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Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial (NCT03147040), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml–1 min–1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials.

Treatment options for advanced vulvar cancer are limited. We evaluated pembrolizumab monotherapy in patients with advanced vulvar squamous cell carcinoma (SCC) enrolled in the phase 2 multicohort, open-label KEYNOTE-158 study (NCT02628067).Eligible patients had histologically or cytologically documented advanced vulvar SCC with prior treatment failure, measurable disease per RECIST v1.1, ECOG performance status 0-1, and a tumor sample available for biomarker analysis. Pembrolizumab 200 mg was administered intravenously Q3W for up to 35 cycles (approximately 2 years). The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central radiologic review in all patients and subgroups based on PD-L1 combined positive score (≥1 [PD-L1-positive] versus1 [PD-L1-negative]).101 patients were enrolled. Median time from first dose to data cutoff was 36.0 months. The ORR (95% CI) was 10.9% (5.6%-18.7%) among all patients, 9.5% (4.2%-17.9%) among the 84 patients with PD-L1-positive tumors, and 28.6% (3.7%-71.0%) among the 7 patients with PD-L1-negative tumors. Among patients with a response, median DOR was 20.4 (range, 2.1+ to 28.0) months. Median (95% CI) PFS and OS were 2.1 (2.0-2.1) and 6.2 (4.9-9.4) months, respectively. Treatment-related AEs occurred in 50.5% of patients (grade 3-5, 11.9%) and led to discontinuation of treatment in 5.0% of patients. Two deaths were considered treatment-related (hepatitis, n = 2).Pembrolizumab monotherapy was associated with durable responses in a subset of patients with vulvar SCC. Responses occurred regardless of tumor PD-L1 status. No new safety signals emerged; overall, pembrolizumab was well tolerated.

Palbociclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 used in the treatment of locally advanced and metastatic breast cancer, and is extensively metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). A pharmacokinetic/pharmacodynamic relationship between palbociclib exposure and neutropenia is well known. This study aimed to investigate the effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib. We performed a randomized crossover trial comparing the pharmacokinetics of palbociclib monotherapy 125 mg once daily (q.d.) with palbociclib 125 mg q.d. plus oral erythromycin 500 mg three times daily for seven days. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Eleven evaluable patients have been enrolled. For palbociclib monotherapy, geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0–24h), maximum plasma concentration (Cmax), and minimum plasma concentration (Cmin) were 1.46 × 103 ng•h/mL (coefficient of variation (CV) 45.0%), 80.5 ng/mL (CV 48.5%), and 48.4 ng/mL (CV 38.8%), respectively, compared with 2.09 × 103 ng•h/mL (CV 49.3%, P = 0.000977), 115 ng/mL (CV 53.7%, P = 0.00562), and 70.7 ng/mL (CV 47.5%, P = 0.000488) when palbociclib was administered concomitantly with erythromycin. Geometric mean ratios (90% confidence intervals) of AUC0–24h, Cmax, and Cmin for palbociclib plus erythromycin vs. palbociclib monotherapy were 1.43 (1.24–1.66), 1.43 (1.20–1.69), and 1.46 (1.30–1.63). Minor differences in adverse events were observed, and only one grade ≥ 3 toxicity was observed in this short period of time. To conclude, concomitant intake of palbociclib with the moderate CYP3A4 inhibitor erythromycin resulted in an increase in palbociclib AUC0–24h and Cmax of both 43%. Therefore, a dose reduction of palbociclib to 75 mg q.d. is rational, when palbociclib and moderate CYP3A4 inhibitors are used concomitantly.

Palbociclib, ribociclib, and abemaciclib are inhibitors of the cyclin-dependent kinases 4 and 6 approved for the treatment of locally advanced or metastatic breast cancer. In this review, we provide an overview of the available clinical pharmacokinetic and pharmacodynamic characteristics of these novel drugs, summarize the results of food-effect and drug-drug interaction studies, and highlight exposure-response and exposure-toxicity relationships. All three drugs exhibit a large inter-individual variability in exposure (coefficient of variation range 40-95% for minimum plasma concentration), are extensively metabolized by cytochrome P450 3A4, and have their brain penetration limited by efflux transporters. Abemaciclib has three active metabolites with similar potency that are clinically relevant (i.e., M2, M20, M18), whereas the metabolites of palbociclib and ribociclib are not of clinical significance. Pharmacokinetic exposure increases in a dose-proportional manner for palbociclib, whereas exposure increases under- and over-proportionally with an increasing dose for abemaciclib and ribociclib, respectively. High exposure is associated with an increased risk of neutropenia, and for ribociclib also to corrected QT prolongation. For abemaciclib, a clear exposure-efficacy relationship has been described, while for palbociclib and ribociclib exposure-response analyses remain inconclusive. Future studies are needed to address exposure-efficacy relationships to further improve dosing.

Background: Outcomes in advanced anal squamous cell carcinoma are poor, with few treatment options and controlled clinical trials. We evaluated the efficacy and safety of pembrolizumab in patients with advanced anal squamous cell carcinoma (cohort A) from the phase 2 KEYNOTE-158 study. Methods: Eligible patients enrolled in the ongoing non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study, which was done across 38 centres worldwide, were aged 18 years or older; had histologically or cytologically confirmed advanced or metastatic anal squamous cell carcinoma; had previous failure of or intolerance to standard therapy or no standard therapy options; and had a PD-L1-evaluable tissue sample. Patients received pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or until disease progression, unacceptable toxicity, investigator's decision to withdraw the patient from the study, or withdrawal of patient consent. The primary endpoint was objective response, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy and safety analyses included all patients who received at least one dose of pembrolizumab. The trial is registered with ClinicalTrials.gov, NCT02628067. Findings: Between March 3, 2016, and July 23, 2018, 163 patients were screened, of whom 112 were enrolled and treated in the anal cancer cohort. 91 (81%) patients were female, 104 (93%) had M1 disease, and 75 (67%) had PD-L1-positive tumours. The median time from first dose to data cutoff (June 27, 2019) was 34·7 months (IQR 32·5–36·4). 12 (11%, 95% CI 6–18) patients had an objective response, including 11 (15%, 8–25) of 75 patients with PD-L1-positive tumours and one (3%; 0–17) of 30 patients with PD-L1-negative tumours. 68 (61%) patients had treatment-related adverse events (20 [18%] patients had grade 3–4 adverse events), the most common of which were fatigue (17 patients), diarrhoea (13), hypothyroidism (13), and nausea (13). Serious treatment-related adverse events occurred in 12 (11%) patients. 25 (22%) patients had immune-mediated adverse events, and one (1%) had an infusion reaction. There were no treatment-related deaths. Interpretation: Pembrolizumab monotherapy is a possible treatment option with a favourable benefit–risk ratio for patients with previously treated advanced anal squamous cell carcinoma who have no alternative satisfactory treatment options. Funding: Merck Sharp & Dohme.

A model for the homeostasis of glucose through the regulating hormones glucagon and insulin is described. It contains a subsystem that models the internalization of the glucagon receptor. Internalization is a mechanism in cell signaling, through which G-protein coupled receptors are taken from the surface of the cell to the endosome. The model is used to interpret data from a glucagon challenge test in which subjects have been under treatment with a novel glucagon receptor anti-sense drug which is aimed at reducing the number of receptors in the liver. It is shown how the receptor internalization results in tolerance of the blood glucose concentration to glucagon-induced hyperglycemia. We quantify the reduction of the number of receptors using the model and the data before and after treatment. Electronic supplementary material The online version of this article (doi:10.1007/s10928-019-09655-2) contains supplementary material, which is available to authorized users.

Objectives: Advanced vulvar carcinoma typically affects the elderly and treatment options are limited. Moderate antitumor activity of pembrolizumab (ORR, 6%) was noted in a small population of patients (pts) with PD-L1-positive vulvar cancer in the phase 1b KEYNOTE-028 study. KEYNOTE-158 ( ClinicalTrials.gov , NCT02628067) is a larger, nonrandomized, multicohort, open-label, phase 2 study that evaluates pembrolizumab in pts with previously treated advanced cancers irrespective of tumor PD-L1 expression. We report results for pts in the vulvar carcinoma cohort receiving pembrolizumab monotherapy. Methods: Enrolled pts were aged ≥18 y with histologically/cytologically documented advanced vulvar squamous cell carcinoma with prior treatment failure; measurable disease per RECIST v1.1; ECOG performance status ≤1; and tumor samples available for biomarker analysis, including PD-L1. PD-L1 positivity was defined as combined positive score ≥1 with expression evaluated using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA). Pts received pembrolizumab 200 mg Q3W until disease progression, unacceptable toxicity, or completion of 35 treatment cycles. Tumor imaging was performed every 9 weeks for 1 y and every 12 weeks thereafter. Response was assessed per RECIST v1.1 by independent central radiologic review. The primary endpoint was ORR. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. Results: A total of 101 pts were enrolled. As of October 5, 2020, median time from start of treatment to data cutoff was 36.0 (range, 15.4–55.2) months. Median age was 64.0 (range, 31–87) y; 9 (8.9%) pts had no prior therapy, 57 (56.4%) had 1, 23 (22.8%) had 2, and 11 (10.9%) had 3 or more lines of prior therapy. Tumors were PD-L1–positive in 84 pts (83.2%), PD-L1–negative in 7 pts (6.9%), and non-evaluable/not assessed in 10 pts (9.9%). Overall, ORR was 10.9% (95% CI, 5.6–18.7); 1 pt had a CR and 10 pts had PR. Among pts with PD-L1–positive tumors, 8 of 84 (9.5%; 95% CI, 4.2–17.9) had CR or PR; among pts with PD-L1–negative tumors, 2 of 7 (28.6%; 95% CI, 3.7–71.0) had CR or PR. Among pts with a response, median DOR was 20.4 months (range, 2.1+ to 28.0). Among all enrolled pts (n=101), median PFS was 2.1 months (95% CI, 2.0–2.1) and median OS was 6.2 months (95% CI, 4.9–9.4 months). Treatment-related AEs occurred in 51 pts (50.5%), including 12 pts (11.9%) who had grade 3–5 events (no event occurred in >1 pt). There were 2 deaths (2.0%) considered related to treatment (hepatitis, n=1; fulminant hepatitis, n=1). Neither pt had comorbidities or pre-existing liver disease to contribute to these events; no other contributing factors were identified. A total of 5 pts (5.0%) discontinued because of treatment-related AEs. Immune-mediated AEs occurred in 18 pts (17.8%). Conclusions: Pembrolizumab monotherapy was associated with durable responses in a subset of pts with vulvar carcinoma (ORR, 10.9%; median DOR, 20.4 months). Responses occurred in both PD-L1-positive and PD-L1-negative pts.

ISIS 388626 is an antisense sodium-glucose cotransporter 2 (SGLT2) inhibitor designed to treat type 2 diabetes mellitus by induction of glucosuria. ISIS 388626 was demonstrated to be safe and effective in preclinical trails in several species. We undertook the present study to evaluate the safety and efficacy of 13 weekly doses of 50, 100, and 200 mg of ISIS 388626 in humans. ISIS 388626 increased 24-hour urinary glucose excretion dose dependently with 508.9 ± 781.45 mg/day in the 100-mg and 1299.8 ± 1833.4 mg/day in the 200-mg cohort, versus 88.7 ± 259.29 mg/day in the placebo group. ISIS 388626 induced a reversible increase in serum creatinine, with the largest effect after eight doses of ISIS 388626 (200 mg; 0.38 ± 0.089 mg/dl; 44% increase over baseline). Three subjects were discontinued as a result of creatinine increases. The renal clearance test revealed no indications for impairment of glomerular filtration or renal perfusion. The creatinine increases were accompanied by a rise in the levels of urinary renal damage markers [β-2-microglobulin (B2M), total protein, kidney injury molecule (KIM1), α-glutathione S-transferase (aGST), N-acetyl-β-(d)-glucosaminidase (NAG)]. Other treatment-related adverse events included mild injection site reactions occurring in 8-19% of the subjects. In conclusion, ISIS 388626 treatment induced glucosuria at a dose level of 200 mg/week. This intended pharmacological effect was small, amounting to approximately 1% of the total amount of filtered glucose. Changes in serum and urinary markers were indicative of transient renal dysfunction, most probably of tubular origin. Whether the glucosuria is caused by specific SGLT2 inhibition or general tubular dysfunction or a combination remains uncertain.

4020 Background: Patients (pts) with anal squamous cell carcinoma (ASCC) have poor outcomes and few treatment options. We report a pooled analysis of pembrolizumab (pembro) antitumor activity and safety in the ASCC cohorts of the multicohort studies KEYNOTE-028 (NCT02054806; phase 1b) and KEYNOTE-158 (NCT02628067; phase 2), providing a robust sample size and longer follow-up. Methods: Eligible pts were aged ≥18 y with histologically/cytologically confirmed metastatic/unresectable ASCC, had prior failure of/intolerance to standard therapy or no standard therapy options, measurable disease (RECIST v1.1), ECOG PS 0/1, and a tissue sample evaluable for PD-L1/biomarkers (KEYNOTE-028 required PD-L1 positivity). Baseline PD-L1 expression was assessed using a prototype IHC assay (QualTek) in KEYNOTE-028 and the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies) in KEYNOTE-158. Pts received pembro 10 mg/kg Q2W (KEYNOTE-028) or 200 mg Q3W (KEYNOTE-158) for 2 y or until PD/unacceptable AEs. The primary endpoint in both studies was ORR (per RECIST v1.1). Secondary endpoints were duration of response (DOR), PFS, OS, and safety. Results: 137 pts with ASCC were treated in KEYNOTE-028 (n = 25) or KEYNOTE-158 (n = 112) and were included in this analysis (median age, 61 y; 83.2% women; 73.0% had PD-L1–positive tumors). Median follow-up was 11.7 mo; 124 pts (90.5%) had discontinued treatment. ORR (95% CI) was 10.9% (6.3%–17.4%). 8 pts had CR and 7 had PR. ORR (95% CI) by PD-L1 status was 14.0% (7.9%–22.4%) in the PD-L1 positive group and 3.3% (0.1%–17.2%) in the PD-L1 negative group. Among all treated pts, median DOR was not reached (range, 6.0+ to 57.5+ mo). By Kaplan-Meier estimation, 84.6% of responders had a DOR ≥24 mo. Median PFS was 2.1 mo (95% CI, 2.0–2.1) and median OS was 11.7 mo (95% CI, 8.8–14.5). The 12-mo PFS and OS rates were 14.5% and 47.4%. 85 pts (62.0%) had +1 treatment-related AE, 24 pts (17.5%) with grade 3–4 events (no grade 5 events). 32 pts (23.4%) had immune-mediated AEs; 2 pts (1.5%) had infusion related reactions. Conclusions: In pts with previously treated advanced ASCC, pembro showed durable antitumor activity, particularly in pts with PD-L1–positive tumors, and manageable toxicity. Clinical trial information: NCT02054806 (KEYNOTE-028), NCT02628067 (KEYNOTE-158) .

The antisense compound ISIS 388626 selectively inhibits renal glucose reabsorption by inhibiting the sodium–glucose cotransporter‐2 (SGLT2) mRNA expression. It is developed as an insulin‐independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics after subcutaneous administration of the drug were planned to be evaluated in healthy volunteers in a single‐ascending‐dose study (50–400 mg) and a multiple‐ascending‐dose study (6 weeks; weekly doses of 50–400 mg with loading dose regimen of three doses during the first week). The study was halted early because increases in serum creatinine occurred in the subjects participating in the 100 mg multiple‐dose cohort. The pronounced changes in serum creatinine were accompanied by increased urinary excretion of beta‐2‐microglobulin and KIM1. The possible mechanisms for these findings remain elusive and are in contrast to preclinical findings as comparable treatment with ISIS 388626 of animals did not reveal similar changes. Although exposure was limited, there was an indication that glucosuria increased upon active treatment. Before the concept of antisense‐mediated blocking of SGLT2 with ISIS 388626 can be explored further, more preclinical data are needed to justify further investigations.

Lifestyle modifications, including diet, are important in the prevention and management of type 2 diabetes mellitus (T2DM). However, limited information is available on the effects of single doses of meal replacements, particularly with regard to their effect on postprandial glucose. Therefore, a study was performed comparing the effects of a single meal replacement in T2DM patients on postprandial serum glucose, insulin, and glucagon. This randomized, double-blind, partial cross-over study was performed in 36 T2DM patients who continued their oral anti-diabetic medication. Each patient received three out of four treatments separated by 7 days. The treatments were a proprietary casein hydrolysate (insuVida™) alone or with additional leucine, unhydrolyzed casein, or placebo. Blood sampling was done for 4 hr. Treatments were compared using repeated measures ANOVA. Results are given as an estimate of the difference (%) for the 4-hr epoch. Glucose concentrations were lowered by -4.7% by insuVida and insuVida plus added leucine compared to placebo (95% CI: -1.6 to -7.7%), while the effect of unhydrolyzed casein was -1.7% (-4.8 to 1.5%). Addition of leucine to insuVida induced the greatest increase in insulin (i.e., 51.8%; 41.1 to 63.4%). All three treatments increased glucagon concentrations by 14% (8 to 20%) compared to placebo. A single dose of insuVida™ with or without addition of leucine significantly lowered plasma glucose compared to placebo and intact casein in T2DM patients. This is most likely due to an insulinotropic effect of insuVida. The data suggest that this type of intervention may be a viable treatment strategy in T2DM.