulus Kristanto, Michail Ignatiadis, Martine Piccart, Laurence Buisseret. First-line chemo-immunotherapy with durvalumab, paclitaxel and carboplatin with or without anti-CD73 antibody oleclumab in advanced or metastatic triple-negative breast cancer: Preliminary results of the randomized phase II SYNERGY trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-02.

Apalutamide, a competent inhibitor of the androgen receptor, has shown promising clinical efficacy results for patients with advanced prostate cancer. Here, we describe the rationale and design for the SAVE trial, a multi-center, Phase II study, wherein 202 men with biochemical progression after radical prostatectomy are randomly assigned 1:1 to apalutamide plus salvage radiotherapy (SRT) or androgen-deprivation therapy with an luteinizing hormone-releasing hormone agonist or antagonist plus SRT. The primary objective is to compare sexual function between the two treatment arms based on the expanded prostate cancer index-26 sexual domain score at nine months after start of hormonal treatment. The key secondary objectives are to assess quality of life, to evaluate the safety profile and the short-term efficacy of apalutamide in combination with SRT. ClinicalTrials.gov identifier: NCT03899077.

438 Background: HER2 overexpression has been found in invasive UC, suggesting a role for HER2 in disease progression and prognosis (Kruger Int J Oncol 2002). T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. Preclinical models showed that T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572). Methods: Pts aged ≥18 y had pathologically documented advanced/metastatic UC with centrally confirmed HER2 expression by immunohistochemistry (IHC) 2+/3+ (cohort 3; high expression) or IHC 1+ (cohort 4; low expression) who received prior platinum-based therapy with documented progression. Pts received T-DXd at 5.4 mg/kg and nivo 360 mg IV every 3 weeks (recommended dose for expansion). The primary endpoint was confirmed objective response rate (ORR) assessed by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints (assessed by ICR) included duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS), and safety. Results: At the primary analysis data cutoff (July 22, 2021), 34 pts (cohort 3, n = 30; cohort 4, n = 4) received T-DXd and nivo. Median age was 70.9 y (range, 41.4-80.5), 88.2% were male, 61.8% received ≥1 prior regimens for locally advanced/metastatic disease, and 26.5% had a history of liver metastases. Median treatment duration (all pts) was 3.2 mo (range, 1-21) for T-DXd and 4.1 mo (range, 1-20) for nivo. In cohort 3, ORR by ICR was 36.7% (95% CI, 19.9-56.1; complete response, 13.3%; partial response, 23.3%), median DOR was 13.1 mo (95% CI, 4.1- NE), median PFS was 6.9 mo (95% CI, 2.7-14.4), median TTR was 1.9 mo (range 1.2-6.9), and median OS was 11.0 mo (95% CI, 7.2-NE). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 73.5% of all pts (44.1% related to T-DXd; 26.5% related to nivo). TEAEs leading to drug discontinuation occurred in 32.4% of all pts (17.6% related to T-DXd; 23.5% related to nivo). The most common any-grade TEAEs were nausea (73.5%), fatigue (52.9%), and vomiting (44.1%). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.5% of all pts (2 G1; 4 G2; 1 G3; 1 G5). Conclusions: T-DXd combined with nivo showed antitumor activity in pts with high-expressing HER2 UC. The safety profile was consistent with prior studies for T-DXd in other indications and nivo monotherapy in UC pts. Adjudicated ILD/pneumonitis was within the range observed in other T-DXd monotherapy studies. Ongoing clinical trials are further exploring T-DXd in this population. Clinical trial information: NCT03523572.

Targeted anticancer therapies act by interfering with defined molecular entities and/or biologic pathways. Because of their more specific mechanism of action, adverse events (AEs) on healthy tissues are intended to be minimal, resulting in a different toxicity profile from that observed with conventional cytotoxic chemotherapy. Pulmonary AEs are rare but potentially life-threatening and it is, therefore, critical to recognize early on and manage appropriately.In this review, we aim to offer an overview of both more frequent and rare pulmonary AEs caused by targeted anticancer therapies and discuss possible treatment algorithms. Anti-vascular endothelial growth factor, anti-human epidermal growth factor receptor and anti-CD20 therapy will be reviewed, as well as immune checkpoint inhibitors, anaplastic lymphoma kinase inhibitors and mammalian target of rapamycin inhibitors.Novel agents used in the treatment of cancer have specific side-effects, the result of allergic reactions, on-target and off-target effects. Clinical syndromes associated with pulmonary toxicity vary from bronchospasms, hypersensitivity reactions, pneumonitis, acute respiratory distress, lung bleeding, pleural effusion to pneumothorax. Knowledge of risk factors, a high index of suspicion and a complete diagnostic work-up are essential for limiting the risk of these events becoming life threatening. The development of treatment algorithms is extremely helpful in managing these events. It is probable that these toxicities will be even more frequent with the introduction of combination therapies with the obvious challenge of discerning the responsible agent.

Ado- trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine; mertansine). T-DM1 retains the mechanisms of action of trastuzumab, but also acts as a, selectively delivered, tubulin inhibitor. Following antigen-mediated binding to the tumor cell, T-DM1 is endocytosed and intracellularly catabolized resulting in the release of its cytotoxic moiety.T-DM1 has completed Phase III development and compared favorably with the lapatinib/capecitabine combination with a superior response rate (objective response rate [ORR]) and duration of response, longer duration of disease control (progression-free survival [PFS]), prolonged overall survival and improved tolerability and quality of life in patients with prior treatment with trastuzumab and a taxane. In a separate Phase III, T-DM1 was compared with any other chosen regimen in patients who had at least received two prior HER2-directed therapies. T-DM1 nearly doubled PFS.T-DM1 (Kadcyla) has become the treatment of choice in second-line and beyond for patients with advanced HER2-expressing breast cancer.

Objective: The subcutaneous (SC) formulation of trastuzumab represents an alternative to the intravenous (IV) infusion in the treatment of patients with HER2-positive metastatic and early breast cancer. We compared the two formulations in terms of time and cost differential. Study desing: We conducted a time, motion and cost assessment study in a lean operating day care oncology unit to determine and compare the time and costs of trastuzumab SC versus IV administration in patients with HER2-positive breast cancer. Outcomes were the mean costs and the mean dedicated time of the health care professional (HCP) and patient chair time. Direct observation methodology was applied to collect data and statistical analysis was performed. Results: The total preparation and administration time for trastuzumab IV was 4.07 times longer than the total time required for the trastuzumab SC administration. The total patient time spent in the day care oncology unit (in minutes) was 71% shorter with using SC administration. IV administration costs (sic)50.4 ($54,89) more in HCP time and consumable supplies and (sic)162.53 ($177.00) of drug wastage. SC administration was associated with a total time saving of 53.7 min for the HCPs and 122.5 min for the patients. The administration of trastuzumab SC was translated in a cost saving of (sic)212.93 ($231.73) per patient episode compared to trastuzumab IV, which could lead to a total potential saving of (sic)3,832.74 ($4,171.06) over a full course of treatment (18 cycles) Conclusion: SC administration of trastuzumab was associated with a substantial reduction in active HCP time, patient chair time, unit time, and overall cost. These time and cost could be used to increase capacity within existing resources in a lean operating day dare oncology unit. (C) 2017 Published by Elsevier Ireland Ltd.