Ezabenlimab (BI 754091), an anti-PD-1 antibody, in patients with advanced solid tumours.

BACKGROUND: Ezabenlimab (BI 754091) is a humanised monoclonal antibody targeting programmed cell death protein-1. We report results from open-label, dose-escalation/expansion, Phase I trials that evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics and antitumour activity of ezabenlimab at the recommended Phase II dose in patients with selected advanced solid tumours. STUDY DESIGN: Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States. Study 1381.4 (NCT03433898) was conducted in Japan. Study 1381.3 (NCT03780725) was conducted in the Netherlands. The primary endpoints were: number of patients experiencing dose-limiting toxicities (DLTs) in the first cycle (dose escalation parts), number of patients with DLTs during the entire treatment period and objective response (dose expansion part of Study 1381.1). RESULTS: Overall, 117 patients received ezabenlimab intravenously every 3 weeks (80 mg, n = 3; 240 mg, n = 111; 400 mg, n = 3). No DLTs were observed and the MTD was not reached. Fifty-eight patients (52.3%) had grade ≥ 3 adverse events, most commonly anaemia (10.8%) and fatigue (2.7%). In 111 assessed patients treated with ezabenlimab 240 mg, disease control rate was 56.8% and objective response rate was 16.2%. Three patients had complete response; at data cut-off (November 2021) one remained in response and was still receiving ongoing treatment (duration of response [DoR]: 906 days). Partial responses occurred across several tumour types; DoR ranged from 67 to 757 days. CONCLUSIONS: Ezabenlimab was well tolerated and associated with durable antitumour activity in multiple solid tumours, comparable to other immune checkpoint inhibitors in similar patient populations and treatment settings.

Comparing the rate of immunotherapy treatment change due to toxicity by sex.

BACKGROUND: Immuno-oncology therapy (IO) is associated with a variety of treatment-related toxicities. However, the impact of toxicity on the treatment discontinuation rate between males and females is unknown. We hypothesized that immune-related adverse events would lead to more frequent treatment changes in females since autoimmune diseases occur more frequently in females. AIMS: Our aim was to determine if there was a difference in the rate of immunotherapy treatment change due to toxicity between males and females. METHODS AND RESULTS: The Oncology Research Information Exchange Network Avatar Database collected clinical data from 10 United States cancer centers. Of 1035 patients receiving IO, 447 were analyzed, excluding those who did not have documentation noting if a patient changed treatment (n = 573). Fifteen patients with unknown or gender-specific cancer were excluded. All cancer types and stages were included. The primary endpoint was documented treatment change due to toxicity. Four hundred and forty-seven patients (281 males and 166 females) received IO treatment. The most common cancers treated were kidney, skin, and lung for 99, 84, and 54 patients, respectively. Females had a shorter IO course than males (median 3.7 vs. 5.1 months, respectively, p = .02). Fifty-four patients changed treatment due to toxicity. There was no significant difference between females and males on chi-square test (11.4% vs. 12.5%, respectively, p = 0.75) and multivariable logistic regression (OR 0.924, 95% CI 0.453-1.885, p = .827). Significantly more patients with chronic obstructive pulmonary disease (COPD) changed therapy due to toxicity (OR 2.491, 95% CI 1.025-6.054, p = .044). CONCLUSION: Females received a shorter course of IO than males. However, there was no significant difference in the treatment discontinuation rate due to toxicity between males and females receiving IO. Toxicity-related treatment change was associated with COPD.

Analysis of Radiation Therapy Quality Assurance in NRG Oncology RTOG 0848.

PURPOSE: NRG/Radiation Therapy Oncology Group 0848 is a 2-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiation therapy (RT) after adjuvant chemotherapy (second step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed on each patient who underwent RT. This analysis aims to evaluate adherence to protocol-specified contouring and treatment planning and to report the types and frequencies of deviations requiring revisions. METHODS AND MATERIALS: In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume through the creation of specific regions of interest. The planning target volume was a uniform 0.5 cm clinical treatment volume expansion. One of 2 radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and resubmitted until approved. Treatment started after final approval of the RT plan. RESULTS: From 2014 to 2018, 354 patients were enrolled in the second randomization. Of these, 160 patients received RT and were included in the QA analysis. Resubmissions were more common for patients planned with 3-dimensional conformal RT (43%) than with intensity modulated RT (31%). In total, at least 1 resubmission of the treatment plan was required for 33% of patients. Among patients requiring resubmission, most only needed 1 resubmission (87%). The most common reasons for resubmission were unacceptable deviations with respect to the preoperative gross target volume (60.7%) and the pancreaticojejunostomy (47.5%). CONCLUSION: One-third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on real-time, pretreatment QA in trials evaluating the use of RT, particularly for pancreas cancer. Rigorous QA is critically important for clinical trials involving RT to ensure that the true effect of RT is assessed. Moreover, RT QA serves as an educational process through providing feedback from specialists to practicing radiation oncologists on best practices.

A Phase Ib Dose-Escalation Study of LCL161 Plus Oral Topotecan for Patients With Relapsed/Refractory Small Cell Lung Cancer and Select Gynecologic Malignancies.

BACKGROUND: This was an open-label, multicenter, single-arm phase Ib dose-escalation study of oral LCL161 administered in combination with oral topotecan in patients with relapsed/refractory small cell lung cancer (SCLC) and select gynecological cancers. METHODS: Cohorts of 3-6 patients initiated treatment with LCL161 and topotecan in escalating doses. LCL161 was administered orally on days 1, 8, and 15 of each 21-day cycle; topotecan was administered orally for the first 5 days of each 21-day cycle. RESULTS: A total of 35 patients were enrolled in 6 cohorts; 30 patients were female; 4 patients had SCLC and 19 patients had ovarian cancer. Median prior lines of therapy were 3 (1-10). Median duration of treatment was 7.1 weeks (0.1-174). The most frequent grade 3/4 treatment-related adverse events were thrombocytopenia (51.43%) and anemia (31.43%). ORR was 9.7%; 58% of patients had SD. The study was stopped early before the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) were determined. CONCLUSION: The addition of LCL161 to oral topotecan caused more myelosuppression when dosed together than what was associated with either drug alone. Moreover, the drug combination did not improve outcomes. The study was terminated early (ClinicalTrials.gov Identifier: NCT02649673).

Prognostic impact of natural killer cell recovery on minimal residual disease after autologous stem cell transplantation in multiple myeloma.

INTRODUCTION: Natural killer cells are a potent effector lymphocyte subset that can induce cytotoxicity without the need for antigen sensitization or presentation. NK cells are a tempting target -for immune therapy, monoclonal antibody, or genetic engineering-to enhance immune surveillance mechanisms against myeloma cells. MATERIALS AND METHODS: We hypothesized an association between natural killer cell recovery after autologous stem cell transplantation (ASCT) and disease outcomes in multiple myeloma patients. We concluded a prospective study that started enrolling patients in January 2020 to identify the association between absolute NK cell count two to three after ASCT and disease outcomes after autologous stem cell transplantation in multiple myeloma using univariate and multivariate analysis. RESULTS: Natural killer cell recovery was evaluated during the third month after ASCT, day +60 to +90 post-ASCT. Our patients had a mean NK cell count of 90.53, ranging from 14 to 282 Cell/µL (Std Dev 84.64 Cell/µL). The odds of having a minimal residual disease (MRD-positivity) among patients with partial remission before transplantation is four times higher than patients with very good partial response or better (95% confidence interval 0.45-35.79). Our patients were classified into two groups based on MRD status after ASCT, an MRD-negative group of eight participants and an MRD-positive group of seven participants. The mean absolute NK cell count was significantly higher in the MRD-negative cohort, 131.38 Cell/µL, versus 43.86 Cell/µL in the MRD-positive group (p = 0.049). CONCLUSION: We conclude that for multiple myeloma patients treated with ASCT, high absolute NK cell counts two to three months after ASCT is an independent predictor for MRD negativity.

A Phase 1b Trial of Prexasertib in Combination with Standard-of-Care Agents in Advanced or Metastatic Cancer.

BACKGROUND: The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy. OBJECTIVES: The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations. PATIENTS AND METHODS: This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib-drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8). Alternate dose schedules/regimens intended to mitigate toxicity and maximize dose exposure and efficacy were also explored in sub-parts. RESULTS: In Part A, the maximum tolerated dose (MTD) of prexasertib in combination with cisplatin (75 mg/m2) was declared at 80 mg/m2, with cisplatin administered on Day 1 and prexasertib on Day 2 of a 21-day cycle. The overall objective response rate (ORR) in Part A was 12.7%, and 28 of 55 evaluable patients (50.9%) had a decrease in target lesions from baseline. The most frequent treatment-related adverse events (AEs) in Part A were hematologic, with the most common being white blood cell count decreased/neutrophil count decreased, experienced by 73.0% (any grade) and 66.7% (grade 3 or higher) of patients. In Part B, an MTD of 70 mg/m2 was established for prexasertib administered in combination with cetuximab (500 mg /m2), both administered on Day 1 of a 14-day cycle. The overall ORR in Part B was 4.9%, and 7 of 31 evaluable patients (22.6%) had decreased target lesions compared with baseline. White blood cell count decreased/neutrophil count decreased was also the most common treatment-related AE (56.1% any grade; 53.7% grade 3 or higher). In Parts A and B, hematologic toxicities, even with the addition of prophylactic granulocyte colony-stimulating factor, resulted in frequent dose adjustments (> 60% of patients). In Part C, evaluation of prexasertib + pemetrexed was halted due to dose-limiting toxicities in two of the first three patients; MTD was not established. In Part D, the MTD of prexasertib in combination with 5-fluorouracil (label dose) was declared at 40 mg /m2, both administered on Day 1 of a 14-day cycle. In Part D, overall ORR was 12.5%. CONCLUSIONS: This study demonstrated the proof-of-concept that prexasertib can be combined with cisplatin, cetuximab, and 5-fluorouracil. Schedule was a key determinant of the tolerability and feasibility of combining prexasertib with these standard-of-care agents. Reversible hematologic toxicity was the most frequent AE and was dose-limiting. Insights gleaned from this study will inform future combination strategies for the development of prexasertib and next-generation CHK1 inhibitors. CLINICALTRIALS. GOV IDENTIFIER: NCT02124148 (date of registration 28 April 2014).

Tolerability and antitumor activity of cemiplimab, a human monoclonal anti-PD-1, as monotherapy in patients with pretreated non-small cell lung cancer (NSCLC): Data from the Phase 1 NSCLC expansion cohort.

OBJECTIVES: Blockade of programmed cell death-1 (PD-1) and its ligand (PD-L1) has transformed the treatment of NSCLC. In a first-in-human, Phase 1, dose escalation and cohort expansion study, cemiplimab, a monoclonal antibody directed against PD-1, was evaluated for the treatment of patients with advanced solid tumors (NCT02383212). Here, we report results in patients with advanced NSCLC from the dose expansion cohort. MATERIALS AND METHODS: Immune-checkpoint inhibitor naive patients with advanced NSCLC (stage III/IV), irrespective of PD-L1 status, who had progressed after, or were refractory to first- or later-line therapy were enrolled and received cemiplimab 200 mg every 2 weeks intravenously for up to 48 weeks. Primary study objectives were to assess safety and tolerability, and to evaluate clinical activity of cemiplimab. RESULTS: Twenty patients with NSCLC were enrolled. Median age was 64.0 years (range: 50-82); 65.0 % were male; 80.0 % had an ECOG performance status of 1; 60.0 % had a histology of adenocarcinoma. Median number of prior lines of systemic therapy was 2 (range: 1-4). Median duration of follow-up was 7.0 months (range: 1.0-18.2). All patients experienced ≥1 treatment-emergent adverse event (TEAE) of any grade. Most common TEAEs were arthralgia, asthenia, cough, and dyspnea (each 4/20; 20.0 %). Grade ≥3 TEAEs occurred in 60.0 % (12/20) of patients. Of patients with measurable disease per independent central review (ICR), five had partial response (PR), four had stable disease (SD) and 10 had progressive disease. Objective response rate (ORR; complete response + PR) was 25.0 % (95 % CI: 8.7-49.1 %). Duration of response exceeded 8 months in four of the five responding patients at the time of data cut-off (April 30, 2019). The disease control rate per ICR (ORR + SD) was 50.0 % (95 % CI: 27.2-72.8 %). CONCLUSION: Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated patients with NSCLC.

Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma: Final results of cohorts A, G, H and I of IVY Phase I study.

Interleukin (IL)-10 has anti-inflammatory and CD8+ T-cell-stimulating properties. Pegilodecakin (pegylated recombinant human IL-10) induces intratumoral antigen-specific CD8 + T-cells and upregulates IFNγ and major histocompatibility complexes (MHC) I and II. Pegilodecakin has single-agent activity with manageable toxicity in advanced renal cell carcinama (aRCC) (data cutoff 24 March 2016). Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long-term follow-up with pegilodecakin + anti-programmed cell death 1 (anti-PD-1) inhibitors (data cutoff 19 February 2019). Phase 1/1b multi-cohort dose escalation IVY study enrolled 353 patients. Sixty-six patients with aRCC were treated with pegilodecakin alone or with pazopanib or anti-PD-1 inhibitor in cohorts A, G, H and I (data cutoff 19 February 2019). Primary endpoints included safety and tolerability. Secondary endpoint was tumor response by immune-related response criteria (irRC). Pegilodecakin plus nivolumab or pembrolizumab yielded median progression-free survival (mPFS) of 13.9 months and 6-month PFS probability of 60%, 76% 1-year overall survival (OS) probability and 61% 2-year OS probability. Pegilodecakin monotherapy produced mPFS of 1.8 months, 6-month PFS probability 25%, 1-year OS 50%, and 2-year OS 17%. Median OS was not reached in both combinations. Objective response rates (ORRs) were 33% with pazopanib and 43% with anti-PD-1. Most common Grade 3/4 treatment-related adverse events included anemia, thrombocytopenia and hypertriglyceridemia. In these heavily pretreated renal cell carcinama cohorts of IVY, pegilodecakin+anti-PD-1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti-PD-1 inhibitors was consistent as previously reported.

Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer.

PURPOSE: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). METHODS: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection. RESULTS: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m2 dose would induce a 40-50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03. CONCLUSION: Integrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib. CLINICALTRIALS. GOV IDENTIFIERS: NCT02243150; NCT02499770; NCT02514447.

Immunologic and tumor responses of pegilodecakin with 5-FU/LV and oxaliplatin (FOLFOX) in pancreatic ductal adenocarcinoma (PDAC).

Background Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited and checkpoint blockade inhibitors have been disappointing in this disease. Pegilodecakin has demonstrated single agent anti-tumor activity in immune-sensitive tumors. Phase 1 and preclinical data indicate synergy of pegilodecakin with 5-FU and platins. We assessed the safety and activity of pegilodecakin+FOLFOX in patients with PDAC. Methods IVY (NCT02009449) was an open-label phase 1b trial in the United States. Here we report on all enrolled patients from cohort C. Heavily pretreated patients were treated with pegilodecakin (self-administered subcutaneously daily at 2.5, 5, or 10 µg/kg) + 5-flurouracil/leucovorin/oxaliplatin (FOLFOX), dosed per manufacturers prescribing information, until tumor progression. Eligible patients had measurable disease per immune-related response criteria (irRC), were ≥ 18 years of age, and had ECOG performance status of 0 or 1. Patients were evaluated for primary(safety) and secondary (tumor response per irRC) endpoints. Results From 5 August 2014-12 July 2016, 39 patients enrolled in cohort C. All patients were evaluable for safety. In this advanced population, regimen had manageable toxicities with no immune-related adverse events (irAEs) greater than grade 1. The most common grade 3/4/5 TEAEs were thrombocytopenia (21[53.8%] of 39) and anemia (17[43.6%] of 39). In evaluable PDAC patients, the best overall response of pegilodecakin+FOLFOX was 3(14%) with CRs in 2(9%) patients. Conclusions Pegilodecakin+FOLFOX had an acceptable tolerability profile in PDAC, with no substantial irAEs seen, and promising efficacy with the combination yielding a 2-year OS of 24% (95% CI 10-42). These data led to the phase 3 study with pegilodecakin+FOLFOX as second-line therapy of PDAC (SEQUOIA).

Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study.

INTRODUCTION: Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation). METHODS: In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m2 or placebo before topotecan 1.5 mg/m2 on days 1-5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy. RESULTS: Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P < 0.0001) and occurrence of SN (40.6% versus 75.9%; adjusted one-sided P = 0.016), with numerical improvements in additional neutrophil, red blood cell, and platelet measures. Patients receiving trilaciclib had fewer grade ≥ 3 hematologic adverse events than patients receiving placebo, particularly neutropenia (75.0% versus 85.7%) and anemia (28.1% versus 60.7%). Myelopreservation benefits extended to improvements in PROs, specifically in those related to fatigue. Antitumor efficacy was comparable between treatment arms. CONCLUSIONS: Compared with placebo, the addition of trilaciclib prior to topotecan for the treatment of patients with previously treated ES-SCLC improves the patient experience of receiving chemotherapy, as demonstrated by a reduction in chemotherapy-induced myelosuppression, improved safety profile, improved quality of life and no detrimental effects on antitumor efficacy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02514447.

Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA-Mutant Cancers.

PURPOSE: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib. PATIENTS AND METHODS: Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. RESULTS: A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. CONCLUSIONS: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.

Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis.

BACKGROUND: Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma. METHODS: Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome. RESULTS: 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24-43), and median treatment duration was 2.8 months (range 0.5-42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses. CONCLUSIONS: After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.

Safety and Clinical Activity of MEDI1873, a Novel GITR Agonist, in Advanced Solid Tumors.

PURPOSE: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor-related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. PATIENTS AND METHODS: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. RESULTS: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug-antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. CONCLUSIONS: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.

BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours. METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 µg/kg or 20 µg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449. FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26·9 months (IQR 22·3-31·5) for patients with non-small-cell lung cancer, 33·0 months (29·2-35·1) for those with melanoma, and 22·7 months (20·9-27·0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma). INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.

A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors.

Purpose Navicixizumab (OMP-305B83) is a bispecific antibody that inhibits delta-like ligand 4 and vascular endothelial growth factor. This Phase 1a trial assessed escalating doses of navicixizumab in refractory solid tumors patients. Design A 3 + 3 dose escalation design was used followed by the treatment of additional patients in an expansion cohort. Study objectives were determination of the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, immunogenicity and efficacy. Results Sixty-six patients were treated once every 3 weeks in 8 dose-escalation cohorts (0.5, 1, 2.5, 3.5, 5, 7.5, 10, and 12.5 mg/kg) and an expansion cohort (7.5 mg/kg). The median age was 60 years and 68% of the patients were female. The most commonly enrolled tumor types were ovarian (12), colorectal (11) and breast, pancreatic, uterine and endometrial (4 each) cancers. As only 1 dose limiting toxicity occurred, the maximum tolerated dose was not reached, but 7.5 mg/kg was chosen as the dose for the expansion cohort. The treatment related adverse events (≥15% of patients) were hypertension (57.6%), headache (28.8%), fatigue (25.8%), and pulmonary hypertension (18.2%). Pulmonary hypertension was mostly asymptomatic at doses ≤5 mg/kg (6 Gr1, 1 Gr2), but was more severe at higher doses (4 Gr2, 1 Gr3). Navicixizumab's half-life was 11.4 days and there was a moderate (29%) incidence of anti-drug antibody formation. Four patients (3 ovarian cancer, 1 uterine carcinosarcoma) had a partial response and 17 patients had stable disease. Nineteen patients had a reduction in the size of their target lesions including 7/11 patients with ovarian cancer. Four patients remained on study for >300 days and 2 of these patients were on study for >500 days. Conclusions Navicixizumab can be safely administered with manageable toxicities and these data showed preliminary signs of antitumor activity in multiple tumor types, but was most promising in ovarian cancer. As a result these data justify its continued development in combination Phase 1b clinical trials.

Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade.

The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.