Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment.

Immune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone. Combined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone. In this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline. Twenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints. Tremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment. NCT03204812.

Subudhi SK ，Siddiqui BA ，Aparicio AM ，Yadav SS ，Basu S ，Chen H ，Jindal S ，Tidwell RSS ，Varma A ，Logothetis CJ ，Allison JP ，Corn PG ，Sharma P ... -  《Journal for ImmunoTherapy of Cancer》

Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations.

Karzai F ，VanderWeele D ，Madan RA ，Owens H ，Cordes LM ，Hankin A ，Couvillon A ，Nichols E ，Bilusic M ，Beshiri ML ，Kelly K ，Krishnasamy V ，Lee S ，Lee MJ ，Yuno A ，Trepel JB ，Merino MJ ，Dittamore R ，Marté J ，Donahue RN ，Schlom J ，Killian KJ ，Meltzer PS ，Steinberg SM ，Gulley JL ，Lee JM ，Dahut WL ... -  《Journal for ImmunoTherapy of Cancer》

A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone.

Checkpoint inhibitors can induce profound anticancer responses, but programmed cell death protein-1 (PD-1) inhibition monotherapy has shown minimal activity in prostate cancer. A published report showed that men with prostate cancer who were resistant to the second-generation androgen receptor inhibitor enzalutamide had increased programmed death-ligand 1 (PD-L1) expression on circulating antigen-presenting cells. We hypothesized that the addition of PD-1 inhibition in these patients could induce a meaningful cancer response. We evaluated enzalutamide plus the PD-1 inhibitor pembrolizumab in a single-arm phase II study of 28 men with metastatic castration-resistant prostate cancer (mprogressing on enzalutamide alone. Pembrolizumab 200 mg intravenous was given every 3 weeks for four doses with enzalutamide. The primary endpoint was prostate-specific antigen (PSA) decline of ≥50%. Secondary endpoints were objective response, PSA progression-free survival (PFS), time to subsequent treatment, and time to death. Baseline tumor biopsies were obtained when feasible, and samples were sequenced and evaluated for the expression of PD-L1, microsatellite instability (MSI), mutational and neoepitope burdens. Five (18%) of 28 patients had a PSA decline of ≥50%. Three (25%) of 12 patients with measurable disease at baseline achieved an objective response. Of the five responders, two continue with PSA and radiographic response after 39.3 and 37.8 months. For the entire cohort, median follow-up was 37 months, and median PSA PFS time was 3.8 months (95% CI: 2.8 to 9.9 months). Time to subsequent treatment was 7.21 months (95% CI: 5.1 to 11.1 months). Median overall survival for all patients was 21.9 months (95% CI: 14.7 to 28 .4 months), versus 41.7 months (95% CI: 22.16 to not reached (NR)) in the responders. Of the three responders with baseline biopsies, one had MSI high disease with mutations consistent with DNA-repair defects. None had detectable PD-L1 expression. Pembrolizumab has activity in mCRPC when added to enzalutamide. Responses were deep and durable and did not require tumor PD-L1 expression or DNA-repair defects. clinicaltrials.gov (NCT02312557).

Graff JN ，Beer TM ，Alumkal JJ ，Slottke RE ，Redmond WL ，Thomas GV ，Thompson RF ，Wood MA ，Koguchi Y ，Chen Y ，Latour E ，Bergan RC ，Drake CG ，Moran AE ... -  《Journal for ImmunoTherapy of Cancer》

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.

PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC). We did a multicentre, non-randomised, open-label, phase 1b study at five cancer centres in the USA. We enrolled immunotherapy-naive patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947. Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18·8 weeks (IQR 11-33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 95% CI 9-44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3-60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8-58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12-74] of ten patients). Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, and was selected as the dose for phase 3 studies, which are ongoing. MedImmune.

Antonia S ，Goldberg SB ，Balmanoukian A ，Chaft JE ，Sanborn RE ，Gupta A ，Narwal R ，Steele K ，Gu Y ，Karakunnel JJ ，Rizvi NA ... -  《-》

Safety and clinical activity of durvalumab combined with tremelimumab in recurrent/metastatic head and neck squamous cell carcinoma: a multicenter phase I study.

Programmed cell death protein 1 (PD-1) inhibitors prolong survival versus chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), which often expresses cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-ligand 1 (PD-L1), providing a rationale for combined PD-(L)1 and CTLA-4 blockade. We report a phase I, open-label study of the PD-L1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab (NCT02262741). In dose exploration, two cohorts of previously treated patients received durvalumab 10 mg/kg plus tremelimumab 3 mg/kg, or durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, for up to 12 months. Dose expansion comprised two cohorts of previously untreated patients with R/M HNSCC having baseline PD-L1 tumor cell (TC) expression ≥25% and <25% and one cohort of immunotherapy-pretreated patients with any PD-L1 level. All received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, then durvalumab 10 mg/kg, for up to 12 months. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR) by RECIST version 1.1, pharmacokinetics, pharmacodynamics, and immunogenicity. A total of 71 patients were treated. The median duration of exposure was 13.6 weeks for durvalumab and 13.1 weeks for tremelimumab. In dose exploration, no dose-limiting toxicities occurred. No maximum tolerated dose was identified. Treatment-related adverse events (TRAEs) occurred in 69.0% of patients; grade 3/4 and serious TRAEs occurred in 31.0% and 18.3%, respectively. TRAEs led to discontinuation in 9.9%. There were no treatment-related deaths. The ORR was 5.6% (95% confidence interval 1.6-13.8), including one complete response and three partial responses, all patients were in dose expansion with PD-L1 TC ≥25% and no prior immunotherapy exposure; three had ongoing responses ≥12 months. The median overall survival in the total population was 8.6 months. Soluble PD-L1 suppression was almost complete in all cohorts, suggesting target engagement. CD4+Ki67+ T cells were significantly elevated in all dose-expansion cohorts. Treatment was well tolerated. However, response rates were low despite target engagement, no drug-drug interactions, and no drug-neutralizing antibodies to durvalumab.

Algazi A ，Papadopoulos KP ，Tsai F ，Hansen AR ，Angra N ，Das M ，Sheth S ，Siu LL ... -  《ESMO Open》