Adjuvant PD-1 Research Articles

Perioperative chemoimmunotherapy in a patient with stage IIIB non-small cell lung cancer.

We present a case of a 56-year-old male patient with stage IIIB (T3N2M0) poorly differentiated squamous cell carcinoma of the lung. Four cycles of chemotherapy were first applied, and the patient had stable disease. However, the patient refused to receive radiotherapy, therefore second-line treatment chemotherapy combined with anti-PD-1 immunotherapy was applied. Partial response was reached at the 4th cycle of chemotherapy combined with anti-PD-1 immunotherapy. The neoadjuvant strategy was prolonged to 10 cycles but no significant change was observed on tumor size. The patient then underwent video-assisted thoracoscopic left lower lobectomy. Eight cycles of adjuvant PD-1 immunotherapy were applied postoperatively. Perioperative immunotherapy demonstrated good curative effect in this patient and no recurrence was observed at the clinic 40 months following surgery. Here we intend to explore the concept of immunotherapy combined with chemotherapy and surgery in neoadjuvant and adjuvant setting, and to investigate the possibility of extending this strategy in patients with stage IIIB non-small cell lung cancer (NSCLC).

IMMU-05. DISRUPTION OF THE CCR2 CHEMOKINE RECEPTOR PATHWAY OVERCOMES THERAPEUTIC RESISTANCE TO PD-1 BLOCKADE IN MALIGNANT GLIOMA

Abstract INTRODUCTION Large scale clinical trials have failed to determine efficacy of adjuvant PD-1 blockade in recurrent glioblastoma (GBM). However, recent phase 2 clinical trial results demonstrating the potential of neo-adjuvant anti-PD-1 treatment have renewed enthusiasm for the use of immune checkpoint inhibitors (ICIs) in GBM. Additional benefit of ICIs in GBM will likely derive from development of novel therapies directed against immunosuppressive resistance mechanisms. Chemokine receptor 2 (CCR2) expressing tumor infiltrative immune suppressive myeloid cells represent a targetable axis within ICI resistant gliomas. We have established that CCR2 disruption unmasks an effect of anti-PD-1 therapy in ICI resistant murine glioma models. However, the mechanism(s) by which combined inhibition of PD-1 and CCR2 achieves efficacy is unknown. OBJECTIVE Determine the impact of combination anti-PD-1 and CCR2 antagonism on immune cells within anti-PD-1 resistant gliomas. METHODS Immune cell characteristics were determined in CCR2 antagonist (CCX872)/anti-PD-1 treated KR158 or 005 GSC glioma-bearing wild type or CCR2+/rfp/CX3CR1+/gfp reporter mice. RESULTS CCX872 increased median survival (32 vs. 50 days, P=.002) in KR158 tumor-bearing animals and in combination with anti-PD-1 significantly increased durable survival (P=.0005). In 005 GSC glioma-bearing mice, combination therapy also enhanced median survival (30 vs. 49 days, P=.005). CCX872 decreased CD45+/CD11bhi/Ly6Chi MDSCs (40%, P=.038) within gliomas, and increased these cells within bone marrow in both models (74%, P=.020). Three distinct intra-tumoral populations of CCR2+ and CX3CR1+ cells were identified in both glioma models including CCR2+/CX3CR1-/CD45hi/CD11blo, CCR2+/CX3CR1+/CD45hi/CD11bhi/Ly6Chi, and CX3CR1+/CD45lo/CD11bhi/F4/80+/MHCII+, with both CCR2+ populations being reduced by CCX872 treatment. Examination of tumor infiltrating lymphocytes revealed both increased presence and decreased exhaustion (PD-1+/Tim3+) of CD4+ (P=.029) and CD8+ (P=.011) T-cells following CCX872/anti-PD-1 treatment. CONCLUSION CCX872/anti-PD-1 combination therapy is effective in clinically relevant murine glioma models, providing a basis to progress this novel combinatorial treatment to human clinical trials.

PCN226 THE COST-EFFECTIVENESS AND RELAPSE-REDUCTION BENEFIT OF INTRODUCING ADJUVANT NIVOLUMAB FOR PATIENTS WITH COMPLETELY WITH RESECTED MELANOMA WITH LYMPH NODE INVOLVEMENT OR METASTATIC DISEASE IN THE UK

The recent introduction of adjuvant treatments for melanoma patients impacts both patient outcomes and the costs for the National Health Service, given the previous standard of care was routine surveillance (RS). We compared the cost-effectiveness and relapse-reduction benefit of adjuvant PD-1 inhibitor nivolumab versus RS. A state-transition cost-effectiveness model was developed to compare nivolumab with RS for melanoma patients with lymph node involvement or metastatic disease after complete resection, subsequently used within the UK appraisal process. Recurrence-free survival (RFS) was estimated based on a patient-level meta-regression of the Phase III trial CheckMate 238, which compared nivolumab with ipilimumab, and CA184-029, which compared ipilimumab with placebo. Post relapse survival was estimated from weighted metastatic melanoma survival from the literature and loco-regional survival from CA184-029. The model considered a 60 year life-time horizon and included drug, administration, disease monitoring, adverse event, subsequent treatment and terminal care costs. The model structure enabled extensive testing of uncertainty including the impact of immunotherapy re-treatment. Quality of life inputs were based on EQ-5D utility data collected in CheckMate 238. The main cost driver was adjuvant treatment, however, adjuvant treatments reduced downstream costs of monitoring, subsequent therapy and terminal care as a result of improved RFS. Nivolumab resulted in an overall cost difference of £32,624 versus RS and an improved quality-adjusted life year gain (QALY) of 1.81 over a patient’s lifetime. This resulted in an incremental cost-effectiveness ratio (ICER) of £18,018 per QALY gained. Despite the limitations of Markov modelling, the model structure allowed for a full exploration of uncertainty around key clinical parameters demonstrating that adjuvant nivolumab is a highly cost-effective treatment option resulting in fewer relapses, predicted increased OS and reduced downstream treatment costs versus RS.

Concurrent and Adjuvant PD-1 Blockade Combined With Induction Chemotherapy Plus Radiotherapy in Nasopharyngeal Carcinoma

Concurrent and Adjuvant PD-1 Blockade Combined With Induction Chemotherapy Plus Radiotherapy in Nasopharyngeal Carcinoma

Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.

PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study, we investigated the impact of nivolumab therapy on peripheral blood regulatory T cells (Treg) and its relation to patient outcomes. Peripheral blood Tregs and conventional CD4+ T cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq. Percentages of circulating Tregs and phosphorylated-STAT3 (pSTAT3) expression levels were assessed by flow cytometry and validated in an independent cohort of active disease patients. Suppressive function of Tregs was assessed in allogeneic mixed lymphocyte reactions. Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg-suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg-suppressive function. PD-1 blockade also led to IL10 production by T cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL10 production in vitro. These results demonstrate that induction of pSTAT3, reduced suppressive function, and a paradoxical increase in Treg proliferation are novel correlates of patient benefit from PD-1 blockade.

PECULIAR: An open label, multicenter, single-arm, phase 2 study of neoadjuvant pembrolizumab (PEM) and epacadostat (EPA), preceding radical cystectomy (Cy), for patients (pts) with muscle-invasive urothelial bladder cancer (MIUBC).

TPS4595 Background: MIUBC is a systemic disease and > 40% of pts develop recurrence after Cy. Despite neoadjuvant chemotherapy yields Level 1 evidence, it is underutilized worldwide and a small survival improvement is deemed over Cy alone. PEM is an EMA and FDA-approved therapy for metastatic UC after platinum failure or for cisplatin-ineligible pts. EPA, an anti-IDO1 agent, combined with PEM, safely improved the response-rate in UC in phase 1 trial. Our hypothesis is that PEM+EPA, given neoadjuvantly, could further improve downstaging MIUBC. Methods: Pts with T2-T3b N0 UC with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence) will receive 3 cycles of PEM 200mg intravenously, q3 weekly. EPA will be orally taken at the dose of 100 mg BID, from d1 until 10 days before Cy. Cy should be performed within 3 weeks of the last PEM dose. Computed tomography (CT) scan, 18FDG-PET/CT scan, and multiparametric bladder MRI (mpMRI) will be done during screening and before Cy to stage and evaluate response. After Cy, pts will be managed according to EAU guidelines. Adjuvant anti PD-1 therapy is not allowed. PD-L1 status will be assessed using Dako anti-PD-L1 antibody (clone 22C3), relying on the combined positivity score (CPS). Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be included in the ITT analysis. The H1 is pT0≥25% and H0 pT0≤15%. A MinMax 2-stage design will be used to estimate the number of pts required. Out of 71 total pts, with the first stage of 43 pts, ≥6 pT0 will be required in the first stage, and ≥14 pT0 in the whole study population. Correlative research on blood samples will include immune-cell profiling and cytokine assessment. In tumor samples, genomic analyses will be done with FoundationONE test (Foundation Medicine Inc.). Tumor mutational burden (TMB) will be determined on 1.1 Mbp of sequenced DNA and reported as mutations (mut) per megabase (Mb) and microsatellite instability (MSI) will determined on 114 loci (EudraCT number 2017-002379-24). Clinical trial information: 2017-002379-24.

PECULIAR: An open label, multicenter, single-arm, phase 2 study of neoadjuvant pembrolizumab (PEM) and epacadostat (EPA), preceding radical cystectomy (Cy), for patients (pts) with muscle-invasive urothelial bladder cancer (MIUBC).

TPS534 Background: MIUBC is a systemic disease and > 40% of pts develop recurrence after Cy. Despite neoadjuvant chemotherapy yields Level 1 evidence, it is underutilized worldwide and a small survival improvement is deemed over Cy alone. PEM (MK-3475) is the standard-of-care for second-line metastatic UC and is being evaluated as single-agent neoadjuvant therapy for MIUBC (NCT02736266). EPA, an anti-IDO1 agent, combined with PEM, safely improved the response-rate in metastatic UC. Our hypothesis is that PEM+EPA, given neoadjuvantly, could further improve downstaging MIUBC. Methods: Pts with T2-T4a N0 UC with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence), regardless of cisplatin eligibility, will receive 3 cycles of PEM 200mg intravenously, q3 weekly. EPA will be orally taken at the dose of 100 mg BID, from d1 until 10 days before Cy. Cy should be performed within 3 weeks of the last PEM dose. Computed tomography (CT) scan, 18FDG-PET/CT scan, and multiparametric bladder MRI (mpMRI) will be done during screening and before Cy to stage and evaluate response. After Cy, pts will be managed according to EAU guidelines. Adjuvant anti PD-1 therapy is not allowed. PD-L1 status will be assessed on TURB specimen (Dako, clone 22C3), relying on the combined positivity score (CPS, 10% cutoff). Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be includes in the ITT analysis. The H1 is pT0≥20% and H0 pT0≤10%. A 2-stage design will be used to estimate the number of pts required. Out of 90 pts overall, with the first stage of 49 pts, ≥6 pT0 will be required in the first stage, and ≥13 pT0 in the whole study population (80% power and a 2-sided test of significance at the 10% level). Correlative research on tissue/blood samples will include immune-cell profiling, cytokine assessment, gene expression analyses and next-generation sequencing (FoundationOne). Radiologic findings from mpMRI will be associated with pathologic response (EudraCT number 2017-002379-24). Clinical trial information: 2017-002379-24.

A phase III randomized study comparing perioperative nivolumab vs. observation in patients with localized renal cell carcinoma undergoing nephrectomy (PROSPER RCC).

TPS710 Background: The anti-PD-1 antibody nivolumab (nivo) improves overall survival (OS) in metastatic treatment refractory RCC and is generally tolerable. In 2017, there is no standard adjuvant therapy proven to increase OS over surgery alone in non-metastatic (M0) disease. Mouse solid tumor models have revealed an OS benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivo in RCC patients (pts) are showing preliminary feasibility and safety with no surgical delays/complications. PROSPER RCC will examine if the addition of perioperative nivo to radical or partial nephrectomy can improve clinical outcomes in pts with locally advanced RCC. We are implementing a three-pronged, multidisciplinary approach of presurgical priming with nivo followed by resection and adjuvant PD-1 blockade with the goal of increasing cure and recurrence-free survival (RFS) rates in M0 RCC. Methods: Tumor biopsy prior to randomization is mandatory to ensure RCC diagnosis but will also permit unparalleled correlative science in this global, unblinded, phase 3 National Clinical Trials Network randomized study. 766 pts with clinical stage ≥T2 or any node positive M0 RCC of any histology will be enrolled. The study arm will receive nivo 240mg IV for 2 doses prior to surgery followed by adjuvant dosing for 9 mo (q2 wks x 3 mo followed by q4 wks x 6 mo). The control arm will undergo the current standard of care: surgical resection followed by observation. Pts are stratified by clinical T stage, node positivity, and histology. There is 84.2% power to detect a 14.4% absolute increase in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 yrs (HR 0.70). The study is also powered to detect a significant OS benefit (HR 0.67). Safety, feasibility, and quality of life are key secondary endpoints. PROSPER RCC exemplifies team science and incorporates a host of correlative work to examine the significance of the baseline immune milieu and changes induced by neoadjuvant priming and to identify predictive gene expression patterns. New collaborations welcomed. Clinical trial information: NCT03055013.

The Impact of the Timing of PD-1 Inhibition on Disease Control for Brain Metastases Treated with Stereotactic Radiosurgery

PD-1 inhibitors have shown single-agent activity against brain metastases, but their synergy with radiosurgery is unknown. The purpose of this study was to evaluate whether the timing of anti-PD-1 therapy when combined with stereotactic radiosurgery (SRS) for brain metastases may affect treatment outcomes. For this retrospective study, an institutional database of patients with intracranial metastases treated with SRS between 2014 and 2016 was reviewed for individuals who had received immunotherapy (IT) with the PD-1 inhibitors Nivolumab and Pembrolizumab. Patients were divided into two cohorts based on the timing of IT. Individuals were classified as having received concurrent IT if they received anti-PD-1 agents prior to or within within three weeks of SRS. Adjuvant IT was defined as administration of PD-1 inhibitors more than three weeks after SRS. The student's t-test aFisher’s exact test were utilized to compare baseline clinical and demographic covariates. The Kaplan-Meier method and log-rank test were then used to estimate and compare local control (LC), distant brain control (DBC), and overall survival (OS) between these two cohorts. Cox proportional hazards models were used to identify predictors of these outcome metrics. Fifty patients were eligible for this analysis, and the majority had been diagnosed with either metastatic non-small cell lung cancer (NSCLC, n=24) or melanoma (n=22). Twenty-seven (54%) received concurrent IT, and 23 (46%) received adjuvant IT (median time between SRS and adjuvant IT: 3.1 months, range 0.9 months – 11.9 months). Concurrent CTLA-4 was administered along with PD-1 blockade in only 2 patients (4%). Twelve patients (24%) had previously undergone whole brain radiation therapy (WBRT), and 37 patients (74%) had received prior chemotherapy. Mean follow-up time was 7.1 months. Baseline clinical and demographic characteristics were comparable between the two groups. At six months, LC was 100% for patients receiving concurrent IT and 76% in the adjuvant IT group (p=0.04). Similarly, DBC was 71% and 41%, respectively ( p=0.02). OS was not significantly different between the two groups (p = 0.36). On multivariate analysis, controlling for age, performance status, and prior WBRT, concurrent IT was predictive of both improved LC (HR = 0.07, p = 0.049) and improved DBC (HR = 0.30, p = 0.02). Subset analysis demonstrates that improved DBC with the administration of concurrent IT was seen in patients with both melanoma (p=0.02) and NSCLC (p=0.04). In this heavily pre-treated cohort undergoing radiosurgery for brain metastases, concurrent PD-1 IT administered within three weeks of SRS appears to improve LC and DBC when compared to adjuvant PD-1 blockade.

Transforming the Perioperative Treatment Paradigm in Non-Metastatic RCC-A Possible Path Forward.

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

A phase III randomized study comparing perioperative nivolumab vs. observation in patients with localized renal cell carcinoma undergoing nephrectomy (PROSPER RCC).

TPS4596 Background: The anti-PD-1 antibody nivolumab (nivo) improves overall survival (OS) in metastatic treatment refractory RCC and is generally tolerable. In 2017, there is no standard adjuvant therapy proven to increase OS over surgery alone in non-metastatic (M0) disease. Mouse solid tumor models have revealed an OS benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivo in RCC patients (pts) have shown preliminary feasibility and safety with no surgical delays or complications. The PROSPER RCC trial will examine if the addition of perioperative nivo to radical or partial nephrectomy can improve clinical outcomes in pts with locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in M0 RCC, we propose a three-pronged, multidisciplinary approach of presurgical priming with nivo followed by resection and adjuvant PD-1 blockade. Methods: Tumorbiopsy prior to randomization is mandatory to ensure the correct diagnosis and will permit unparalleled correlative science in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. 766 pts with clinical stage ≥T2 or any node positive M0 RCC of any histology will be enrolled. The study arm will receive nivo 240mg IV for 2 doses prior to surgery followed by nivo adjuvantly for 9 months (q2 wks x 3 mo followed by q4 wks x 6 mo). The control arm will undergo the current standard of care: surgical resection followed by observation. Pts are stratified by clinical T stage, node positivity, and histology. There is 84.2% power to detect a 14.4% absolute increase in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 yrs (HR 0.70). The study is also powered to detect a significant OS benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the significance of the baseline immune milieu and changes after neoadjuvant priming and to identify predictive gene expression patterns. Additional collaborations are welcomed.

395O Potential predictive value for adjuvant PD-1 blockade based on histologic subtype in resected lung adenocarcinoma

395O Potential predictive value for adjuvant PD-1 blockade based on histologic subtype in resected lung adenocarcinoma

PD-L1 expression, immune cell correlates, and PD-1+ lymphocytes in sentinel lymph node positive melanoma patients: Implications for adjuvant PD-1 clinical trials.

e20011 Background: Patients with positive sentinel lymph node biopsies (SLNB) that undergo a completion lymphadenectomy have variable five-year survival rates ranging from 39-70%. PD-1 and PD-L1 in...