Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study.

INTRODUCTION: Preclinical studies have demonstrated increased efficacy with combined DNA damage response inhibition and immune checkpoint blockade compared with either alone. We assessed olaparib in combination with durvalumab in patients with relapsed small cell lung cancer (SCLC). METHODS: Patients with previously treated limited or extensive-stage SCLC received oral olaparib 300 mg twice daily, as run-in for 4 weeks, then with durvalumab (1500 mg intravenously every 4 weeks) until disease progression. Primary endpoints were safety, tolerability, and 12-week disease control rate (DCR). Secondary endpoints included 28-week DCR, objective response rate (ORR), duration of response, progression-free survival, overall survival, change in tumor size, and programmed death-ligand 1 (PD-L1) expression subgroup analyses. RESULTS: Forty patients were enrolled and analyzed for safety; 38 were analyzed for efficacy. Eleven patients (28.9% [90% confidence interval (CI), 17.2-43.3]) had disease control at 12 weeks. ORR was 10.5% (95% CI, 2.9-24.8). Median progression-free and overall survival were 2.4 (95% CI, 0.9-3.0)months and 7.6(95% CI, 5.6-8.8)months, respectively. The most common adverse events (≥40.0%) were anemia, nausea, and fatigue. Grade ≥ 3 adverse events occurred in 32 patients (80.0%). PD-L1 levels, tumor mutational burden, and other genetic mutations were evaluated, but no significant correlations with clinical outcomes wereobserved. CONCLUSIONS: Tolerability of olaparib with durvalumab was consistent with the safety profile of each agent alone. Although the 12-week DCR did not meet the prespecified target (60%), four patients responded, and median overall survival was promising for a pretreated SCLC population. Further analyses are required to identify patients most likely to benefit from this treatment approach.

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. FUNDING: AstraZeneca.

Treatment-resistant synovitis and radiographic progression are increased in elderly-onset rheumatoid arthritis patients: findings from a prospective observational longitudinal early arthritis cohort study.

BACKGROUND: Clinical outcomes in elderly-onset rheumatoid arthritis (EORA), starting after the age of 60, are conflicting. Thus, we aimed to investigate in a unique biopsy-driven, treatment-naïve early arthritis cohort, the relationship between synovial pathobiology of elderly- (EORA) and younger-onset rheumatoid arthritis (YORA) patients through clinical, imaging and treatment response outcome-measures. METHODS: Patients (n = 140) with early RA (<12months) starting before (YORA, n = 99) or after (EORA, n = 41) age 60 had an ultrasound-guided synovial biopsy prior to conventional immunosuppressive therapy and after 6 months. Clinical, ultrasound and radiographic data were collected prospectively and compared between groups and against immunohistological features. Using multivariate logistic regression, we determined predictors of clinical response (disease activity score-28-erythrocyte sedimentation rate [DAS28-ESR]<3.2) at 6 months and radiographic progression (≥1-unit-increase in Sharp van der Heijde [SvdH] score) at 12 months. RESULTS: EORA patients were more frequently male and presented most commonly with an abrupt, polymyalgia rheumatica-like onset and extra-articular features. Both before and after treatment, DAS28-ESR was similar but ultrasound synovial-thickening (p<0.05) and power-Doppler (p<0.01) synovitis and SvdH (p<0.001) scores were higher in EORA patients. EORA was independently associated with poor treatment response at 6 months (OR=0.28, p = 0.047) and radiographic progression at 12 months (OR=4.08, p = 0.029). Synovial pathotype, synovitis scores and cellular infiltration were similar before treatment, but a pauci-immune-fibroid pathotype tended to be more common in YORA at 6 months (p = 0.093). Moreover, YORA patients had a marked improvement of all synovitis parameters (p<0.001), whereas EORA presented only mild decreases in synovitis (p<0.05), sublining macrophage (p<0.05) and T cell scores (p<0.05), with no significant changes in lining macrophages, B cells or plasma cells. CONCLUSION: Early EORA presents differently and has a worse overall prognosis than YORA, with poorer clinical, histological, ultrasonographic and radiographic outcomes.

Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes.

There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (https://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage.

Ultrasound-guided synovial biopsy of the wrist does not alter subsequent clinical or ultrasound disease activity assessments: a prospective study for incorporation of imaging in clinical trials.

OBJECTIVES: Ultrasound-guided synovial biopsy (UGSB) is a minimally-invasive procedure capable of retrieving good quality tissue from small and large joints. The use of UGSB in prospective clinical trials poses a dilemma as to whether biopsied joints may be later included in core data sets for clinical or imagining response, as the procedure itself may alter disease activity assessment. In this study, we examine the impact of UGSB of the wrist on subsequent clinical and ultrasound (US) assessments in a cohort of rheumatoid arthritis (RA) patients prior to initiation of anti-TNF-alpha therapy. METHODS: Patients had active disease (DAS>5.1) involving their wrist. Both wrists were scanned and the most inflamed one underwent an UGSB. Ultrasonographic and clinical assessments were repeated at the patients' subsequent visit, without any changes in disease-modifying treatment between visits. US images were scored semi-quantitatively and quantitatively for synovial thickness (ST) and power Doppler (PD). Mixed-effects model and paired-Wilcoxon signed rank test were used to assess the effect of UGSB on these scores. RESULTS: Twenty-nine patients were enrolled. No significant difference in mean ST (p=0.32) or PD (p=0.21) was demonstrated pre- and post-biopsy (mean time 14.7 days). Similar results were obtained using quantitative measures. The DAS-28 and its components did not change significantly post-biopsy. CONCLUSIONS: In this population, UGSB of the wrist did not significantly alter subsequent clinical or US assessments, indicating that a wrist joint, which has undergone UGSB, may be incorporated into an US dataset or clinical outcome assessment tools, such as the DAS-28, without prejudice.

Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis.

Ectopic lymphoid-like structures (ELSs) reminiscent of secondary lymphoid organs often develop at sites of chronic inflammation where they contribute to immune-mediated pathology. Through evaluation of synovial tissues from rheumatoid arthritis (RA) patients, we now show that low interleukin-27 (IL-27) expression corresponds with an increased incidence of ELS and gene signatures associated with their development and activity. The presence of synovial ELS was also noted in mice deficient in the IL-27 receptor (IL-27R) after the onset of inflammatory arthritis. Here, pathology was associated with increased synovial expression of pro-inflammatory cytokines, homeostatic chemokines, and transcriptional regulators linked with lymphoid neogenesis. In both clinical and experimental RA, synovial ELS coincided with the heightened local expression of cytokines and transcription factors of the Th17 and T follicular helper (Tfh) cell lineages, and included podoplanin-expressing T cells within lymphoid aggregates. IL-27 inhibited the differentiation of podoplanin-expressing Th17 cells, and an increased number of these cells were observed in IL-27R-deficient mice with inflammatory arthritis. Thus, IL-27 appears to negatively regulate ELS development in RA through control of effector T cells. These studies open new opportunities for patient stratification and treatment.

Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions.

Lactate has long been considered a "waste" by-product of cell metabolism, and it accumulates at sites of inflammation. Recent findings have identified lactate as an active metabolite in cell signalling, although its effects on immune cells during inflammation are largely unexplored. Here we ask whether lactate is responsible for T cells remaining entrapped in inflammatory sites, where they perpetuate the chronic inflammatory process. We show that lactate accumulates in the synovia of rheumatoid arthritis patients. Extracellular sodium lactate and lactic acid inhibit the motility of CD4+ and CD8+ T cells, respectively. This selective control of T cell motility is mediated via subtype-specific transporters (Slc5a12 and Slc16a1) that we find selectively expressed by CD4+ and CD8+ subsets, respectively. We further show both in vitro and in vivo that the sodium lactate-mediated inhibition of CD4+ T cell motility is due to an interference with glycolysis activated upon engagement of the chemokine receptor CXCR3 with the chemokine CXCL10. In contrast, we find the lactic acid effect on CD8+ T cell motility to be independent of glycolysis control. In CD4+ T helper cells, sodium lactate also induces a switch towards the Th17 subset that produces large amounts of the proinflammatory cytokine IL-17, whereas in CD8+ T cells, lactic acid causes the loss of their cytolytic function. We further show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of rheumatoid arthritis patients. Finally, pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in an in vivo model of peritonitis. By establishing a novel role of lactate in control of proinflammatory T cell motility and effector functions, our findings provide a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders.