Effect of Trastuzumab Deruxtecan on QT/QTc Interval and Pharmacokinetics in HER2-Positive or HER2-Low Metastatic/Unresectable Breast Cancer.

HER2-targeted anticancer therapies may be associated with cardiovascular adverse events. This study evaluated effects of the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd, DS-8201a) on QT/QTc interval and its pharmacokinetics. Patients with heavily pretreated, metastatic HER2-expressing breast cancer were enrolled at seven study sites in Japan. T-DXd was administered intravenously at 6.4 mg/kg on day 1 of each 21-day cycle. Primary end points were baseline-adjusted QTcF interval and pharmacokinetics parameters. Key secondary end points included safety events, serum concentration of T-DXd and DXd at the time of electrocardiographic measurements, and antitumor activity parameters. Among 51 total patients, 47 (92.2%) had HER2-low breast cancer (immunohistochemistry 1+ or 2+ and in situ hybridization-negative/equivocal/missing). Pharmacokinetic parameters after a single dose of T-DXd were consistent with previous studies. After multiple doses, T-DXd showed moderate accumulation (accumulation ratio (cycle 3/cycle 1), 1.35), but DXd showed minimal accumulation (1.09). The upper bound of the 90% confidence interval for mean ΔQTcF interval was < 10 ms at all timepoints, and at mean maximum serum concentration was also < 10 ms. Based on concentration-QT analysis, ΔQTcF increased with increasing concentrations of T-DXd and DXd. No clinically meaningful QTcF prolongation was observed. T-DXd had a manageable safety profile and showed antitumor activity in HER2-low breast cancer. In this study, a T-DXd dose of 6.4 mg/kg, higher than the 5.4-mg/kg dose currently approved for breast cancer, was not associated with clinically relevant QTcF prolongation in heavily pretreated patients with HER2-expressing metastatic breast cancer. This study adds to our understanding of T-DXd for treatment of HER2-low breast cancer.

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study.

PURPOSE: Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-) breast cancer (ClinicalTrials.gov identifier: NCT02564900) are reported. PATIENTS AND METHODS: Eligible patients had advanced/metastatic HER2-low-expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS: Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd-induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION: The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study.

BACKGROUND: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive gastric or gastro-oesophageal junction cancer who received trastuzumab deruxtecan at the recommended doses for expansion. METHODS: This was an open-label, dose-escalation and dose-expansion phase 1 trial done at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years old in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive gastric or gastro-oesophageal junction cancer with previous trastuzumab treatment who received trastuzumab deruxtecan were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with gastric or gastro-oesophageal junction cancer has completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978. FINDINGS: Between Aug 28, 2015, and Aug 10, 2018, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. The most frequent grade 3 or worse treatment-emergent adverse events included anaemia (13 [30%]) and decreases in neutrophil (nine [20%]), platelet (eight [18%]), and white blood cell (seven [16%]) counts. Serious treatment-emergent adverse events occurred in 11 (25%) patients. There were four pneumonitis cases (three grade 2 and one grade 3). There were no drug-related deaths due to treatment-emergent adverse events. 19 (43·2%; 95% CI 28·3-59·0) of 44 patients had a confirmed objective response. INTERPRETATION: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in heavily pretreated patients with HER2-positive gastric or gastro-oesophageal junction cancer. These results support further investigation of trastuzumab deruxtecan for HER2-positive gastric or gastro-oesophageal junction cancer post-trastuzumab. FUNDING: Daiichi Sankyo Co, Ltd.

Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.

BACKGROUND: Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours. METHODS: This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900. FINDINGS: Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events-febrile neutropenia, intestinal perforation, and cholangitis-were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater. INTERPRETATION: The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg. FUNDING: Daiichi Sankyo Co, Ltd.

Radiosynthesis and evaluation of 11C-labeled diaryl-substituted imidazole and indole derivatives for mapping cyclooxygenase-2.

11C-labeled analogs of 4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole ([11C]1), 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide ([11C]2) and 2-(4-aminosulfonylphenyl)-3-(4-methoxyphenyl)indole ([11C]3), which have been shown to have excellent potency and high selectivity for cyclooxygenase isoform 2 (COX-2) inhibiting activity, were prepared and evaluated in rats as potential radiopharmaceuticals for imaging the COX-2 enzyme by positron emission tomography. These 11C-labeled COX-2 inhibitors were synthesized in high radiochemical yields by O-[11C]methylation of phenolic precursors with [11C]methyl triflate in acetone containing NaOH as a base. In vivo evaluation in rats bearing AH109A hepatoma showed no specific binding of any tracer to COX-2 in any tissue such as the brain, heart, lung, kidney, and AH109A hepatoma. In ex vivo autoradiography, [11C]1 showed regionally different distribution in the brain, while [11C]2 and [11C]3 were not substantially taken up by the brain. In in vitro monolayer efflux assays, compound 3 was found to be a substrate for the P-glycoprotein (P-gp) efflux pump, but pretreatment of rats with the potent P-gp inhibitor, cyclosporine A, did not have any significant influence on the cerebral uptake of [11C]3. These results indicate that all three tracers were not suitable for in vivo imaging of COX-2. There seem to be some obstacles to finding a useful candidate for in vivo imaging application of COX-2 selective inhibitors only by standard consideration of in vitro affinity and selectivity, and the lipophilicity of the compound.

Radiosynthesis and in vivo evaluation of 11C-labeled 1,5-diarylpyrazole derivatives for mapping cyclooxygenases.

We prepared 11C-labeled 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole ([11C]1) and 4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide ([11C]2) for imaging COX-1 and COX-2 isoforms, respectively, by positron emission tomography. [11C]1 and [11C]2 were synthesized in high radiochemical yields by O-[11C]methylation with [11C]methyl triflate in acetone containing an equivalent of NaOH as a base with respect to the phenolic precursors. In vivo evaluation in rats bearing AH109A hepatoma demonstrated minimal specific binding of [11C] to COX-1 in peripheral organs, such as the spleen and small intestine. Carrier-saturable uptake of [11C]2 was found in the spleen, but COX-2-specific binding of [11C]2 was not identifiable in the brain, AH109A hepatoma or other peripheral organs, although ex vivo autoradiography showed regionally different distribution in the brain and AH109A. The results suggest that neither [11C]1 nor [11C]2 is a suitable radioligand for in vivo biomarkers of COX enzymes, mainly because of marked non-specific binding.