Combination Therapy Arm Research Articles

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III NSCLC (TRAILBLAZER): Efficacy, safety and feasibility of surgical conversion outcomes from a proof-of-concept, phase 2 trial.

8082 Background: Consolidation immunotherapy after chemoradiation is the standard of care for unresectable stage III NSCLC. Addition of immunotherapy-based induction treatment may further improve outcome, partly by enabling surgery. We conducted a proof-of-concept, phase 2 trial to assess neoadjuvant SHR-1701 (an anti-PD-L1/TGF-β bifunctional fusion protein) with or without chemotherapy, followed by surgery or radiotherapy in unresectable stage III NSCLC and without EGFR/ ALK alterations. Methods: Patients with MDT-assessed surgically unresectable disease were given 3 cycles of neoadjuvant SHR-1701 (30 mg/kg Q3W) with or without chemotherapy (paclitaxel 175 mg/m2 Q3W + carboplatin AUC = 5 Q3W).Patients with PD-L1 TPS &lt; 50% received combination therapy (arm A) and those with PD-L1 TPS ≥50% were randomized (1:1) to receive combination therapy (arm B) or SHR-1701 alone (arm C). After reassessment by MDT, patients received either surgery or definitive radiotherapy (60 Gy/30 fractions) plus concurrent cisplatin (30 mg/m2 QW), all followed by consolidation SHR-1701 for 16 cycles. The primary endpoints were post-induction objective response rate (ORR) and 18-month event-free survival (EFS) rate. Arm A+B (patients receiving neoadjuvant chemoimmunotherapy) was the primary analysis cohort. Results: Between Nov. 20, 2020 and Jan. 27, 2022, 107 patients were enrolled (arm A/B/C, n = 88/9/10). Median follow-up was 22.2 months. In arm A+B, both primary endpoints were met, with a post-induction ORR of 58% (95% CI 47-68) and an 18-month EFS rate of 56.6% (95% CI 45.2-66.5). In arm C, the post-induction ORR was 40% (95% CI 12-74) and 18-month EFS rate was 77.1% (95% CI 34.5-93.9). 24-month overall survival rate was 78.3% (95% CI 68.0-85.7) in arm A+B and 100% in arm C. Overall, 27 (25% of 107; arm A+B/C, n = 24/3) patients underwent surgery; all achieved R0 resection. Among them, 12 (44%) MPR and seven (26%) pCR were recorded. The 18-month EFS rate was 74.1% (95% CI 53.2-86.7) in resected patients and 57.3% (43.0-69.3) in those receiving radiotherapy. Across arms, all grade ≥3 TRAEs with frequency ≥10% were hematological toxicities. No new safety signals were identified. Conclusions: NeoadjuvantSHR-1701 with chemotherapy, followed by surgery or radiotherapy, showed promising anti-tumor activity with a tolerable safety profile in unresectable stage III NSCLC. We provided first evidence that surgical conversion was feasible in a notable proportion of patients, and was associated with better survival outcomes. Clinical trial information: NCT04580498 .

A phase 1 dose-escalation and expansion study of an intratumorally administered dual STING agonist (ONM-501) alone and in combination with cemiplimab in patients with advanced solid tumors and lymphomas.

TPS2693 Background: The Stimulator of Interferon Genes (STING) pathway has garnered significant interest as a target for anticancer interventions due to its role in driving the production of pro-inflammatory cytokines and activating tumor-specific cell killing. Cyclic dinucleotides (CDNs) such as cGAMP, the endogenous STING agonist, are not ideal clinical candidates for exogenous routes of delivery. Early trials showed limited efficacy with CDNs due to rapid clearance, degradation and/or off-target toxicity. ONM-501 is comprised of a STING-activating pH-sensitive PC7A polymer conjugated with cGAMP. At physiologic pH, ONM-501 forms a micelle, preventing degradation of cGAMP. In the acidic tumor microenvironment, ONM-501 effects STING agonism through a multi-faceted mode of action: 1) endocytosis of nanoparticles and pH-activated micelle dissociation and payload release in endolysosomes enhances intracellular delivery of cGAMP 2) the combination of cGAMP canonical binding, and PC7A polymer noncanonical binding on STING yields synergistic STING activation and 3) stabilization of STING by PC7A polymers delays its degradation and prolongs STING activation. In pre-clinical models, these factors combine to help generate a stronger and more prolonged innate immune response that more effectively translates to a robust adaptive immune response. ONM-501 is being investigated in this first-in-human Phase 1 trial as monotherapy and combination therapy with the anti-PD1 antibody, cemiplimab, for patients with solid tumors and lymphomas. Methods: ONM5001 (NCT06022029) is a first-in-human, open-label, multi-center clinical trial. Adult patients with solid tumors or lymphomas for which no standard therapy exists or for which patients decline palliative standard therapy who have at least one injectable lesion are eligible for this study. This Phase 1 study consists of three parts: monotherapy dose escalation; combination therapy dose finding; and combination therapy dose expansion in specific tumor indication(s) that will be selected based on data from mono- and combination therapy dose finding. Each dosing cycle of ONM-501 is 21 days: patients receive an intratumoral injection of ONM-501 weekly for three weeks, followed by three weeks without injection. Cemiplimab is administered intravenously during combination therapy arms according to standard administration protocol, once every three weeks. The primary endpoint is to evaluate safety of ONM-501 monotherapy as evidenced by the number of dose limiting toxicities and treatment-emergent adverse events, and to determine the recommended dose for expansion. Secondary endpoints include characterization of pharmacokinetics and pharmacodynamics, as well as initial efficacy based on RECIST evaluation criteria. Enrollment began in November 2023. Clinical trial information: NCT06022029 .

The therapeutic effect of radiotherapy combined with systemic therapy compared to radiotherapy alone in patients with simple brain metastasis after first-line treatment of limited-stage small cell lung cancer: a retrospective study

PurposeWe aimed to compare the therapeutic effect of radiotherapy (RT) plus systemic therapy (ST) with RT alone in patients with simple brain metastasis (BM) after first-line treatment of limited-stage small cell lung cancer (LS-SCLC).MethodsThe patients were treated at a single center from January 2011 to January 2022. BM only without metastases to other organs was defined as simple BM. The eligible patients were divided into RT alone (monotherapy arm) and RT plus ST (combined therapy arm). Univariate and multivariate Cox proportional hazards analyses were used to examine factors associated with increased risk of extracranial progression. After 1:1 propensity score matching analysis, two groups were compared for extracranial progression-free survival (ePFS), PFS, overall survival (OS), and intracranial PFS (iPFS).Results133 patients were identified and 100 were analyzed (monotherapy arm: n = 50, combined therapy arm: n = 50). The ePFS of the combined therapy was significantly longer than that of the monotherapy, with a median ePFS of 13.2 months (95% CI, 6.6–19.8) in combined therapy and 8.2 months (95% CI, 5.7–10.7) in monotherapy (P = 0.04). There were no statistically significant differences in PFS (P = 0.057), OS (P = 0.309), or iPFS (P = 0.448). Multifactorial analysis showed that combined therapy was independently associated with better ePFS compared with monotherapy (HR = 0.617, P = 0.034); more than 5 BMs were associated with worse ePFS compared with 1–5 BMs (HR = 1.808, P = 0.012).ConclusionsCompared with RT alone, combined therapy improves ePFS in patients with simple BM after first-line treatment of LS-SCLC. Combined therapy and 1–5 BMs reduce the risk of extracranial recurrence.

Novel β-lactam-β-lactamase inhibitors as monotherapy versus combination for the treatment of drug-resistant Pseudomonas aeruginosa infections: A multicenter cohort study

BackgroundData comparing the clinical outcomes of novel β-lactam-β-lactamase inhibitors given in combination versus monotherapy for the treatment of multidrug-resistant (MDR) P. aeruginosa infections are lacking. MethodThis retrospective cohort study included patients who received novel β-lactam–β-lactamase inhibitors as monotherapy or in combination for the treatment of MDR P. aeruginosa infections. The study was conducted between 2017 and 2022 in 6 tertiary care hospitals in Saudi Arabia. Overall in-hospital mortality, 30-day mortality, clinical cure, and acute kidney injury (AKI) were compared between recipients of monotherapy versus combination using multivariate logistic regression analysis. Result118 patients and 82 patients were included in monotherapy and combination therapy arms, respectively. The cohort represented an ill population with 56% in the intensive care unit and 37% in septic shock. A total of 19% of patients presented with bacteremia. Compared to monotherapy, combination therapy did not significantly differ in clinical cure (57% vs. 68%; P = 0.313; OR, 0.63; 95% CI, 0.36–1.14) in-hospital mortality (45% vs. 37%; P = 0.267; OR, 1.38; 95% CI, 0.78–2.45), or 30-day mortality (27% vs. 24%; P = 0.619; OR, 1.18; 95% CI, 0.62–1.25). However, AKI (32% vs. 12%; P = 0.0006; OR, 3.45; 95% CI, 1.67–7.13) was significantly more common in patients who received combination therapy. ConclusionNovel β-lactam–β-lactamase inhibitors when used in combination with other antibiotics did not add clinical benefit compared to their use as monotherapy in the treatment of MDR P. aeruginosa infections. A Combination regimen was associated with an increased risk of nephrotoxicity.

Effect of extended treatment with IAP inhibitor xevinapant post radiotherapy (RT) on efficacy and the tumor microenvironment (TME) in preclinical models.

6027 Background: Xevinapant is a first-in-class, oral IAP (inhibitor of apoptosis protein) inhibitor designed to restore cancer cell sensitivity to apoptosis, induced by RT and chemotherapy, and enhance antitumor immunity. In a randomized phase 2 study of patients with unresected locally advanced squamous cell carcinoma of the head and neck, xevinapant + chemoradiotherapy (CRT) significantly improved 18-month locoregional control and improved 3-year progression-free survival and 5-year overall survival vs placebo + CRT. A phase 3 confirmatory study (TrilynX NCT04459715) and a phase 3 study to evaluate xevinapant + RT in post-operative, high-risk, cisplatin-ineligible patients (XRay Vision NCT05386550) are ongoing. In these studies, we investigate 3 additional cycles of xevinapant or placebo monotherapy after completing combination treatment. Based on the role of IAPs in apoptosis, immunity, and stromal activation, continual dosing of xevinapant post RT may have additional therapeutic benefits. Methods: MC38 syngeneic tumor-bearing mice were treated with vehicle control, RT alone (3.6Gy once daily [QD], 5 days), or RT + xevinapant (100 mg/kg QD, 1, 2, or 4 weeks). To assess treatment-mediated TME modulation, immune cells in tumors were evaluated by fluorescence-activated cell sorting (FACS)–based immunophenotyping, and tumor-specific T cell responses were investigated by enzyme-linked immunosorbent spot (ELISpot) assays. To understand the effect of xevinapant on RT-induced cancer associated fibroblast (CAF) activation, CAF gene expression was profiled on cell lines and patient-derived primary cultures. Results: Xevinapant + RT increased antitumor efficacy compared with vehicle control or RT alone. Moreover, RT in combination with extended dosing of xevinapant for 4 weeks significantly improved therapeutic efficacy and prolonged survival compared with RT + shorter xevinapant dosing durations. FACS analysis demonstrated trends of increased numbers of CD8+ T cells, natural killer cells, and dendritic cells and decreased numbers of regulatory T cells in mice treated with xevinapant + RT. FACS and ELISpot further suggested an increase in antigen-specific T cell counts from baseline with combination therapy arm vs vehicle control or RT alone. Xevinapant may also suppress RT-mediated CAF activation, as indicated by downregulation of activation markers and CAF-derived secretory proteins. Conclusions: In preclinical models, extended dosing of xevinapant for 4 weeks post RT improved antitumor efficacy. Our data suggest that the effect may be, in part, modulated by TME responses, including enhanced antitumor immunity and suppressed pro-tumorigenic phenotype of CAFs. Based on these results, further evaluation is warranted to determine the mechanisms that underscore the therapeutic benefit offered by extended dosing of xevinapant.

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer

Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial. To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone. The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022. Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing. The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm. In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals. ClinicalTrials.gov Identifier: NCT03599765.

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn’s Disease: A Pragmatic Randomized Trial

Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. gov, Number: NCT02772965.

Combination therapy with simultaneous delivery of spinal cord stimulation modalities: COMBO randomized controlled trial.

Aim: The Combining Mechanisms for Better Outcomes randomized controlled trial assessed the effectiveness of various spinal cord stimulation (SCS) modalities for chronic pain. Specifically, combination therapy (simultaneous use of customized sub-perception field and paresthesia-based SCS) versus monotherapy (paresthesia-based SCS) was evaluated. Methods: Participants were prospectively enrolled (key inclusion criterion: chronic pain for ≥6months). Primary end point was theproportion with ≥50% pain reduction without increased opioids at the3 month follow-up. Patients were followed for 2 years. Results: The primary end point was met (n=89; p<0.0001) in 88% of patients in the combination-therapy arm (n=36/41) and 71% in the monotherapy arm (n=34/48). Responder rates at 1 and 2 years (with available SCS modalities) were 84% and 85%, respectively. Sustained functional outcomesimprovement was observed out to 2 years. Conclusion: SCS-based combination therapy can improve outcomes in patients with chronic pain. Clinical Trial Registration: NCT03689920 (ClinicalTrials.gov), Combining Mechanisms for Better Outcomes (COMBO).

Time to Complete Response within 24 Months As a Good Surrogate Marker of 8 Year-Progression Free Survival in Extranodal Marginal Zone Lymphoma

Background: Extranodal marginal zone lymphoma (EMZL) represents the most common marginal zone lymphoma (MZL) subtype and it generally has a very indolent course, thus requiring long and costly trials to provide evidence on novel therapies. The IELSG-19 open-label phase 3 trial was conducted at 78 centers in six countries and showed the advantage of double therapy (rituximab-chlorambucil) over single therapy (rituximab or chlorambucil). Based on this trial, we assessed whether time to complete response within 24 months (TTCR24) could be a surrogate marker of progression-free survival (PFS) in EMZL. Methods: We used a recently developed method which derives conditional survival estimates under a landmark Cox proportional hazards model. This method allows us 1) to estimate surrogacy via the proportion of treatment effect explained by surrogate information and 2) to decompose this proportion between information gathered on the true outcome and the incremental value of the surrogate outcome alone. True outcome was 8 year-PFS and candidate surrogate marker was TTCR24. For both outcomes, treatment effect was defined using restricted mean survival time difference (RMST) between the two study arms: the difference in mean progression-free survival time restricted at 8 years and the difference in mean time to CR. Results: Among 401 patients (median follow-up: 7.4 years), 8y-PFS was not achieved in the combined therapy arm vs 8.35 years in the single therapy arm. At 2 years, TTCR24 was 83% vs 65%, while 2y-PFS was 87% vs 75%, respectively. In terms of RMST, patients under double therapy had a shorter TTCR24 by 3.8 months and a longer PFS by 11 months, compared to patients under single therapy. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95% CI: 0.27,1.87). When decomposed, the proportion of treatment effect on 8y-PFS was explained by PFS24 was 75% (95% CI: 0.31, 1.27) and the incremental value of TTCR24 was 20% (95% CI: -0.23,0.86). Conclusion: We found that TTCR24 predicted 95% of the treatment effect on 8y-PFS and, when used as surrogate marker, it could reduce the needed follow-up time of a phase 3 trial by four. From this, one could conclude that a new therapy in EMZL would be effective if it offers a significantly shorter TTCR than the one obtained by rituximab-chlorambucil (5.5 months). Although this single-trial approach suffers of the lack of a trial-level evidence, there are, to date, too few MZL phase 3 trials to undertake a meta-analysis. The very strong surrogacy offered by TTCR24 could make it the most relevant surrogate marker in EMZL in the coming years.

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer (EXTEND): A Multicenter, Randomized Phase II Trial

<h3>Purpose/Objective(s)</h3> There has been increased utilization of metastasis directed therapy (MDT) for oligometastatic prostate cancer. Despite data demonstrating the benefit of upfront hormone therapy (HT) and synergy between radiation and HT, there exists no randomized trials testing their combination. As it is accepted by most clinicians and men with prostate cancer that time off HT holds intrinsic value, we evaluated whether the addition of metastasis directed therapy (MDT) to intermittent HT in men with oligometastatic prostate cancer facilities time off HT by improving PFS and eugonad PFS. <h3>Materials/Methods</h3> EXTEND (NCT03599765) is a phase II randomized basket trial for multiple solid tumors testing whether the addition of MDT improves PFS. The primary endpoint was pre-specified to be independently assessed and reported for the prostate intermittent HT basket at 41 events. Men with ≤5 metastases were randomized after ≥2 months of HT to continuing HT with or without MDT. HT consisted of a luteinizing hormone-releasing hormone agonist/antagonist with or without a 2^nd generation androgen-receptor targeting agent (SART). The primary endpoint was progression, defined as death or radiographic, clinical, or biochemical progression. A planned HT break occurred 6 months after enrollment, after which HT was withheld until progression. The study was designed to have 80% power to detect an improvement in median PFS from 18 to 36 months, with a type I error of 0.1. Exploratory analysis included flow cytometry and TCR sequencing from peripheral blood at baseline and 3 months follow up. <h3>Results</h3> Between Sept 2018 to Nov 2020, 87 men were randomized, 43 combined therapy and 44 to HT-only. Arms were well balanced. At a median follow-up of 22.1 months (range 13.0 to 39.3 months), 41 events were observed. PFS was improved by the receipt of MDT (median not reached vs 15.8 months for HT-only, P<0.001; HR=0.25 [95% CI, 0.12 to 0.55]). Among secondary endpoints, time from eugonad testosterone levels (>150 ng/dL) to progression was improved by MDT (median not reached vs 6.1 months, P=0.03), as was time to appearance of new lesions (2-year rate 33% vs 41%, P=0.04). Three grade 3 toxicities were observed in each arm. Subgroup analysis identified PFS improvement with MDT in patients who received (HR=0.24 [95% CI, 0.08 to 0.71]) or did not receive a SART (HR=0.36 [95% CI, 0.15 to 0.83]). Flow cytometry and TCR sequencing demonstrated increases in markers of T cell activation, proliferation, and clonal expansion limited to the combined therapy arm. <h3>Conclusion</h3> EXTEND represents the first randomized study to evaluate MDT with HT in oligometastatic prostate cancer and demonstrated improvement in PFS and eugonad PFS. Combination of MDT with intermittent HT may allow for both excellent disease control while facilitating prolonged eugonad testosterone intervals.

Risk Factors for Nephrotoxicity in Methicillin-Resistant Staphylococcus aureus Bacteraemia: A Post Hoc Analysis of the CAMERA2 Trial.

Clinical risk factors for nephrotoxicity in Staphylococcus aureus bacteraemia remain largely undetermined, despite its common occurrence and clinical significance. In an international, multicentre, prospective clinical trial (CAMERA2), which compared standard therapy (vancomycin monotherapy) to combination therapy (adding an anti-staphylococcal beta-lactam) for methicillin-resistant S. aureus bacteraemia, significantly more people in the combination therapy arm experienced acute kidney injury compared with those in the monotherapy arm (23% vs 6%). The aim of this post hoc analysis was to explore in greater depth the risk factors for acute kidney injury from the CAMERA2 trial. Among participants of the CAMERA2 trial, demographic-related, infection-related and treatment-related risk factors were assessed for their relationship with acute kidney injury by univariable and multivariable logistic regression. Acute kidney injury was defined by a modified-KDIGO (Kidney Disease: Improving Global Outcomes) criteria (not including urinary output). Of the 266 participants included, age (p = 0.04), randomisation to combination therapy (p = 0.002), vancomycin area under the concentration-time curve (p = 0.03) and receipt of (flu)cloxacillin as the companion beta-lactam (p < 0.001) were significantly associated with acute kidney injury. On a multivariable analysis, concurrent use of (flu)cloxacillin increased the risk of acute kidney injury over four times compared with the use of cefazolin or no beta-lactam. The association of vancomycin area under the concentration-time curve with acute kidney injury also persisted in the multivariable model. For participants receiving vancomycin for S. aureus bacteraemia, use of (flu)cloxacillin and increased vancomycin area under the concentration-time curve were risk factors for acute kidney injury. These represent potentially modifiable risk factors for nephrotoxicity and highlight the importance of avoiding the use of concurrent nephrotoxins.

A phase 1b study (STELLAR-002) of XL092 administered in combination with nivolumab (NIVO) with or without ipilimumab (IPI) or bempegaldesleukin (BEMPEG) in patients (pts) with advanced solid tumors.

TPS4600 Background: XL092 is a novel oral inhibitor of receptor tyrosine kinases, including MET, VEGFR2, and TAM kinases (AXL, MER), which are implicated in tumor growth, metastasis, angiogenesis, and immune suppression of the tumor microenvironment. XL092 has a relatively short half-life (̃21h) to support convenient daily dosing and help manage tolerability. Preclinical studies of XL092 with an anti‒PD-1 immune checkpoint inhibitor (ICI) demonstrated antitumor activity in tumor models, and BEMPEG (IL-2 pathway agonist) showed synergy with anti‒PD-L1 and anti‒CTLA-4 agents. This phase 1b trial will evaluate the safety and clinical activity of XL092 alone and in combination with NIVO (anti‒PD-1 mAb) ±IPI (anti‒CTLA-4 mAb) or ±BEMPEG in pts with advanced solid tumors including genitourinary cancers. Presented here is the study design. Methods: This multicenter phase 1b, open-label study (NCT05176483) will enroll pts with unresectable advanced or metastatic solid tumors in dose-escalation and expansion stages. In the dose-escalation stage, ̃36 pts will be enrolled in three XL092 combination therapy cohorts using a rolling 6 design. Cohort A: XL092 (starting dose [SD] 100 mg PO QD) + NIVO (360 mg IV Q3W); Cohort B: XL092 (SD 80 mg PO QD) + NIVO (3 mg/kg IV Q3W × 4, then 480 mg IV Q4W) + IPI (1 mg/kg Q3W × 4); Cohort C: XL092 (SD 100 mg PO QD) + NIVO (360 mg IV Q3W) + BEMPEG (0.006 mg/kg IV Q3W). The primary objective of the dose-escalation stage is to determine the recommended doses of XL092 with the NIVO regimens to be used in the expansion stage. The expansion stage will include cohorts of advanced genitourinary tumors: Cohort 1, clear-cell renal cell carcinoma (ccRCC), no prior systemic therapy; Cohort 2, ccRCC, 1 prior ICI combination regimen; Cohort 3, metastatic castration-resistant prostate cancer (mCRPC), 1 prior novel-hormonal therapy; Cohort 4, urothelial carcinoma (UC), 1 prior platinum-based regimen, ICI-naïve; Cohort 5, UC, ≤2 prior systemic regimens, ICI-experienced; Cohort 6, non-ccRCC, no prior systemic therapy. In each cohort, pts will be randomized to one of the following treatments (based on tumor cohort): single-agent XL092 (Cohorts 2‒6); XL092+NIVO (Cohorts 1‒6); NIVO+IPI (Cohort 1); XL092+NIVO+IPI (Cohorts 1, 3, 6); NIVO+BEMPEG (Cohort 1), XL092+NIVO+BEMPEG (Cohort 1, 2, 4‒6). Thirty pts will be enrolled in each single-agent XL092 arm and 40 pts in each combination therapy arm. Expansion stage objectives are to assess preliminary efficacy, safety, and pharmacokinetics of XL092 alone or in combination in each tumor-specific cohort. Primary efficacy endpoints include objective response rate by investigator per RECIST v1.1 and progression-free survival by blinded independent radiology committee per Prostate Working Group 3 criteria (mCRPC cohort only). The study is currently enrolling pts. Clinical trial information: NCT05176483.

Cost Effectiveness of Ribociclib and Palbociclib in the Second-Line Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer in Post-Menopausal Indian Women

In this study, we evaluate the cost and outcomes of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus fulvestrant, fulvestrant alone, and conventional chemotherapy as the second-line therapy for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in India. Using a Markov model, the clinical effectiveness of managing HR+, HER2- MBC in postmenopausal women with either aCDK4/6i (either ribociclib or palbociclib) and fulvestrant, fulvestrantalone, and chemotherapy (single-agent paclitaxel or capecitabine) was measured in terms of quality-adjusted life-years (QALYs). The costs were estimated from two different points of view: scenario I, as per the prevailing market prices of the drugs; and scenario II, as per the reimbursement rates set up by the publicly financed national health insurance scheme. Incremental cost per QALY gained with a given treatment option was compared against the next best alternative and was assessed for cost effectiveness using a threshold of 1-time the per capita gross domestic product (GDP) in India from a societal perspective. In scenario I, an MBC patient was found to incur a lifetime cost of Indian Rupees (₹)2.54 million ($34,644), ₹2.53 million ($34,496), ₹512,598 ($6,984), ₹326,026 ($4,442) and ₹237,115 ($3,230) for the ribociclib and palbociclib combination arms, fulvestrant monotherapy, single-agent paclitaxel and the single-agent capecitabine treatment arms, respectively. The lifetime cost for CDK4/6i (ribociclib and palbociclib) combination therapy, fulvestrant monotherapy, paclitaxel, and capecitabine arms was estimated to be ₹1.94 million ($26,459), ₹1.92 million ($26,220), ₹315,387 ($4,296), ₹187,392 ($2,553) and ₹153,263 ($2,088), respectively, in scenario II. The mean QALYs lived per MBC patient with CDK4/6i (either ribociclib or palbociclib) combination therapy, fulvestrant, paclitaxel and capecitabine were estimated to be 1.4, 1.0, 0.9 and 0.7, respectively. None of the treatment arms are cost effective at current prices and reimbursement rates at a threshold of 1-time the per capita GDP of India. However, a 78% reduction in the current market price or a 72% reduction in the reimbursement rate of fulvestrant in the government-funded insurance program will make it a cost-effective treatment option for HR+, HER2- MBC patients in India. CDK4/6i (ribociclib and palbociclib) therapyis not a cost-effective treatment option for MBC patients. A 72% reduction in the reimbursement rate for fulvestrant monotherapy will make it a cost-effective treatment option in the Indian context.

Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy—Analysis of the Phase 3 XELAVIRI Trial

IntroductionEarly tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial.MethodsDpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex.ResultsIn 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in RAS/BRAF wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: p < 0.001, HR 0.532; OS: p < 0.001, HR 0.574 vs. PFS: p = 0.107; OS: p = 0.965).ConclusionsInitial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

A retrospective observational cohort study of the clinical epidemiology of bloodstream infections due to carbapenem-resistant Klebsiella pneumoniae in an OXA-48 endemic setting

This study aimed to characterize the epidemiology and clinical outcomes of patients with bloodstream infections (BSIs) due to carbapenem-resistant Klebsiella pneumoniae (CRKP) in an OXA-48-predominant environment. This was a retrospective single-centre cohort study including all consecutive patients with CRKP BSIs treated between 1 January 2014 and 31 December 2018. Multivariate analysis, subgroup analysis and propensity-score-matched analysis were employed to analyse 30-day mortality as the primary outcome. Clinical cure at day 14 was also analysed for the whole cohort. In total, 124 patients with unique isolates met all the inclusion criteria. OXA-48 was the most common type of carbapenemase (85.5%). Inappropriate therapy was significantly associated with 30-day mortality [70.6% vs 39.7%, adjusted odds ratio (aOR) 4.65, 95% confidence interval (CI) 1.50-14.40, P=0.008] and 14-day clinical failure (78.5% vs 56.2%, aOR 3.14, 95% CI 1.09-9.02, P=0.033) in multivariate analyses. Among those treated appropriately, the 30-day mortality rates were similar in monotherapy and combination therapy arms (OR 2.85, 95% CI 0.68-11.95, P=0.15). INCREMENT CPE mortality score (aOR 1.16, 95% CI 1.01-1.33, P=0.029), sepsis at BSI onset (aOR 2.90, 95% CI 1.02-8.27, P=0.046), and inappropriate therapy (aOR 4.65, 95% CI 1.50-14.40, P=0.008) were identified as independent risk factors for 30-day mortality. Colistin resistance in CRKP had no significant impact on 30-day mortality. These results were also confirmed in all propensity-score-matched analyses and sensitivity analyses. Appropriate regimens were associated with better clinical outcomes than inappropriate therapies for BSIs with CRKP predominantly possessing OXA-48.

OP01 Withdrawal of infliximab or anti-metabolite therapy in Crohn’s Disease patients in sustained remission on combination therapy: A randomized unblinded controlled trial (SPARE)

Abstract Background Combination therapy with infliximab and anti-metabolites is a standard option for patients with Crohn’s disease (CD). The implications of long term use of combination therapy may lead patients and clinicians to contemplate treatment de-escalation once steroid-free remission has been achieved. The aim of our study was to assess the relapse rates and time spent in remission over 2 years, after withdrawal of infliximab or anti-metabolite compared to continuation of combination therapy. Methods CD patients treated with a combination therapy of infliximab (IFX) and anti-metabolite &amp;gt; 8 months and in sustained steroid-free remission &amp;gt; 6 months were recruited in 64 centers in France, United Kingdom, Belgium, Sweden, Australia, Germany and The Netherlands. Patients were randomized into 3 arms - continuing combination therapy (arm A); stopping IFX (arm B); or stopping anti-metabolite (arm C). In case of a relapse [defined by CDAI and an objective marker of inflammation (CRP or fecal calprotectin)], patients were retreated by resuming infliximab in arm B or the anti-metabolite in arm C, according to a pre-defined scheme, including optimization of IFX up to 10 mg/Kg if necessary in all arms. The two co-primary endpoints were the relapse rate and mean survival time spent in remission over 2 years. A major secondary endpoint was treatment failure (complications or not recapturing remission). Results 254 patients were screened, 211 randomized, 5 withdrew consent and 1 was lost to follow-up, leaving 205 patients for the analysis - 67 randomized to arm A, 71 to arm B and 67 to arm C. Demographic and clinical characteristics are shown in Table 1. The two-year relapse rates were 14% (IC95%: 4–23%) in arm A, 40% (IC95%: 28–51%) in arm B, and 10% (IC95%: 2–18%) in arm C (p=0.0003 arm B vs arm A and &amp;lt;0.0001 arm B vs arm C) (figure 1). The time spent in remission was 1.91 yrs (IC95%: 1.83–1.99), 1.89 yrs (IC95%: 1.82–1.96) and 1.93 yrs (IC95%: 1.86–2.00) in arm A, B and C, respectively. Out of the 39 relapsers, 28 were retreated/optimized. Remission was achieved in 1/2 retreated patients in arm A, 22/23 in arm B and 2/3 in arm C. Treatment failure was observed in 4/67, 4/71 and 3/67 patients, in these three arms, respectively. No malignancy was observed, one tuberculosis in arm C and two severe infections (pneumonia and viral pericarditis) in arm B. Conclusion Infliximab withdrawal, but not antimetabolite withdrawal, was associated with a significantly higher risk of relapse than continuation of combination therapy. Almost all patients who stopped IFX achieved rapid remission when resuming treatment. The time spent in remission over 2 years was similar across groups.

Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma.

We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC). We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis. Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery. Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil.

Preliminary Safety and Efficacy Data from Patients (Pts) with Relapsed/Refractory (R/R) B-Cell Malignancies Treated with the Novel B-Cell Lymphoma 2 (BCL2) Inhibitor BGB-11417 in Monotherapy or in Combination with Zanubrutinib

Preliminary Safety and Efficacy Data from Patients (Pts) with Relapsed/Refractory (R/R) B-Cell Malignancies Treated with the Novel B-Cell Lymphoma 2 (BCL2) Inhibitor BGB-11417 in Monotherapy or in Combination with Zanubrutinib

First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer.

A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.