Previous Monotherapy Research Articles

Tisotumab vedotin in head and neck squamous cell carcinoma: Updated analysis from innovaTV 207 Part C.

6012 Background: Recurrent or metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) is treated in the first-line with an immunotherapy-based approach, including in combination with platinum-based chemotherapy or as monotherapy, or platinum-based combination plus targeted therapy. Still, most pts experience disease progression, and the efficacy of subsequent line treatment options is limited. Tisotumab vedotin (TV) is an investigational antibody-drug conjugate directed to tissue factor. TV at 1.7 mg/kg IV Q2W has demonstrated encouraging antitumor activity in 2L-4L r/m HNSCC from the innovaTV 207 (NCT03485209) study. Here, we present data from the full cohort, Part C. Methods: innovaTV 207 is an open-label, global, phase 2, multicohort, multicenter study evaluating TV monotherapy or in combination for advanced solid tumors. In Part C, pts with r/m HNSCC received TV monotherapy (1.7 mg/kg IV Q2W). All pts were required to have received a platinum-based regimen, either in the r/m setting, or have persistent disease following platinum-based chemoradiation and a checkpoint inhibitor (CPI), if eligible. Primary endpoint was confirmed objective response rate (cORR) per investigator. Secondary endpoints included duration of response (DOR), time-to-response (TTR), and safety. Results: As of 6 Sept 2023, 40 pts with HNSCC were treated. 39 (97.5%) pts received prior platinum-based therapy. In the r/m setting, 25 (62.5%) pts received ≤2 prior lines of systemic therapy (median: 2; range: 1-3), 40 (100%) pts received prior CPI, 23 (57.5%) pts received prior taxane, and 27 (67.5%) pts received prior cetuximab. The most common subsites at diagnosis were oropharynx (n=16, of which 12 were p16 positive), larynx (n=10), and oral cavity (n=9). In the full cohort, cORR was 32.5% (95% CI, 18.6-49.1), with 1 complete response and 12 partial responses. Median DOR was 5.6 mo (95% CI, 3.0-NR) and median TTR was 1.4 mo. Among pts with ≤2 prior lines (n=25), cORR was 40.0% (95% CI, 21.1-61.3). In this subgroup, DOR is not yet mature (range: 1.2+ to 7.9+ mo), and among the 10 responders, 6 pts remain in response; median TTR was 1.5 mo. In the full cohort, 85.0% of pts had at least 1 treatment-related adverse event (TRAE). Grade ≥3 TRAEs occurred in 25.0% of pts, of which the most common were peripheral neuropathy events (12.5%). Adverse events of special interest were prespecified for ocular, peripheral neuropathy, and bleeding events, and occurred in 21 (52.5%), 19 (47.5%), and 15 (37.5%) pts, respectively. Updated efficacy and safety data are planned. Conclusions: TV demonstrated encouraging antitumor activity in a heavily pretreated r/m HNSCC population with a manageable safety profile consistent with previous TV monotherapy data. The study is ongoing; TV represents a promising treatment option for pts with r/m HNSCC who have progressed after prior platinum-based therapy and immunotherapy. Clinical trial information: NCT03485209 .

SYNERGIA-MOROCCO: EFFECTIVENESS OF HYPERTENSION MANAGEMENT WITH AN AMLODIPINE AND PERINDOPRIL ARGININE-BASED STRATEGY IN MOROCCO: STUDY DESIGN AND PRELIMINARY DATA

Objective: In Morocco, 1 in 3 adults currently live with hypertension; over 70%1 are not aware or not effectively treated. Among treated hypertensive patients, many receive monotherapy and remain uncontrolled. WHO recommends the addition of an angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker or a diuretic in patients who are uncontrolled on a calcium-channel blocker and a monthly follow-up after initiation until patients reach targets. However, there is limited evidence from real-world observational studies in Morocco on the effectiveness of this approach on blood pressure control. This study aims to evaluate the effectiveness of an amlodipine and perindopril arginine-based strategy for 90 days in hypertensive patients previously uncontrolled on monotherapy of amlodipine. Design and method: This is a multicenter prospective observational study. Eighty (80) primary care physicians across Morocco will recruit about 1 600 uncontrolled hypertensive adult patients who start perindopril-arginine on top of previous amlodipine monotherapy. During the study, physicians will be free to adapt treatment per their judgement, including dose adaptations, the addition of a third drug or the use of a single pill combination (SPC) as a substitute for the free combination of amlodipine/perindopril at the same dose when patients become controlled. The primary outcome will be the change in sitting office blood pressure between baseline and day 90. Secondary outcomes will include; the change in the blood pressure between baseline and the initiation of the SPC and between the initiation of the SPC and the end of the study, and the difference in the proportion of participants with side effects between the free combination and SPC. Results: The first patient was enrolled in the study on October 30, 2023. On January 10, 2024, 1 400 patients were recruited, and 760 had the 30-day follow-up visit. Conclusions: In Morocco, hypertension is a significant public health issue but current treatment optimisation strategies lack evidence from real-world data. The recruitments started as planned, and this will be the first real-world study from Morocco on the short-term effectiveness of treating hypertension with an amlodipine and perindopril arginine-based combination strategy on blood pressure control.

Niraparib, Dostarlimab, and Bevacizumab as Combination Therapy in Pretreated, Advanced Platinum-Resistant Ovarian Cancer: Findings From Cohort A of the OPAL Phase II Trial.

To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)-deficient, and 17.1% were HR repair (HRR)-mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

Maintenance Pembrolizumab Therapy in Patients with Metastatic HER2-negative Breast Cancer with Prior Response to Chemotherapy.

Accumulating toxicities hinder indefinite chemotherapy for many patients with metastatic/recurrent HER2-negative breast cancer. We conducted a phase II trial of pembrolizumab monotherapy following induction chemotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative inflammatory breast cancer (IBC) and non-IBC triple-negative breast cancer (TNBC) and a biomarker study. Patients with a complete response, partial response, or stable disease (SD) after at least three cycles of chemotherapy for HER2-negative breast cancer received pembrolizumab, regardless of programmed death-ligand 1 expression. Pembrolizumab (200 mg) was administered every 3 weeks until disease progression, intolerable toxicity, or 2 years of pembrolizumab exposure. The endpoints included the 4-month disease control rate (DCR), progression-free survival (PFS), overall survival, and response biomarkers in the blood. Of 43 treated patients, 11 had metastatic IBC and 32 non-IBC TNBC. The 4-month DCR was 58.1% [95% confidence interval (CI), 43.4-72.9]. For all patients, the median PFS was 4.8 months (95% CI, 3.0-7.1 months). The toxicity profile was similar to the previous pembrolizumab monotherapy study. Patients with high T-cell clonality at baseline had a longer PFS with pembrolizumab treatment than did those with low T-cell clonality (10.4 vs. 3.6 months, P = 0.04). Patients who achieved SD also demonstrated a significant increase in T-cell clonality during therapy compared with those who did not achieve SD (20% vs. 5.9% mean increase, respectively; P = 0.04). Pembrolizumab monotherapy achieved durable treatment responses. Patients with a high baseline T-cell clonality had prolonged disease control with pembrolizumab.

Efficacy of Osimertinib Continuation Plus Metronomic Oral Vinorelbine for EGFRmutant Advanced NSCLC Beyond Limited Progression on Osimertinib.

Treatment options for advanced non-small-cell lung cancer (NSCLC) after osimertinib failure are limited, and osimertinib continuation is recommended for selected patients. Metronomic oral vinorelbine is an effective treatment with less toxicity for advanced NSCLC. The objective of the study was to investigate the effects of osimertinib plus metronomic oral vinorelbine on epidermal growth factor receptor (EGFR)-mutant advanced NSCLC beyond limited progression on osimertinib. We have reviewed the medical records of 28 patients with EGFR-mutant advanced NSCLC who had received osimertinib continuation plus metronomic oral vinorelbine beyond limited progression on osimertinib. We also evaluated the clinicopathological characteristics of enrolled patients, as well as the efficacy and toxicity of the treatment. After a median follow-up period of 14.1 months, 57.1% (16/28) of cases showed NSCLC progression. The median progression-free survival (PFS) period under osimertinib plus metronomic oral vinorelbine was 9.4 months (95% confidence interval, 1.562-17.238 months), with a disease control rate of 89.3% and objective response rate of 17.9%. PFS did not differ between patients who had previously received osimertinib as first- (n = 16) and second-line (n = 12) therapy (median, 11.4 and 4.7 months, P = 0.391). In addition, the median PFS duration did not differ according to the efficacy (PFS2 ≥ 6 months vs. <6 months) of previous osimertinib monotherapy (median, 5.8 and 9.4 months, P = 0.677). Osimertinib continuation in conjunction with metronomic oral vinorelbine may enable overcoming TKI resistance and prolong the survival of patients with EGFR-mutant advanced NSCLC beyond limited progression on osimertinib treatment.

ACCLAIM-1 dose escalation: Determination of quaratusugene ozeplasmid and osimertinib recommended phase 2 dose (RP2D).

e15081 Background: Expression of TUSC2, a tumor suppressor gene, is decreased in 82% of patients with NSCLC. Quaratusugene ozeplasmid, which restores TUSC2 expression, consists of a plasmid containing the TUSC2 gene encapsulated in lipid nanoparticles. Preclinical work in mouse xenografts demonstrated markedly improved control of EGFR mutant tumors when quaratusugene ozeplasmid was combined with osimertinib. A previous monotherapy study led to a RP2D of 0.06 mg/kg which was also used in a study in combination with erlotinib. The present study evaluated escalating doses of quaratusugene ozeplasmid with standard osimertinib dosing. Methods: Eligible patients were NSCLC patients with EGFR mutations and progression on osimertinib. Quaratusugene ozeplasmid was administered IV every 21 days in escalating doses and osimertinib 80 mg was administered PO daily. Dexamethasone, acetaminophen, and diphenhydramine were given prior to each treatment to prevent a post-infusion inflammatory syndrome. Efficacy was evaluated at baseline and after every even cycle of treatment using RECIST 1.1 criteria. Safety was evaluated using CTCAE v5, with dose limiting toxicities (DLTs) generally defined as ≥Gr 3 adverse events (AEs). Three dose levels (0.06, 0.09, and 0.12 mg/kg) of quaratusugene ozeplasmid were planned. A standard dose escalation with 3-6 patients/dose level was used. Results: Eight patients were enrolled (2M/6F), median age 59.5 years, with 3 at 0.06 mg/kg, 4 at 0.09 mg/kg, and 1 at 0.12 mg/kg. There were no DLTs. The most common AEs in preliminary data, regardless of relationship, in ≥ 20% were, in order of frequency, myalgia, pyrexia, chills, diarrhea, headache, influenza-like illness and pain. The only Grade 3/4 AEs were lymphopenia and neutropenia in 1 patient each. There was a post-infusion syndrome of myalgia, pyrexia, and chills that started 3-4 hours after quaratusugene ozeplasmid infusion and resolved over several hours with acetaminophen and diphenhydramine therapy. One patient at the 0.06 mg/kg dose level, previously treated with carboplatin, pemetrexed, and osimertinib, had a partial remission (PR) by investigator evaluation and treatment is ongoing after 11 cycles with PR. Another patient at the 0.09 mg/kg dose level, previously treated with osimertinib, has stable disease and is continuing treatment after 9 cycles. Conclusions: There was 1 PR with quaratusugene ozeplasmid and osimertinib combination therapy in the 8 patients enrolled in the Phase 1 dose escalation, all of whom had progressed on osimertinib. Quaratusugene ozeplasmid was generally well tolerated, and was associated with a post-infusion syndrome of fever and chills managed with steroids, acetaminophen and diphenhydramine. Based on these data, the RP2D of quaratusugene ozeplasmid in combination with osimertinib in patients with NSCLC progressing after osimertinib treatment is expected to be 0.12 mg/kg. Clinical trial information: NCT04486833 .

Metastatic Castration-Resistant Prostate Cancer, Immune Checkpoint Inhibitors, and Beyond.

The therapeutic landscape of several genitourinary malignancies has been revolutionized by the development of immune checkpoint inhibitors (ICIs); however, the utility of immunotherapies in prostate cancer has been limited, partly due to the immunologically "cold" tumor terrain of prostate cancer. As of today, pembrolizumab is the only immune checkpoint inhibitor approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in a select group of patients with high microsatellite instability (MSI-H), deficient mismatch repair (dMMR), or high tumor mutational burden (TMB). Looking ahead, several combinatorial approaches with ICIs involving radioligands, radiotherapy, PARP inhibitors, interleukin inhibitors, and cancer vaccines are exploring a potential synergistic effect. Furthermore, B7-H3 is an alternative checkpoint that may hold promise in adding to the treatment landscape of mCRPC. This review aims to summarize previous monotherapy and combination therapy trials of ICIs as well as novel immunotherapy combination therapeutic strategies and treatment targets in mCRPC.

Abemaciclib in combination with pembrolizumab for HR+, HER2− metastatic breast cancer: Phase 1b study

This nonrandomized, open-label, multi-cohort Phase 1b study (NCT02779751) investigated the safety and efficacy of abemaciclib plus pembrolizumab with/without anastrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) without prior CDK4 and 6 inhibitor exposure. Patients were divided into two cohorts: treatment naïve (cohort 1) and pretreated (cohort 2). Patients received abemaciclib plus pembrolizumab with (cohort 1) or without (cohort 2) anastrozole over 21-day cycles. The primary objective was safety, and secondary objectives included efficacy and pharmacokinetics (PK). Cohort 1/2 enrolled 26/28 patients, respectively. Neutropenia (30.8/28.6%), AST increase (34.6/17.9%), ALT increase (42.3/10.7%), and diarrhea (3.8/10.7%) were the most frequent grade ≥3 adverse events in cohort 1/2, respectively. A total of two deaths occurred, which investigators attributed to treatment-related adverse events (AEs), both in cohort 1. Higher rates of all grade and grade ≥3 interstitial lung disease (ILD)/pneumonitis were observed compared to previously reported with abemaciclib and pembrolizumab monotherapy. The PK profiles were consistent between cohorts and with previous monotherapy studies. In cohorts 1/2, the overall response rate and disease control rate were 23.1/28.6% and 84.6/82.1%, respectively. Median progression-free survival and overall survivals were 8.9 (95% CI: 3.9–11.1) and 26.3 months (95% CI: 20.0–31.0) for cohort 2; cohort 1 data are immature. Abemaciclib plus pembrolizumab demonstrated antitumor activity, but high rates of ILD/pneumonitis and severe transaminase elevations occurred with/without anastrozole compared to the previous reporting. Benefit/risk analysis does not support further evaluation of this combination in the treatment of HR+, HER2− MBC.

Effectiveness and safety of tafluprost in primary open-angle glaucoma and ocular hypertension: a post-marketing phase IV study in China

BackgroundProstaglandin analogs (PGAs) are the first-line treatment for primary open-angle glaucoma (POAG) and ocular hypertension (OH). This study aimed to confirm the effectiveness and safety of Tapros® (0.0015% tafluprost eye drops) in Chinese patients with POAG and OH.MethodsThis phase IV, multicenter, non-comparative, prospective study enrolled patients with POAG and OH in China between 12/27/2017 and 04/15/2020. Patients who were treatment-naïve or untreated within one month (group A) or with unreached intraocular pressure (IOP) target after previous monotherapy of other PGAs (group B) or non-PGA IOP-lowering drugs (group C) were treated with 0.0015% tafluprost for three months. The IOP reduction, response rate, and safety were observed.ResultsThere were 165, 89, and 31 patients in groups A, B, and C, with baseline IOPs of 22.4 ± 4.7, 21.0 ± 3.5, and 22.5 ± 3.2 mmHg, respectively. The least-square means and percentages of IOP reduction at 3 months for groups A, B, and C were 4.7 (19.8%), 1.6 (6.1%), and 4.6 mmHg (20.3%), respectively. A significant reduction in IOP was observed at each visit compared with baseline (all P < 0.05). At the final visit, 57.0% of the participants in group A achieved an IOP reduction of ≥ 20%, while 40.4% and 77.4% in groups B and C achieved an IOP reduction of ≥ 10%. Fifty-eight treatment-related adverse events occurred in 46 participants (15.7%), of which the most common one was conjunctival hyperemia (34/293, 11.6%).ConclusionsTafluprost showed a sustained and significant effect with tolerable adverse events in Chinese patients with POAG and OH who were treatment-naïve or untreated within one month or received prior treatments with unsatisfying outcomes.

EFFECT OF SINGLE PILL COMBINATIONS ON CENTRAL SYSTOLIC BLOOD PRESSURE

Objective: Central systolic blood pressure (cSBP) is considered an important haemodynamic parameter, and a relevant prognostic risk factor. Data about control of cSBP with single-pill combination (SPC) treatment are lacking. Therefore we assessed the effect of perindopril/amlodipine (P/A; dual SPC arm) and perindopril/amlodipine/indapamide (P/A/I; triple SPC arm) in naïve and uncontrolled hypertensive patients on 24-hour cSBP compared to office BP. Design and method: 440 adults with essential hypertension were assessed in the 16-week interventional, open-label, prospective, international, multicentre trial PRECIOUS. ABPM was performed at the baseline and end of the trial (Mobilograph PWA). At inclusion, naïve or patients uncontrolled on previous mono or dual therapy other than P/A were assigned to dual SPC arm with initial dose of 4/5 mg P/A. Patients uncontrolled on previous dual or triple therapy were assigned to triple SPC arm with initial dose of 4/5/1.25 mg P/A/I. If not reaching office BP control, initial dose was up titrated in 4-week intervals to 8/5 mg, 8/10 mg P/A or 8/10/2.5 mg P/A/I in dual SPC arm and to 8/5/2.5 mg or 8/10/2.5 mg P/A/I in triple SPC arm. Results: In 16 weeks mean office BP decreased from 156.3 ± 10.9/98.6 ± 8 mmHg to 128.4 ± 9.4/81.7 ± 7.2 mmHg in dual SPC arm and from 157.9 ± 12.6/97.5 ± 9.5 mmHg to 127.7 ± 11.4/80.3 ± 7.5 mmHg in triple SPC arm. The average cSBP decreased from 132.1 ± 9.4 mmHg to 115.4 ± 8.9 mmHg in dual SPC and from 135.8 ± 11.1 mmHg to 114.7 ± 9.8 mmHg in triple SPC arm. All BP reductions were statistically significant (p &lt; 0.001). 77.7% of patients achieved normal office BP values in dual SPC arm and 82.5% in triple SPC arm. A reduction of cSBP below 120 mmHg was reached by 68.9% of patients in dual SPC and by 71.5% in triple SPC arm. Conclusions: In triple SPC arm, higher proportion of patients reached target office BP which was reflected also in lower cSBP compared to dual SPC arm. This is important information showing the advantageous effect of triple SPC on cSBP. Usefulness of putting cSBP as additive information, reflecting effect of SPC treatment in clinical practice, will need to be proven with longer patients’ follow up.

Phase 1/2a trial of nadunolimab, a first-in-class fully humanized monoclonal antibody against IL1RAP, in combination with cisplatin and gemcitabine (CG) in patients with non-small cell lung cancer (NSCLC).

9020 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed by cancer and stromal cells of many solid tumors. The IL-1 pathway is active in tumors and upregulated in response to chemotherapy. IL1RAP interacts with IL-1R1 and modulates downstream factors (e.g. IL-6, IL-8) and CRP level. Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α and IL-1β signaling. Here, results are reported from the phase 1/2a clinical trial CANFOUR evaluating nadunolimab combined with CG in NSCLC. Methods: Patients (pts) with unresectable, locally advanced or metastatic NSCLC, progressed on pembrolizumab or in first line for advanced disease, were eligible. Pts received 1 (n =17), 2.5 (n = 3) or 5 mg/kg (= 13) nadunolimab given Q1W in Cycle 1 and Q2W from Cycle 2, combined with standard CG. Due to risk of infusion-related reactions, a priming dose of 0.5 mg/kg nadunolimab was given one week before CG. Primary objective was safety; secondary objectives included ORR, PFS and OS, and exploratory objectives included effects on serum and tumor tissue biomarkers. Results: Thirty-three pts were enrolled: median age 64 years (39-77), 30% female, 42% ECOG 0, 55% non-squamous histology, 82% stage IV, 45% received previous pembrolizumab monotherapy. Treatment-related adverse events of grade≥3 were observed in 73% of pts, including neutropenia (58%), febrile neutropenia (9%), thrombocytopenia (30%) and anemia (18%). Neutropenia could be managed by G-CSF. Thirty pts received combination therapy and were included in the efficacy analysis. Three pts did not receive chemotherapy due to clinical deterioration (n = 2) or consent withdrawal (n = 1). ORR was 53% (95% CI 34-72%), disease control rate 80% (61-92%) and median duration of response 5.5 months (3.7-7.0) with 23% of pts still on treatment. The lower limit of the 95% CI for the observed ORR excludes the pre-specified 30%. ORR in pts with squamous histology was 46% and non-squamous 56%. Median PFS was 6.7 months (5.5-7.3) and median OS 13.7 months. The neutrophil-lymphocyte ratio was reduced throughout the trial and was driven by the reduction in circulating neutrophil numbers. IL1RAP expression on both cancer and stromal cells was confirmed in tumor biopsies. Conclusions: Nadunolimab combined with CG shows manageable safety and promising efficacy with a response rate of 53% in NSCLC pts. Nadunolimab is currently evaluated in several clinical trials investigating chemotherapy or IO combinations, including carboplatin and pemetrexed in non-squamous NSCLC. Clinical trial information: NCT03267316.

Model-informed drug development supporting the approval of the avelumab flat-dose regimen in patients with advanced renal cell carcinoma.

Avelumab is an anti–PD‐L1 monoclonal antibody approved as monotherapy for Merkel cell carcinoma (MCC) and urothelial carcinoma (UC), and in combination with axitinib for advanced renal cell carcinoma (aRCC). Although initially approved with weight‐based dosing (10 mg/kg intravenously [IV] every 2 weeks [Q2W]), avelumab was subsequently approved for flat dosing (800 mg IV Q2W) based on population pharmacokinetic (PopPK), exposure‐efficacy, and exposure‐safety modeling in MCC and UC. Here, through modeling and simulation, we provide justification for a flat‐dose regimen of avelumab plus axitinib in aRCC. Simulated exposure metrics from the previous monotherapy PopPK model (1827 patients) for both weight‐based and flat‐dose regimens were compared with exposure metrics from treatment‐naive patients with aRCC who received avelumab plus axitinib (488 patients). The aRCC population exposures were derived from a fit‐for‐purpose PopPK model developed using data from monotherapy and combination studies and the existing base structural PopPK model. Exposure‐response relationships for safety were analyzed, including grade ≥3 treatment‐emergent adverse events (TEAEs), any‐grade infusion‐related reactions, and TEAE any‐grade immune‐related adverse events (irAEs). Weight‐based dosing of avelumab in the aRCC population yielded similar PK exposures to the flat‐dose regimen reference exposures in the monotherapy population. Increased avelumab exposure was not associated with increased probabilities of grade ≥3 TEAEs or any‐grade IRRs, although there was a weak association with an increased probability of any‐grade irAEs. Overall, models in aRCC suggest that the avelumab 800‐mg Q2W flat‐dose regimen would provide similar benefits compared with weight‐based dosing with no meaningful change in the probability of AEs.

Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Long-term follow-up results from the JAVELIN Bladder 100 trial.

487 Background: The phase 3 JAVELIN Bladder 100 trial (NCT02603432) showed significantly longer overall survival (OS) with avelumab + best supportive care (BSC) vs BSC alone in patients (pts) with advanced UC that had not progressed with 1L platinum-containing chemotherapy. Avelumab 1L maintenance is now considered standard of care in treatment guidelines. We report trial data with ≥2-years follow-up in all pts (additional 19 months from the initial analysis). Methods: Pts with unresectable locally advanced or metastatic UC without disease progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin were randomized 1:1 to receive avelumab + BSC or BSC alone. The primary endpoint was OS, assessed from randomization in all pts and in pts with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included progression-free survival (PFS) and safety. Results: 700 pts were randomized (350 per arm); 358 (51.1%) had PD-L1+ tumors. With extended follow-up (median, ≥38 months in both arms for all pts; data cutoff, June 4, 2021), OS remained significantly longer in the avelumab + BSC vs BSC alone arm in all randomized pts and in pts with PD-L1+ tumors (Table). An OS benefit was observed across prespecified subgroups. PFS (by investigator) was longer with avelumab + BSC vs BSC alone in all randomized pts and in pts with PD-L1+ tumors (Table). In the avelumab + BSC and BSC alone arms, respectively, 185 (52.9%) vs 252 (72.0%) pts received a subsequent anticancer drug therapy, including a PD-(L)1 inhibitor in 40 (11.4%) vs 186 (53.1%) pts. Long-term safety was consistent with previous avelumab monotherapy studies, with no new safety signals. Conclusions: Long-term follow-up from the JAVELIN Bladder 100 trial continues to show prolonged OS with avelumab + BSC vs BSC alone. These results further support the standard-of-care role for avelumab as 1L maintenance in pts with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Clinical trial information: NCT02603432. [Table: see text]

Risk Stratification and Treatment Algorithm of Metastatic Renal Cell Carcinoma.

Systemic therapy for metastatic renal cell carcinoma has continuously evolved over the last two decades. Significant improvements in overall survival and quality of life of patients with advanced disease have been observed. With the approval of combination therapies with PD(L)-1 immune checkpoint inhibitors (ICI) as first-line therapy in 2019, the previous standard VEGFR-TKI monotherapy has been replaced as the primary treatment option. In addition to immunotherapy with nivolumab and ipilimumab, three VEGFR-TKI/ICI combinations are now approved. Therapy selection should be preceded by risk stratification using defined criteria from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Clinical parameters, as well as detailed patient counseling on differences in the efficacy profile (response rate, long-term progression-free survival), potential side effects, and impact on quality of life, are of key importance in the individual treatment decision.

Single-Arm Phase 1b/2 Trial of the PI3Kδ Inhibitor Linperlisib Combining with Gemox in Relapsed and/or Refractory Diffuse Large B Cell Lymphoma

IntroductionDiffuse large B cell lymphoma (DLBCL) is an aggressive hematological malignancy where patients rapidly progress on standard therapies. In relapsed/refractory (r/r) DLBCL, there is an urgent need for safe and effective therapies, especially being feasible to combine with other treatment regimens. The gemcitabine (GEM) oxaliplatin (OX) chemotherapy regimen is a standard treatment option with modest side effects providing an opportunity for potential combination with novel agents.The PI3Kδ selective inhibitor linperlisib is a structurally distinct oral agent previously demonstrated to be clinically efficacious with a favorable safety profile in follicular lymphoma and peripheral T cell lymphoma trials.MethodsThis Phase1b/2 trial (NCT04500561) initiated in December 2019. As of July 22, 2021, there were 39 r/r DLBCL patients (pts) enrolled at 6 clinical sites in China. All DLBCL subtypes were represented, and pts had a median of 2 prior systemic therapies, including 1 pt with prior stem cell transplant. Pts were dosed in a 21-day cycle with linperlisib 80 mg QD orally combined with 6 cycles of GEMOX (Gemcitabine 1000 mg/m 2, IV on day 1, Q3W, and Oxaliplatin 1000 mg/m 2 IV on day2, Q3W], followed by linperlisib alone until disease progression, intolerable toxicity, or withdrawal. Safety was evaluated according to NCI-CTCAE v5.0. Efficacy evaluation was conducted every 2 cycles by IWG 2007 criteria.ResultsIn this Phase 1b study of linperlisib + GEMOX in r/r DLBCL, as of July 22, 2021, there were 35 evaluable pts. Two pts discontinued from study due to SAEs occurred at C1D16 and C1D15, and 2pts discontinued from the study due to withdrawing consent at C1D8 and C2D7, there were no post baseline imaging assessment for these patients.The r/r DLBCL pts were BCL-6 (+) (80%, 28 pts), BCL-6 (-) (11.4%, 4 pts), or unknown (8.6%, 3 pts); C-MYC (+) (80%, 28 pts), C-MYC (-) (2.8%, 1 pt), or unknown (17.1%, 6 pts), indicative of aggressive lymphomas. Most pts (74%,29pts) had received R-CHOP as a first line treatment, with later lines of R-EPOCH, R-ICE, lenolinamide, CAR-T, PD-1, and other regimens, with a median of 2 lines of prior systemic therapy. The overall response rate was 60% (21/35 pts) with 5 pts achieving a Complete Response (CR, 14%) and 16 pts with Partial Response (PR, 46%)(Figure 1). In addition, 4 pts had Stable Disease (SD, 11 %), with a 71% Disease Control Rate (DCR). The median time to response was 36 days. As of the data cutoff date, the median Progression Free Survival was 193 days and the median Duration of Response was not reached, and 17 evaluable pts (48.6%) remained on study. Ten pts received linperlisib monotherapy for at least 1 cycle after completing 6 cycles of linperlisib + GEMOX combination therapy, and 2 pts were continuing linperlisib monotherapy treatment for >9 months after enrolling.Linperlisib in combination with GEMOX was well-tolerated. All 39 pts experienced at least 1 Treatment Related Adverse Event (TRAE), of which the majority were Grade 1 or 2 (83.9%). The most common TRAEs (>10% all grades) were neutropenia (72%), leukopenia (62%),thrombocytopenia (56%), anaemia (51%), lymphopenia (15%), ALT increased (41%), ASP increased(54%), hyperamylasemia (23%), hypokalaemia (21%), nausea(31%), vomiting(23%), diarrhea(33%), and anaesthesia(13%).The most frequent ≥Grade 3 TRAE (>5%) were neutropenia (46.2%), thrombocytopenia (35.9%), leukopenia (25.6%), lymphopenia (7.7%). SAEs were reported in 14 pts, including 3 thrombocytopenia, 2 diarrhea, and one case of leukopenia, neutropenia, febrile neutropenia, fever, death NOS, cachexia, pleural effusion, cancer pain, hypotension, vomiting, laryngopharyngitis, pneumonitis, lung infection or skin infection. One pt had dose reduction to 60mg/day due to AE, 2 pts discontinued treatment due to a TRAE. The AEs observed were consistent with that in previous linperlisib monotherapy trials in FL, PTCL and lymphomas.ConclusionsThe combination of linperlisib and GEMOX treatment was well tolerated with a manageable AE profile, and led to a promising ORR in a difficult-to-treat r/r DLBCL. The preliminary data suggest that linperlisib + GEMOX is a safe and active combination. A Phase2 study of linperlisib in combination with GEMOX in r/r DLBCL is currently ongoing. Further, multiple combination treatments are planned as important avenues for future development of linperlisib. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Perioperative management of platelet function and anticoagulation in geriatric patients

Geriatric patients often have cardiovascular diseases that require differentiated perioperative management of hemostasis. The operation-related bleeding risk and the individual thromboembolism risk mutually influence each other, so that adifferentiated preoperative assessment of the further prescription of coagulation-modulating medication is required. In many cases the active coagulation medication can be interrupted without replacement or continued unchanged. In cardiovascular diseases with antiplatelet medication, the preoperative risk-benefit assessment for most operations leads to the continuation of previous platelet aggregation inhibitor monotherapy; however, if there is ahigh risk of cardiovascular thromboembolism with dual platelet inhibition, the individual perioperative medication should be closely coordinated with ageriatrician or cardiologist.In most cases, the intake of vitaminK antagonists (VKA) can be preoperatively interrupted. In cases of high risk of thromboembolism, a temporary bridging with heparin must be carried out. The introduction of the four new direct oral antagonists (DOAC) has made the perioperative management of anticoagulation much easier. Bridging with heparin is not necessary. Perioperatively, only the dosage and timing of interruption of the DOACs have to be determined individually depending on the operative bleeding risk as well as the age, body weight and kidney function of the patient. If bleeding complications arise under the influence of the DOACs, antidotes are available for three of the four DOACs, which in acute cases can be used in addition to prothrombin complex concentrates and fresh frozen plasma to normalize coagulation.

Single pill combinations present a proven fast track in practice to reach the target blood pressure

Abstract Objective To assess the efficacy of ambulatory blood pressure (BP) lowering with perindopril/amlodipine (dual SPC arm) and perindopril/amlodipine/indapamide (triple SPC arm) in newly diagnosed and uncontrolled hypertensive patients. Design and method: 450 adults with essential hypertension were assessed in the interventional, open-label, prospective, international, multicentre PRECIOUS trial. Treatment duration was 16 weeks, divided into four treatment periods. ABPM was performed at the baseline and end of the study (prior to the visit 1 and 5), with a validated automated portable BP-measuring device (Mobil-O-Graph PWA) worn on the non-dominant arm for a 24-hour period, measuring BP in 20 minutes interval during the day and 30 minutes interval during the night. At inclusion, naïve or patients uncontrolled on previous mono or dual therapy (other than perindopril/amlodipine (P/A)) were assigned to dual SPC arm with initial dose of 4/5 mg P/A. Those uncontrolled on previous dual or triple therapy were assigned to triple SPC arm with initial dose of 4/5/1.25 mg perindopril/amlodipine/indapamide (P/A/I). If office BP control was not reached, the initial dose was up titrated in 4-week intervals to 8/5 mg, 8/10 mg P/A or 8/10/2.5 mg P/A/I in dual SPC arm and to 8/5/2.5 mg, or 8/10/2.5 mg P/A/I in triple SPC arm. Results After 16 weeks of treatment the decrease in average ambulatory BP was −16.1/−10.8 mmHg (from 142.8/92.6 mmHg to 125.1/80.8 mmHg) in dual SPC arm and −21.8/−13.5 mmHg (from 147.3/93.3 mmHg to 124.2/79.0 mmHg) in triple SPC arm. The relative reductions in ambulatory BP were −11.1%/−11.3% in dual and −14.5%/−14.2% in triple SPC arm. The absolute as well as relative ABPM reductions were higher for the awake-time BP. All ambulatory BP reductions were statistically significant in both arms (p&amp;lt;0.001). 71% of patients reached the normal 24h SBP levels and 45.6% the normal 24h DBP levels. At the end of the trial, the mean dose of perindopril was 6.4±2.0 mg and of amlodipine 6.5±2.3 mg in dual SPC arm. In triple SPC arm, the mean dose of perindopril was 6.66±1.89 mg, of amlodipine 6.51±2.30 mg, and of indapamide 2.08±0.59 mg. Treatment tolerability was good. 85% of patients experienced no adverse events; the recorded ones were clinically irrelevant. Conclusions Applying dual (perindopril/amlodipine) and triple (perindopril/amlodipine/indapamide) SPC treatment strategy resulted in a significant and fast BP reduction, measured by ABPM, in naïve and in patients uncontrolled on previous therapy. In even 71% of patients normal 24h SBP was reached. It seems that adding long acting diuretic in triple SPC enhanced drug efficacy even though the patients in the triple SPC arm had a more resistant hypertension. Funding Acknowledgement Type of funding sources: None.

Perampanel as only concomitant antiseizure medication in people with epilepsy (Peroc study). A real world study

the objective of this study was to assess the dose-related retention rate of Perampanel (PER), as a reliable proxy for overall tolerability and effectiveness, in adolescent and adults who received PER as a part of routine clinical care and as an adjunctive treatment to a previous monotherapy.

Efficacy and Safety of Fenofibrate-Statin Combination Therapy in Patients With Inadequately Controlled Triglyceride Levels Despite Previous Statin Monotherapy: A Multicenter, Randomized, Double-blind, Phase IV Study

PurposeResidual cardiovascular risk reduction by fenofibrate in patients with high serum triglyceride (TG) levels despite previous statin monotherapy is not well characterized. The purpose of this study was to evaluate the efficacy and safety of a combination of choline fenofibrate and statin in patients with inadequately controlled TG levels despite previous statin monotherapy. MethodsThis prospective, multicenter, randomized, double-blind study was conducted in Korea. A total of 133 patients with controlled LDL-C but elevated TG levels, already receiving statin monotherapy, were enrolled in the study, which was conducted from July 2018 to December 2019. Patients were randomly assigned to receive combination therapy with choline fenofibrate and statin or statin monotherapy in a 1:1 ratio. After 8 weeks of treatment, the lipid profiles and safety parameters of the patients in the 2 groups were compared. FindingsThe study included 127 patients (64 in the combination group and 63 in the control group) older than 19 years. After 8 weeks of therapy, mean serum TG levels significantly decreased from 269.8 to 145.5 mg/dL (P < 0.0001) in the combination therapy group, whereas no significant changes occurred in the statin monotherapy group (from 271.1 to 280.5 mg/dL). Contrarily, the mean serum HDLC levels significantly increased from 45.0 to 50.4 mg/dL (P = 0.0004) in the combination therapy group, whereas there were no significant changes in the monotherapy group (from 44.3 to 44.7 mg/dL). There were no additional serious adverse events in the combination therapy group compared with the statin monotherapy group. ImplicationsThe combination therapy using choline fenofibrate and statin was found to be effective in serum TG control and likely tolerable in patients with high TG levels despite statin monotherapy. A larger study, conducted for a longer duration, is needed to evaluate the effectiveness of this combination in reducing cardiovascular risk. ClinicalTrials.gov identifier: NCT03874260.

The Chemotherapy-Free Combination of Vemurafenib and Rituximab Produces Deep and Durable Responses in Relapsed or Refractory Hairy Cell Leukemia (HCL) Patients

BACKGROUNDPurine analogs are very effective in HCL, but up to 50% of patients relapse. We discovered the BRAF-V600E mutation as the genetic cause of HCL (Tiacci et al., NEJM 2011) and documented, in 26 relapsed/refractory patients, a high response rate (96%) after treatment with the BRAF inhibitor vemurafenib given for a median of 16 weeks (Tiacci, Park et al., NEJM 2015). Responses were achieved after a median of 8 weeks and included 35% complete remissions (CR) and 61% partial remissions (PR). In all cases, residual leukemia was present in the bone marrow and the median relapse-free survival was 9 months from the end of treatment. Since HCL expresses high levels of CD20, rituximab might target leukemic cells resistant to vemurafenib and improve the efficacy of BRAF inhibition in a chemotherapy-free manner.METHODSIn this academic, phase-2, single-arm, single-center trial (EudraCT 2014-003046-27), HCL patients refractory to, or relapsed after, purine analogs received vemurafenib (960 mg twice daily orally) for 8 weeks and concomitant rituximab (375 mg/m2 intravenously) every 2 weeks. Rituximab was also given four times every 2 weeks after the end of vemurafenib dosing. CR required normal blood counts, no splenomegaly, and no leukemic cells visible in the bone marrow biopsy and in the blood based on morphological criteria.RESULTSIn 27 months we enrolled 31 patients (median age: 59 years; range 35-81), who had undergone a median of 3 previous therapies (range 1-14). Eight of 31 cases (26%) were primary refractory to a purine analog and, among the remaining 23 patients, 48% (n=11) had received 4 or more prior treatments. Adverse reactions of vemurafenib plus rituximab were mostly of grade 1-2, did not include myelosuppression and were consistent with the known toxicities of either drug when used alone.Strikingly, CR was achieved by all 25 patients evaluable for efficacy (100%), including 2 patients with incomplete platelet recovery (82 x 109/l and 98 x 109/l, versus 100 x 109/l per protocol definition). These 25 patients, in addition to having all previously received purine analogs, had been also refractory to previous rituximab monotherapy (n=5) and/or had relapsed after a prior BRAF inhibitor (n=7, of whom 5 had obtained a short-lived PR and 2 a CR after the BRAF inhibitor). Notably, 16/23 evaluable patients (70%) obtained a CR after only 4 weeks of vemurafenib and two concomitant doses of rituximab. Minimal residual disease (MRD) by allele-specific PCR (limit of detection: 0.05% BRAF-V600E alleles) was absent in the bone marrow of 14/23 (65%) evaluable patients; in 8 of these 14 patients (57%), MRD clearing was obtained even before sequential rituximab dosing post-vemurafenib.In evaluable patients who already completed treatment (n=25), progression-free survival was 100% after a median of 14 months (range 5-27). Among the 14 MRD-negative cases, 10 underwent follow-up bone marrow evaluations and 9 of them (90%) maintain the MRD-negativity after a median of 14.5 months (range 3-18.5); in the remaining patient, MRD reappeared 12.5 months later. Updated results on all patients (n=31) will be presented.CONCLUSIONSVemurafenib plus rituximab represents a short, safe and non-myelotoxic regimen that produces deep and durable responses in heavily pre-treated relapsed/refractory HCL patients, and is clearly superior to historical results obtained with vemurafenib or rituximab alone. Testing this regimen in the frontline setting is warranted, and should be carried out in a randomized clinical trial against the chemotherapy-based standard of care. DisclosuresTiacci:Roche: Research Funding. Zaja:Novartis: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria; Janssem: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Celgene: Honoraria, Research Funding. Zinzani:Celgene, Roche, Janssen, Gilead, Takeda, BMS, MSD, Servier, Sandoz, Mundipharma: Honoraria; Celgene, Janssen, Gilead, Roche, Takeda, BMS, MSD, Sandoz, Servier, Mundipharma: Speakers Bureau; Merck: Consultancy, Other: Advisory board. Gaidano:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Foà:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Falini:Roche: Research Funding.