Initiation Of Nivolumab Therapy Research Articles

A pilot study on EORTC or PERCIST for the prediction of progression-free survival with nivolumab therapy in advanced or metastatic gastric cancers: A STROBE-compliant article.

Recent breakthrough results from immune checkpoint inhibitors (ICIs) have paved the way to a new era of cancer immunotherapy, and have thus led to a paradigm shift of cancer treatment. In particular, inhibition of the antiprogrammed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis with ICI, including nivolumab and pembrolizumab, has been emerging as a novel treatment strategy for advanced gastric cancers. An accurate noninvasive assessment of the response to ICI is important for the management of patients with advanced or metastatic gastric cancer.To examine whether the European Organization for Research and Treatment of Cancer (EORTC) and PET Response Criteria in Solid Tumors (PERCIST) are valuable for predicting progression-free survival (PFS) in patients with advanced or metastatic gastric cancers treated with nivolumab.Six patients with advanced or metastatic gastric cancers who underwent 18F-FDG-PET/computed tomography (CT) scans before, and from 2 to 6 months after initiation of nivolumab therapy between September 2017 and August 2019, were evaluated retrospectively. The correlation between tumor progression and EORTC or PERCIST was assessed with the Fisher's exact test. The PFS was assessed with the Kaplan–Meier method.Two patients were alive without progression, and the remaining 4 patients exhibited tumor progression. Two patients without progression were classified as partial metabolic response (PMR) patients based on EORTC or PERCIST, while the other 4 patients with progression were classified as progressive metabolic disease (PMD) patients based on EORTC (P = .067), or stable metabolic disease (SMD) patients, or PMD patients based on PERCIST (P = .067).The mean and median PFS of all patients was 12.7 months (95% confidence interval [CI], 4.9–20.4 months) and 5 months (95%CI, 4.0–11.0 months). Two EORTC or PERCIST PMR patients showed significantly longer median PFS compared with 4 non-PMR patients (not reached vs 4.0 months, P = .044). Three PERCIST PMR or SMD patients also showed significantly longer median PFS compared with 3 PMD patients (not reached vs 4.0 months, P = .022). These results suggest that EORTC or PERCIST has the potential to predict PFS of patients with advanced or metastatic gastric cancers treated by nivolumab and further studies are needed to determine its value in larger study populations.

ニボルマブ投与開始後に発症した劇症1型糖尿病症例―システマティック・レビューによる比較を含めて―

ニボルマブ投与開始後に発症した劇症1型糖尿病症例―システマティック・レビューによる比較を含めて―

New-onset graves\u2019 disease after the initiation of nivolumab therapy for gastric cancer: a case report

BackgroundImmune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) including thyroid dysfunction. There are only a few reports on Graves’ disease induced by ICIs. We report a case of new-onset Graves’ disease after the initiation of nivolumab therapy in a patient receiving gastric cancer treatment.Case presentationThe patient was a 66-year-old Japanese man, who was administered nivolumab (240 mg every 3 weeks) as a third-line therapy for stage IVb gastric cancer. His thyroid function was normal before the initiation of nivolumab therapy. However, he developed thyrotoxicosis before the third administration of nivolumab. Elevated, bilateral, and diffuse uptake of radioactive tracer was observed in the 99mTc-pertechnetate scintigraphy. Furthermore, the thyroid-stimulating hormone receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) test results, which were negative before the first administration of nivolumab, were positive after starting the therapy. The patient was diagnosed with Graves’ disease, and the treatment with methimazole and potassium iodide restored thyroid function.ConclusionsThis is the first complete report of a case of new-onset Graves’ disease after starting nivolumab therapy, confirmed by diffusely increased thyroid uptake in scintigraphy and the positive conversion of antibodies against thyroid-stimulating hormone receptor. It is important to perform thyroid scintigraphy and ultrasonography to accurately diagnose and treat ICI-induced thyrotoxicosis, because there are various cases in which Graves’ disease is developed with negative and positive TRAb titres.

Paraneoplastic dermatomyositis appearing after nivolumab therapy for gastric cancer: a case report

BackgroundWhile dermatomyositis is often associated with malignancy, several autoimmune diseases like myositis can be caused by immune checkpoint inhibitors. Differentially diagnosing malignancy-associated dermatomyositis or myositis caused by immune checkpoint inhibitors is sometimes difficult, particularly when a patient with malignancy shows the symptoms of myositis after checkpoint inhibitor administration. We experienced such a case in which we had difficulties in diagnosing paraneoplastic dermatomyositis or drug-associated myositis. In this case, all of our team initially assumed that the diagnosis was myositis caused by immune checkpoint inhibitors. However, it turned out finally that the diagnosis was paraneoplastic dermatomyositis. Because the diagnosis was unexpected, we report here.Case presentationWe report the case of a 71-year-old Japanese man who developed clinical symptoms of myositis, such as muscle aches and weakness, after initiation of nivolumab therapy for his gastric cancer. He was initially diagnosed with nivolumab-induced myositis, because the myositis symptoms appeared after nivolumab administration, and nivolumab is known to trigger various drug-associated autoimmune diseases. However, according to his characteristic skin lesions, the type of muscle weakness, his serum marker profiles, electromyography of his deltoid muscle, and magnetic resonance imaging, he was finally diagnosed as having paraneoplastic dermatomyositis. Accordingly, treatment with intravenously administered corticosteroid pulse treatment, immunoglobulin injection, and tacrolimus was applied; his symptoms subsequently improved. However, to our regret, at day 142 after administration, he died due to rapid worsening of his gastric cancer.ConclusionDifferentially diagnosing paraneoplastic dermatomyositis or drug-associated myositis caused by immune checkpoint inhibitors is difficult in some cases. The differential diagnosis is crucial because it influences the decision regarding the appropriateness of the use of immunosuppressive treatment against the autoimmune diseases as well as the decision regarding the appropriateness of the continuous use of immune checkpoint inhibitors against the primary cancers. Because subclinical autoimmune disease may become overt after administering immune checkpoint inhibitors, non-apparent autoimmune diseases, which have already existed, should also be considered to avoid the delay of appropriate treatment, when symptoms of autoimmune diseases are recognized.

Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab

ObjectivesImmune-related adverse events (irAEs) develop in a subset of patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors. The relationship between presence of irAEs and prognosis in these patients remains unknown. Thus, we evaluated the prognostic impact of irAEs caused by nivolumab therapy in mRCC patients who had received prior molecular-targeted therapies. MethodsWe retrospectively evaluated 47 patients with mRCC who were treated with nivolumab after receiving at least 1 molecular-targeted therapy. The irAEs assessed in this study included cutaneous, gastrointestinal, endocrine, pulmonary, hepatobiliary, renal, and other (rheumatic disease and pancreatitis) manifestations. The grade of irAEs was defined based on the Common Terminology Criteria for Adverse Events version 4.0. ResultsIn total, 23/47 patients (48.9%) experienced 29 irAEs. The most frequent irAE was rash/pruritus (12/23, 52.2%). The median progression-free survival (PFS) and overall survival after the initiation of nivolumab therapy were significantly longer in patients with irAEs than in those without irAEs (PFS: 13.1 vs. 4.87 months, P < 0.0001; overall survival: 26.0 vs. not reached, P = 0.0072). The multivariate analysis of PFS showed that irAE development was an independent prognostic factor (hazard ratio: 0.25, P = 0.0009). Additionally, the 2-cycle landmark analysis showed that PFS was significantly longer in patients with irAEs than in those without irAEs (median: not reached vs. 6.28 months, P = 0.0279). ConclusionsThis retrospective study revealed a significant association between nivolumab-associated irAEs and prognosis in previously treated mRCC. Further prospective studies are necessary to confirm our findings.

Correlation between the magnitude of best tumor response and patient survival in nivolumab therapy for metastatic renal cell carcinoma.

The correlation between the magnitudes of best tumor response (bTR) and patient survival in immune checkpoint inhibitor therapy for metastatic renal cell carcinoma (mRCC) remains unclear. In this article, we retrospectively investigated the prognostic association of the magnitude of bTR in nivolumab therapy for mRCC. Fifty-five patients treated with nivolumab after failure of at least one molecular-targeted therapy were evaluated. Assessment of the magnitude of bTR was based on the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. Endpoints were progression-free survival (PFS) and overall survival (OS) after the initiation of nivolumab therapy. In regard to the magnitude of bTR, complete response, partial response, stable disease, and progressive disease were observed in three (5.46%), 15 (27.3%), 19 (34.5%), and 18 (32.7%) patients, respectively. PFS and OS were significantly correlated with the magnitude of bTR (median PFS: not reached (N.R.) [95% confidence interval (CI) 16.8-N.R.] vs. 13.0 [8.38-56.0] vs. 5.95 [4.27-7.30] vs. 1.92 [0.53-3.91] months, p < 0.0001; OS: N.R. [N.R.-N.R.] vs. N.R. [21.4-N.R.] vs. 23.3 [23.3-N.R.] vs. 7.36 [1.41-N.R.] months, p < 0.0001). In addition, multivariate analyses show that the magnitude of bTR was an independent factor for PFS (p < 0.0001) and OS (p = 0.0010). In conclusion, this retrospective study shows the significant correlation between the magnitude of bTR and patient survival in nivolumab therapy for mRCC. The magnitude of bTR can be an effective surrogate marker for survival.

Highlights of This Issue

Hyperprogression (HP) is a paradoxical boost in tumor growth described in a subset of patients treated with immune checkpoint inhibitors that has ignited an international debate on whether this phenomenon is true or only representative of a worse prognosis. Mimicking HP in preclinical models with distinctive genetic profile allowed Lo Russo and colleagues to uncover a critical role of innate immunity in this process that involves the interaction of anti-PD-1 antibody-Fc with FcR on M2-like macrophages. A distinctive immunophenotype of HP tumors characterized by clustered macrophages with epithelioid morphology is potentially able to predict HP.Anti-PD-1 antibodies are approved for non-small cell lung cancer treatment, yet only one-quarter of patients benefit from this therapy. PD-L1 labelling and mutational tumor burden could help the clinician to predict outcome; however, optimal predictive biomarkers are lacking. This study by Richard and colleagues demonstrates that exome analysis before initiation of nivolumab therapy can be highly predictive of PFS and OS when analyzed in multiple dimensions, rather than using only mutational tumor burden. These findings have far-reaching implications in this age of precision medicine for an efficient immunotherapy and should increase the interest of complex analysis of exome for precision medicine in immuno-oncology.Urothelial carcinomas of the upper tract (UTUC) and bladder (UCB) exhibit similar histologic appearance but have distinct clinical and molecular characteristics. To investigate genomic differences between UTUC and UCB, Audenet and colleagues leveraged a prospective molecular characterization initiative to analyze 649 urothelial carcinomas using a targeted next-generation sequencing (NGS) platform. They identified significant differences in the prevalence of common genomic alterations. However, in individual patients with a history of both tumors, the UCB and UTUC were always clonally related. Furthermore, targeted NGS was a robust methodology for identifying UTUC patients in need of germline analysis for Lynch syndrome.The bifunctional roles of SCAN-Zinc finger transcription factor MZF1 in carcinogenesis remains unclear. Based on their previous observations that the garlic-derived compound diallyl trisulfide (DATS) suppresses gastric cancer (GC) growth and enhances its chemosensitivity through epigenetic upregulation of MT2A to attenuate NF-κB activation, Lin and colleagues found an association of MZF1 with MT2A in human GC cell lines and primary tumors, and reveal that MT2A recruits MZF1 to form MT2A/MZF1 complex binding to NFKBIA promoter to establish an “MT2A/MZF1-NF-κB” pathway in suppressing gastric carcinogenesis and enhancing GC chemosensitivity. MT2A/MZF1 thus represents a diagnostic marker and a therapeutic target for GC.

Nivolumab-induced oral and cutaneous bullous pemphigoid: A case report

Introduction: Nivolumab-induced oral and cutaneous bullous pemphigoid have been rarely reported in the literature. Observations: A 64-year-old male patient was treated with nivolumab for melanoma. He presented with oral lesions in the palatal and gingival mucosal lesions. Nine months after the initiation of nivolumab therapy, a cutaneous bullous pemphigoid was found on his right forearm. The level of anti-BPAG2 (or anti-BP 180) was positive with a rate of 83 AU/mL, thereby confirming the diagnosis of bullous pemphigoid. His oral mucosa, first in the posterolateral area of the palate and then in the gingiva, was affected 3 months later. Histological examination revealed a subepidermal bulla with few eosinophils. Comments: Nivolumab is a novel monoclonal human antibody used to potentiate T cell responses, particularly anti-tumor responses. The first diagnosis considered was lichen planus, and it has been excluded from this study based on histological results. Right from lesion onset after treatment initiation, nivolumab was strongly suspected to cause these mucocutaneous lesions. To investigate the causes and effects of nivolumab-induced oral and cutaneous bullous pemphigoid, it would be necessary to record the regression of these lesions at the end of treatment; however, this is not possible due to ethical reasons. The treatment of lesions primarily involves corticosteroid usage; however, rituximab is also used. Conclusion: Oral surgeons must consider the oral side effects of novel targeted therapies, including those of immunological checkpoint inhibitors.

Post-treatment changes in hematological parameters predict response to nivolumab monotherapy in non-small cell lung cancer patients.

BackgroundThe absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known markers of inflammation. We evaluated whether ANC, ALC, AMC and NLR, both before and after treatment with nivolumab, are indicative markers of overall survival (OS) and evaluated change in NLR as a predictive marker of response in non -small cell lung cancer (NSCLC) patients treated with nivolumab.MethodsA total of 109 patients with advanced NSCLC treated with nivolumab were included. ANC, ALC, AMC and NLR were examined at initiation of nivolumab therapy and after two cycles. The prognostic role of ANC, ALC, AMC and NLR with OS and changes in NLR ratio were examined with Kaplan-Meier curves and proportional hazard model.ResultPost-treatment NLR ≥5 after two cycles of nivolumab was associated with poor OS (median OS in NLR = <5 vs NLR = ≥5 was 29.1 (16.2–40.9) vs 24.2(16.1–36.2) months respectively, p<0.001). In addition NLR increased in non-responders after two cycles of nivolumab by 6.6±21.8 as compared to responders (p = 0.027).ConclusionsPost-treatment ANC, ALC and NLR are independent prognostic factors in NSCLC patients treated with nivolumab. Changes in NLR can be an early biomarker for response in NSCLC patients treated with nivolumab.

Rapid-onset diabetic ketoacidosis secondary to nivolumab therapy.

SummaryWe report a case of a 67-year-old man with type 2 diabetes presented with diabetic ketoacidosis, two weeks after his first dose of nivolumab therapy for non–small-cell lung carcinoma. He was started on empagliflozin two days prior in the setting of hyperglycaemia after the initiation of nivolumab therapy. Laboratory evaluation revealed an undetectable C-peptide and a positive anti-glutamic acid decarboxylase (GAD) antibody. He was treated with intravenous fluids and insulin infusion and was subsequently transitioned to subcutaneous insulin and discharged home. He subsequently has developed likely autoimmune thyroiditis and autoimmune encephalitis.Learning points:Glycemic surveillance in patients receiving immune checkpoint inhibitors is recommended.Early glycemic surveillance after commencement of anti-programmed cell death-1 (PD-1) inhibitors may be indicated in selected populations, including patients with underlying type 2 diabetes mellitus and positive anti-glutamic acid decarboxylase (GAD) antibody.Sodium-glucose co transporter-2 (SGLT2) inhibitors should be used with caution in patients on immunotherapy.

Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report

BackgroundAcute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management.Case presentationWe describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation. Considering their mechanism of action, immune checkpoint inhibitors can alter immunological tolerance to concomitant drugs that have been safely used for a long time. For more than 4 years before the initiation of nivolumab therapy, the patient had been receiving the proton pump inhibitor lansoprazole, known to cause drug-induced ATIN, without significant adverse events including kidney injury. He showed rapid improvement in kidney function in 3 days (creatinine decreased from 2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl. Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive.ConclusionsThe rapid improvement of kidney function after discontinuation and DLST positivity indicate that lansoprazole contributed to the development of ATIN during nivolumab therapy. Considering the time course, it is plausible that nivolumab altered the long-lasting immunological tolerance against lansoprazole in this patient. To the best of our knowledge, this is the first case report of DLST positivity for a drug that had been used safely before the initiation of an immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy.

Isolated Adrenocorticotropic Hormone Deficiency and Severe Hypercalcemia After Destructive Thyroiditis in a Patient on Nivolumab Therapy With a Malignant Melanoma

We describe a 58-year-old man with a malignant melanoma metastasis to the liver. After initiation of nivolumab therapy, he developed destructive thyroiditis and subsequently simultaneous isolated adrenocorticotropic hormone (ACTH) deficiency and severe hypercalcemia. Although isolated ACTH deficiency and hypercalcemia due to nivolumab therapy are both rare occurrences, these conditions can often cause a severe clinical course accompanied by a disturbance of consciousness. Therefore, clinicians should pay attention to these possible side effects of nivolumab if the patients have clinical symptoms, such as fatigue and a disturbance of consciousness.

PS02.09 Use of Systemic Corticosteroids During the First Month of Nivolumab Therapy in Patients with Advanced Non-Small Cell Lung Cancer: Topic: Medical Oncology

Checkpoint inhibitors enhance inherent anti-tumor immune responses and are approved for advanced non-small cell lung cancer (NSCLC), while corticosteroids are also frequently used in these patients to quell inflammation. Based on this mechanistic opposition, it is presumed that immunosuppression by corticosteroids will hinder the efficacy of PD-1 inhibitors, but the true nature and magnitude of their interaction remains unknown. We sought to describe the use of corticosteroids in NSCLC patients receiving the PD-1 inhibitor nivolumab. A single-center retrospective review included patients with advanced NSCLC treated with nivolumab starting between April 2015 and April 2016. The use of immunosuppressive doses of systemic corticosteroids (> 10 mg prednisone per day or equivalent) during nivolumab therapy was recorded and associated with objective outcomes of number of completed nivolumab cycles and median overall survival (OS) from start of nivolumab to death. Continuous variables were compared by the Wilcoxon rank-sum test, and median OS was estimated by the Kaplan-Meier method and compared using the log-rank test. In total, 210 patients with NSCLC were treated with at least one complete cycle (two treatments) of nivolumab. 31% (n=66) received immunosuppressive doses of systemic corticosteroids. The most common indications for concurrent corticosteroids included sequelae from active or treated brain metastases (27%), COPD or other respiratory disease (21%), and disease-related pain and constitutional symptoms such as fatigue and lack of appetite (18%). For patients on immunosuppressive doses of steroids at initiation or within the first 30 days of nivolumab therapy (n=25), the median number of nivolumab cycles was two, compared to five cycles in patients not exposed to corticosteroids (p=0.002). Similarly, the median OS for patients on steroids during their first cycle was 4.3 months (95% CI 2.6 - 9.7), compared to 11 months for patients not on steroids (95% CI 9.6 - 13.8). Eleven patients were treated for potential immune-related adverse events (IRAE) not requiring discontinuation of therapy, while 20 patients (9.5%) discontinued therapy following steroid initiation for IRAE. Nearly one-third of NSCLC patients treated with nivolumab were prescribed concurrent systemic corticosteroids during the course of nivolumab therapy. Patients requiring steroids during initiation of nivolumab therapy had shorter nivolumab treatment, suggesting a lack of clinical benefit, and worse overall survival. This finding requires validation in larger cohorts of patients receiving immune checkpoint inhibitors.

Clinical Course After Initiation of Nivolumab Therapy in Patients with EGFR-Mutated Non-Small Cell Lung Cancer With or Without Pd-L1 Expression

Nivolumab has been reported to be more effective in the subset of non-squamous non-small cell lung cancer (NSCLC) patients with tumors harboring wild-type epidermal growth factor receptor (EGFR) and/or expressing programmed death ligand-1 (PD-L1). However, it is unclear whether PD-L1 expression influences the efficacy of nivolumab in patients with EGFR-mutated NSCLC. Therefore, tumor PD-L1 expression was evaluated in five patients with EGFR-mutated NSCLC who had been treated with nivolumab. We have identified patients with NSCLC harboring EGFR gene mutation retrospectively out of a group of 23 consecutive patients treated with nivolumab at our hospital between January 2016 and March 2017. The tumors of patients with EGFR-mutated NSCLC who had received nivolumab treatment based on clinical judgment were analyzed retrospectively. Tumor PD-L1 expression was evaluated by measurement of the tumor proportion score (TPS) using a rabbit antihuman PD-L1 antibody (clone 22C3). Three patients received the treatment with nivolumab as second line treatment, and two patients received the treatment as third line treatment. One out of five patients had a response with treatment with nivolumab and that was the only patient with a positive PD-L1 expression (TPS of 80–90%). The results of the present study suggest that evaluation of tumor PD-L1 expression might be useful for predicting the efficacy of nivolumab, even in patients with EGFR-mutated NSCLC.

Pre-treatment hematological markers as a predictive biomarker for survival in patients with non-small cell lung cancer treated with nivolumab.

11547 Background: The absolute neutrophil count (ANC), absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known markers of inflammation. We evaluated whether ANC, AMC and NLR are prognostic for overall survival (OS) and evaluated change in NLR as a predictive marker of response per RECIST in non -small cell lung cancer (NSCLC) patients treated with nivolumab. Methods: A total of 115 patients with NSCLC treated with nivolumab were included. ANC, AMC and NLR were examined at initiation of nivolumab therapy and after two cycles. The prognostic role of ANC, AMC and NLR on OS and changes in NLR ratio in responders was assessed using Cox regression model. Results: ANC &gt; 6, AMC &gt; 0.5 and NLR &gt; 2.8 at baseline were independently associated with shorter OS (Hazard ratio (HR) 1.17 (1.08-1.27), p = .00001; HR 4.53 (1.99-10.31), p = 0.04 and HR 1.09 (1.04-1.13), p = 0.0002 . Responders had a decrease in NLR by (median (range) -0.93 (-14.7-52.95), p = 0.03) whereas non-responders had an increase in NLR by (median (range) 0.85 (-8.6-132.9), p = 0.03). Conclusions: ANC, AMC andNLR are independent prognostic factors in NSCLC patients treated with nivolumab. Changes in NLR can be an early biomarker for response with nivolumab in NSCLC patients. [Table: see text]

Nivolumab (Anti-PD1) Therapy for Relapsed/ Refractory Primary Central Nervous System Lymphoma and Primary Testicular Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare and aggressive extranodal non-Hodgkin lymphomas with shared molecular features and a poor prognosis. PCNSL is currently treated with high-dose methotrexate (HD-MTX) based induction chemotherapy. Younger patients who are healthy and eligible for consolidation treatment are considered for whole brain radiation (WBRT) or high-dose chemotherapy with autologous stem-cell transplant (ASCT). Despite this, nearly 50% of patients with PCNSL relapse within 2 years of diagnosis and one third of patients have primary refractory disease. PTL is treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). However, almost 50% of patients with PTL progress after induction treatment, frequently with CNS or contralateral testicular involvement. Treatment options are limited for patients with recurrent and refractory PCNSL or PTL, and the majority of patients ultimately die of their disease.We recently identified frequent 9p24.1/ PD-L1(CD274)/ PD-L2 (PDCD1LG2) copy number alterations and additional translocations in PCNSL and PTL (Chapuy and Roemer et al Blood 2016; 127:869-81). These genetic alterations are associated with increased expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. Activation of PD-1 signaling by PD-L1 or PD-L2 binding leads to a reversible state of T-cell "exhaustion" characterized by decreased T-cell receptor signaling, reduced T-cell proliferation and survival, perturbed metabolism and altered transcription factor expression. The activity of PD-1 blockade in other lymphomas with 9p24.1 alterations such as classical Hodgkin's lymphoma prompted us to test the efficacy of this approach in PCNSL and PTL.Patients and Methods: We treated 5 patients with recurrent/refractory PCNSL and PTL with off-label Nivolumab, a humanized IgG4 monoclonal antibody checkpoint inhibitor that targets PD-1 and blocks binding by PD-L1 or PD-L2. Median age was 64 (range, 54-85) years with a median Karnofsky Performance Score (KPS) of 70 (40-80) %. Four patients had multiply recurrent disease (3 patients with PCNSL and 1 patient with PTL and CNS relapse); 1 patient had primary refractory PCNSL. All patients had been treated with standard of care treatments and had no other available options. Prior therapies included HD-MTX based chemotherapy, pemetrexed, high-dose cytarabine, WBRT and thiotepa-based chemotherapy followed by ASCT. All patients signed informed consent and were treated with nivolumab at 3mg/kg intravenously every 2 weeks. Only 1 patient received corticosteroids (dexamethasone 2mg daily) during initial nivolumab treatment; steroids were rapidly tapered and discontinued in 4 weeks. Additionally, 1 patient received 3 doses of rituximab and 2 others received WBRT.All patients had objective radiographic responses to treatment with nivolumab, including 4 complete responses and 1 partial response. The patient with CNS relapse from PTL had complete radiographic resolution of CNS abnormalities with persistent intraocular disease that required vitrectomy. All responses were confirmed at repeat restaging. The median number of nivolumab treatments to objective radiographic response was 3 (range, 2-4). The 4 patients who were symptomatic at the initiation of nivolumab therapy had complete or near-complete resolution of neurologic signs/symptoms and a marked improvement in KPS. All patients are alive and remain progression-free at this time. Four patients continue to receive treatment. The median progression-free survival is 9 (range, 7-11) months.Conclusion: Our pilot series indicates that nivolumab is active in primary refractory and relapsed/refractory PCNSL and PTL with CNS relapse. Based on our preclinical molecular data and these pilot clinical results, a multi-institutional phase 2 open-label, single-arm trial of nivolumab in recurrent and refractory PCNSL and PTL patients (CA209-647) is scheduled to open shortly. DisclosuresLaCasce:Forty Seven: Consultancy; Seattle Genetics: Consultancy. Armand:Infinity Pharmaceuticals: Consultancy; Merck: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Sequenta Inc: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Shipp:Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding.