Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial

Tucatinib; Càncer de mama metastàtic; Metàstasis cerebralTucatinib; Cáncer de mama metastásico; Metástasis cerebralTucatinib; Metastatic Breast cancer; Brain metastasesImportance: It is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs. Objective: To describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up. Design, setting, and participants: HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed. Interventions: Patients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle). Main outcomes and measures: Evaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion-free survival in all patients. Only OS was prespecified before the primary database lock. Results: At baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]). Conclusions and relevance: This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs.This study was sponsored by Seagen Inc, Bothell, Washington, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey

Tusamitamab Ravtansine in Patients with Advanced Solid Tumors: Phase I Study of Safety, Pharmacokinetics, and Antitumor Activity Using Alternative Dosing Regimens

Advanced solid tumors; Pharmacokinetics; Antitumor activityTumors sòlids avançats; Farmacocinètica; Activitat antitumoralTumores sólidos avanzados; Farmacocinética; Actividad antitumoralPurpose: Tusamitamab ravtansine is an antibody–drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers a cytotoxic maytansinoid payload. In a phase I dose-escalation study, the maximum tolerated dose (MTD) was 100 mg/m2 every 2 weeks (Q2W). Here we report results for two alternative schedules. Experimental Design: Adults ages ≥18 years (range, 34–73) with locally advanced/metastatic solid tumors (N = 43; colon/rectum, 29; stomach, 7; pancreas, 4; other, 3) expressing/likely to express CEACAM5 received intravenous tusamitamab ravtansine 120–170 mg/m2 [loading dose (LD)], then 100 mg/m2 Q2W (Q2W-LD, n = 28), or 120–190 mg/m2 fixed dose [every 3 weeks (Q3W), n = 15]. The primary endpoint was dose-limiting toxicities (DLTs) during cycles 1–2 (Q2W-LD) and cycle 1 (Q3W). Results: Reversible DLTs were observed in 2 of 9 patients (grade 2 keratopathy; grade 2 keratitis) with 170 mg/m2 in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m2 in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients in Q3W experienced treatment-related adverse events (AE); 3 of 43 patients discontinued treatment because of AEs. The most common AEs were asthenia, gastrointestinal complaints, keratopathy, keratitis, and peripheral sensory neuropathy. In this small, heavily pretreated population, no confirmed responses were observed; however, stable disease occurred in 35.7% of patients in Q2W-LD and 40.0% of patients in Q3W. Conclusions: Tusamitamab ravtansine had a favorable safety profile with both alternative administration schedules; MTDs were 170 mg/m2 (LD) followed by 100 mg/m2 Q2W, and 170 mg/m2 Q3W as a fixed dose. (NCT02187848). Significance: The collective results of this phase I dose-escalation study will inform further studies of tusamitamab ravtansine in patients with solid tumors with CEACAM5 expression, including patients with non–small cell lung cancer.This work was supported by Sanofi. Medical writing support was provided by Blair Jarvis and Elizabeth Strickland of inScience Communications (Philadelphia, PA). This work was performed in accordance with current Good Publication Practice guidelines and funded by Sanofi

Personalized medicine for metastatic breast cancer

Cel przeglądu. Dzięki nowym technikom sekwencjonowania DNA można identyfikować w materiale biopsyjnymu chorych na raka piersi z przerzutami powtarzające się zmiany w genomie, co może prowadzić do molekularnego selekcjonowania przypadków do badań klinicznych nad lekami ukierunkowanymi. W niniejszym przeglądzie przedstawiano aktualne dane dotyczące powtarzających się zmian w genomie w raku piersi z przerzutami, a także podsumowano wyniki badań klinicznych wczesnej fazy dotyczących nowych leków ukierunkowanych.Najnowsze odkrycia. Postęp kliniczny w zakresie personalizacji leczenia obejmuje zastosowanie leków ukierunkowanych na szlak PI3K/mTOR, receptor czynnika wzrostu fibroblastów, receptor typu drugiego ludzkiego naskórkowego czynnika wzrostu, szlaki naprawy DNA oraz szlaki regulujące cykl komórkowy. Leki ukierunkowane na szlak PI3K/mTOR wykazują aktywność w raku piersi opornym na leczenie hormonalne i trastuzumab. W podgrupie chorych na raka piersi z przerzutami, po preselekcji w kierunku aberracji w zakresie wymienionych szlaków, wykazano potencjalną aktywność leków ukierunkowanych na szlak PI3K/mTOR, FGFR i polimerazę poli(ADP-rybozy). Prowadzone są również badania oceniające skuteczność leczenia skojarzonego z udziałem leków ukierunkowanych, hormonoterapii, leków przeciw HER-2 lub też chemioterapii w grupach chorych z określonymi zmianami genomu w zakresie genów receptorów hormonalnych, szlaku HER-2 czy też pozostałych istotnych szlaków sygnałowych.Podsumowanie. Obecnie wdrażane jest nowe podejście do spersonalizowanego leczenia chorych na raka piersi z przerzutami. Uwzględnia ono selekcję molekularną mającą na celu identyfikację istotnych klinicznie zmian w genomie oraz leczenie ukierunkowane molekularnie. Konieczne jest prowadzenie badań klinicznych, które pozwolą wykazać, czy dane subpopulacje chorych na raka piersi z przerzutami mogą odnieść rzeczywistą korzyść z leczenia dobranego według zmian w genomie.Purpose of review. With recent advances in DNA sequencing technology, recurrent genomic alterations can be identified in tumor samples from patients with metastatic breast cancer (MBC) to enrich clinical trials testing targeted therapies. This review provides an overview of clinically relevant genomic alterations in MBC and summarizes the recent clinical data from early phase trials of novel targeted treatments.Recent findings. The clinical development of personalized treatment includes targeted agents directed against PI3K/mTOR, fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), DNA repair, and cell cycle pathways. PI3K/mTOR pathway drugs are active in endocrine and trastuzumab-resistant disease. Drugs targeted at PI3K/mTOR, FGFR, and poly(ADP-ribose) polymerase show early signs of efficacy in MBC subpopulations enriched with relevant pathway aberrancies. Regimens combining targeted agents with either endocrine, anti-HER2, or chemotherapy treatments are also being studied in hormone receptor-definedand HER2-defined or pathway-enriched subgroups.Summary. A new approach to personalized medicine for MBC that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging. Clinical trials are needed to determine whether rare subpopulations of MBC benefit from genotype-targeted treatments

Anti-TIGIT Antibody Tiragolumab Alone or With Atezolizumab in Patients With Advanced Solid Tumors: A Phase 1a/1b Nonrandomized Controlled Trial

Antibody; Atezolizumab; Advanced solid tumorsAnticuerpo; Atezolizumab; Tumores sólidos avanzadosAnticòs; Atezolizumab; Tumors sòlids avançatsImportance Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in programmed death ligand 1–selected tumors. Objective To evaluate the safety and antitumor activity of the anti-TIGIT antibody tiragolumab and its combination with atezolizumab in patients with advanced solid tumors. Design, Setting, and Participants The GO30103 open-label, first-in-human phase 1a/1b dose-escalation and dose-expansion nonrandomized controlled trial was conducted at 13 sites in 6 countries (Australia, Canada, France, Korea, Spain, and the US). The start dates were May 23, 2016, for phase 1a and October 11, 2016, for phase 1b. Patients were aged 18 years or older with measurable disease at baseline. The clinical cutoff date was October 1, 2021. Data analysis was performed on January 24, 2022. Interventions Patients received fixed-dose intravenous tiragolumab on day 1 of each 21-day cycle (2 mg escalating to 1200 mg) in phase 1a, plus fixed-dose intravenous atezolizumab (1200 mg every 3 weeks) in phase 1b. Patients were treated until disease progression, loss of clinical benefit, or development of unacceptable toxicity. Main Outcomes and Measures The primary end points included the safety, tolerability, and recommended phase 2 dose (RP2D) of tiragolumab or combination tiragolumab plus atezolizumab. The secondary end point included the investigator-assessed objective response rate (ORR). Counts and percentages are used for categorical variables, and medians and ranges are used for continuous variables. Results Among the phase 1a (n = 24) and 1b (n = 49) dose-escalation cohorts, the median age was 60 (range, 40-77) and 54 (range, 25-81) years, respectively. More than half of patients were women (14 of 24 [58%] and 25 of 49 [51%]), and more than a third (10 [42%] and 18 [37%]) had received 4 or more prior cancer therapies. No dose-limiting toxicities occurred, and the maximum tolerated dose of tiragolumab was not reached (NR). The most frequent treatment-related adverse events (AEs) were fatigue (5 of 24 [21%]) in phase 1a and pruritus (5 of 49 [10%]) in phase 1b; the majority of AEs were grade 1 or 2. Immune-mediated AEs occurred in 4 of 24 (17%) and 29 of 49 (59%) patients during phases 1a and 1b, respectively (primarily grade 1 or 2). The RP2D of tiragolumab was 600 mg intravenously every 3 weeks, which was tested in phase 1b dose expansion. The confirmed ORR was 0% during phase 1a, with evidence of antitumor activity in 6% of patients (n = 3) during phase 1b. The safety profile of combination tiragolumab plus atezolizumab in phase 1b was similar in the dose-escalation and dose-expansion cohorts. The confirmed ORR was 46% (6 of 13) in the non–small cell lung cancer (NSCLC) cohort (median duration of response [DOR], NR) and 28% (5 of 18) in the esophageal cancer (EC) cohort (median DOR, 15.2 [95% CI, 7.0 to NR] months). Conclusions and Relevance In this nonrandomized controlled trial, tiragolumab was well tolerated with or without atezolizumab; no new safety signals were observed. Preliminary antitumor activity was demonstrated for the combination regimen in patients with cancer immunotherapy–naive metastatic NSCLC or EC. Trial Registration ClinicalTrials.gov Identifier: NCT02794571This study was sponsored by F. Hoffmann-La Roche Ltd. Medical writing support for the development of this article, under the direction of the authors, was provided by Demi Christofi, MSc, Ashfield MedComms (an Inizio company), and funded by F. Hoffmann-La Roche Ltd

Spinal cord stimulators and radiotherapy: First case report and practice guidelines

Spinal cord stimulators (SCS) are a well-recognised treatment modality in the management of a number of chronic neuropathic pain conditions, particularly failed back syndrome and radiculopathies. The implantable pulse generator (IPG) component of the SCS is designed and operates in a similar fashion to that of a cardiac pacemaker. The IPG consists of an electrical generator, lithium battery, transmitter/receiver and a minicomputer. When stimulated, it generates pulsed electrical signals which stimulate the dorsal columns of the spinal cord, thus alleviating pain. Analogous to a cardiac pacemaker, it can be potentially damaged by ionising radiation from a linear accelerator, in patients undergoing radiotherapy. Herein we report our clinical management of the first reported case of a patient requiring adjuvant breast radiotherapy who had a SCS in situ. We also provide useful practical recommendations on the management of this scenario within a radiation oncology department

Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor

CLR457; Inhibidor Pan-PI3K; Fase ICLR457; Inhibidor Pan-PI3K; Fase ICLR457; Pan-PI3K inhibitor; Phase IBackground CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110β, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities—51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.Novartis Pharmaceuticals Corporation

Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody–drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study

Antibody–drug conjugate; Dose-escalation study; Tusamitamab ravtansineConjugado anticuerpo-fármaco; Estudio de escalada de dosis; Tusamitamab ravtansinaConjugat anticossos-fàrmac; Estudi d'escalada de dosi; Tusamitamab ravtansinaTusamitamab ravtansine (SAR408701) is an antibody–drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. Patients and methods Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Results Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. Conclusions Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.This work was supported by Sanofi, France (no grant number)

Influences of a yoga intervention on the postural skills of the Italian short track speed skating team

Introduction: In preparation for a short track speed skating season, eight men and seven women were given yoga sessions during an 8-week high volume training cycle. The sessions were planned according to the postural aspects specific to short track speed skating technical requirements. Three specific goals were selected for the intervention: 1) to observe whether the practice of yoga as postural training could improve the efficiency and the athlete's repertoire along the muscular synergies solicited in the short track speed skating specific technique 2) to enhance and diversify the motor time-on-task of athletes without changing the prescription of other training stimulus and 3) to lower the risk of injury during periods with high volumes of training. Methods: A total of 36 sessions of yoga were given. Three postural tests were administered before and after the intervention with 14 angles analyzed. Non-parametric Wilcoxon test was used to compare angles' variations. Results: The 36 yoga sessions totalized 986 minutes of motor time-on-task, registering a proportion of 30% of the global motor time-on-task of the training cycle. Improvements were found in eleven of the 14 angles measured when comparing pre- and post-postural tests (P-value from 0.01 to 0.005). During the 8 weeks, excepting traumatic injuries due to short track speed skating accidents, no skaters suffered injuries linked to the high volume of training. Following the intervention, coaches noticed, following their on-ice feedbacks, an adjustment in the efficiency of the skating technique, in particular regarding hip dissociation. Conclusion: These results suggest that yoga could be inserted into out-of-season training cycles, even in a high volume training cycle. Planned with the decision training tools, it allows athletes to diversify their motor time-on-task by integrating a new functional range of generic movements with the solicitation of neuromuscular synergies related to the specificity of their sport. Keywords: conditioning, motor time-on-task, physical literacy, athletic development, decision trainin