Nivolumab Combination Therapy Research Articles

Pneumocystis Jiroveci Mimicking COVID-19 Pneumonia in a Patient who Receiving Ipilimumab and Nivolumab Combination Therapy: A Case Report

The novel coronavirus SARS-CoV-2 , which first appeared in December 2019, threatened the world within a few months. Being preoccupied with the risk of this disease might mislead the clinicians and prevent them from providing the best care to their patients who are also exposed to other risks and conditions. In this article, we present a metastatic melanoma patient, who presented with fever, respiratory symptoms and a diffuse bilateral lung infiltration with ground-glass opacities treated with immunotherapy. He was first suspected of having COVID-19 pneumonia, but then Pneumocystis Jiroveci pneumonia was correctly diagnosed and this had to be decided in a timely manner so as not to lose the patient. Keywords: Cancer, COVID-19, checkpoint inhibitors, computed X-ray tomography; ground glass opacities, pneumocystis

Ivo-Nivo: A Phase II Study of the IDH1 Inhibitor Ivosidenib (AG-120) in Combination with the Checkpoint Blockade Inhibitor Nivolumab for Patients with IDH1 Mutated Relapsed/Refractory AML and High Risk MDS

Background: The normal function of isocitrate dehydrogenase 1 (IDH1) is to catalyze the conversion of cytoplasmic isocitrate to α-ketoglutarate (aKG) in the Krebs cycle. In hematologic malignancies a hotspot mutation at arginine 132 within the conserved active site of IDH1 leads to loss of the expected Krebs Cycle reaction as well as production of the oncometabolite 2- hydroxyglutarate (2-HG). In acute myeloid leukemia (AML) increased cellular 2-HG levels has been shown to impact the tumor microenvironment and promotes tumorigenesis via paracrine stimulation as well repression of the tumor associated immune system. Ivosidenib (AG-120) is a small molecule inhibitor of mIDH1 and is FDA approved for the treatment of patients (pts) with relapsed refractory IDH1 mutant AML. Ivosidenib is known to lower 2-HG levels, independent of response. By reducing 2-HG levels that promote immune escape of IDH-mutant tumors with ivosidenib, we hope to harness the known programmed death receptor pathway dysregulation in AML and high risk myelodysplastic syndrome (MDS). Study Design and Methods: IVO-NIVO is a single arm, multi-institutional phase II investigator initiated clinical trial with a safety cohort to confirm safety and tolerability of combination AG-120 and nivolumab. To be included pts must have MDS or AML with a documented IDH1 mutation in blood or bone marrow within 30 days of inclusion based on mutational testing by PCR or sequencing in a CLIA certified laboratory and be willing to undergo a bone marrow biopsy. Pts will initially start therapy with AG-120, 500mg by mouth daily for 1 cycle. A cycle is defined as 28 days of therapy. On cycle 2 day 1 enrolled pts will receive nivolumab 480 mg that will subsequently be infused every four weeks. Disease response to treatment will be serially assessed through the evaluation of blood (at least monthly) and bone marrow biopsies and aspirates. A complete response assessment will be performed after 6 cycles of therapy. Transplant eligible pts may proceed to allogeneic stem cell transplant (ASCT) if complete response (CR) or morphologic complete remission with incomplete count recovery (CRi) is achieved. Pts that are not eligible for ASCT will continue to receive AG-120- nivolumab combination therapy until documented progression or unacceptable toxicity (figure 1). Safety Cohort: We will have an interim safety analysis after the first 6 pts finishing the first cycle of combination therapy to ensure dosing is safe and tolerable. Pts will undergo clinical assessment with each cycle of therapy, with particular attention to known toxicities like differentiation syndrome that may be life threatening. If 0 to 1 of the first 6 subjects experienced unacceptable toxicities the study will continue as planned. If 2 pts experienced unacceptable toxicities, accrual will be temporarily suspended in order to conduct a review of safety data. If after review, a safety issue is identified and can be corrected, the protocol will be amended accordingly, and enrollment will restart. If an additional 2 pts (4 of 12) or more experience an unacceptable toxicity the patient will be taken off trial and the trial will be terminated. Statistical plan: It is estimated that 45 pts will be enrolled on trial. Using optimal Simon Stage 2 minimax design, if less than 7 of the first 16 pts respond the treatment will be study will be stopped for futility (type 1 error 0.05, type 2 error 0.2). Primary endpoint: We aim to improve the cumulative response rate after 6 cycles of therapy from 40% to 60% (Two-sided alpha risk of 0.05, 1-Beta of 0.8 = 38 pts + 7 additional pts for potential drop-off observed in prior studies) in pts with mIDH1 relapsed/ refractory AML and MDS. Based on published data, it is known that overall response rate is approximately 40% to single agent AG-120 in the relapsed/ refractory IDH1 mutant AML population. Therefore, we expect a 20% ORR improvement compared to historical control after 6 cycles of treatment, based on MDS International Working Group 2006 criteria and AML MDS International Working group MDS/AML criteria. Secondary endpoints: Progression-free survival (the interval between the time of initiation of olaparib to the time of documentation of olaparib failure or last follow-up), overall survival (the interval between the time of initiation of olaparib to the time of death or last follow-up) and percentage of pts that can be bridged to ASCT. Disclosures Prebet: novartis: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Genentech: Consultancy; novartis: Honoraria; pfizer: Honoraria; novartis: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria; pfizer: Honoraria; pfizer: Honoraria; Tetraphase: Consultancy; Agios: Consultancy, Research Funding; pfizer: Honoraria; novartis: Honoraria; Boehringer Ingelheim: Research Funding. OffLabel Disclosure: We will use Ivosidenib and nivolumab in combination as a part of a clinical trial to improve care of patients with relapsed/ refractory AML and MDS

IFN-\u03b3 down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer

BackgroundPancreatic cancer is characterized by a highly immunosuppressive tumor microenvironment and evasion of immune surveillance. Although programmed cell death 1 receptor (PD-1) blockade has achieved certain success in immunogenic cancers, the responses to the PD-1 antibody are not effective or sustained in patients with pancreatic cancer.MethodsFirstly, PD-1 expressions on peripheral CD8+ T-lymphocytes of patients with pancreatic cancer and healthy donors were measured. In in vitro study, peripheral T-lymphocytes were isolated and treated with nivolumab and/or interferon-γ, and next, PD-1-blockade effects, proliferations, cytokine secretions and cytotoxic activities were tested after different treatments. In in vivo study, mice bearing subcutaneous pancreatic cancer cell lines were treated with induced T-lymphocytes and tumor sizes were measured.ResultsPD-1 protein expression is increased on peripheral CD8+ T cells in patients with pancreatic ductal adenocarcinoma compared with that in health donor. PD-1 expression on CD8+ T-lymphocytes was decreased by nivolumab in a concentration-dependent manner in vitro. IFN-γ could directly down-regulate expression of PD-1 in vitro. Furthermore, the combination therapy of nivolumab and IFN-γ resulted in greatest effect of PD-1-blockde (1.73 ± 0.78), compared with IFN-γ along (18.63 ± 0.82) and nivolumab along (13.65 ± 1.22). Moreover, the effects of nivolumab plus IFN-γ largest promoted the T-lymphocytes function of proliferations, cytokine secretions and cytotoxic activities. Most importantly, T-lymphocytes induced by nivolumab plus IFN-γ presented the best repression of tumor growth.ConclusionsIFN-γ plus a PD-1-blockading agent could enhance the immunologic function and might play a crucial role in effective adoptive transfer treatments of pancreatic cancer.

A Phase 1/2 Study Evaluating Multiple Nivolumab Combination Therapy in Participants With Stage IV Non-small Cell Lung Cancer That Has Spread or Has Reoccurred After Failure of Chemotherapy and Immunotherapy

A Phase 1/2 Study Evaluating Multiple Nivolumab Combination Therapy in Participants With Stage IV Non-small Cell Lung Cancer That Has Spread or Has Reoccurred After Failure of Chemotherapy and Immunotherapy

1353P - Real-world outcomes of ipilimumab plus nivolumab for advanced melanoma in the Netherlands

BackgroundIn phase III trials, the results of ipilimumab plus nivolumab combination therapy (IPI+NIVO) are promising for metastatic melanoma (MM), despite many treatment-related grade 3-4 adverse events (AEs). Here, we report real-world outcomes of IPI+NIVO for MM. MethodsPatients with (non-uveal) MM who received 1st-line IPI+NIVO between 2015 and 2017 were selected from the Dutch Melanoma Treatment Registry, a nation-wide population based registry. Probability of 2nd-line treatment was estimated with competing risk analysis and overall survival (OS) with Kaplan-Meier method and Cox regression analysis. ResultsIn total, 2116 pts with MM were treated with systemic therapy of which 151 pts with 1st-line IPI+NIVO. Median age was 58yrs versus 64yrs for pts treated with other systemic therapy in 1st-line. Half of the pts treated with 1st-line IPI+NIVO had elevated LDH, 90% an ECOG PS of≤1, 32% brain metastases (21% symptomatic), 87% stage IV-M1c and 42% had BRAF-mutated melanoma. Grade 3-4 AEs occurred in 90 pts (60%); 39 (26%) had colitis, 37 (25%) hepatitis and 22 (13%) endocrine insufficiency. No deaths due to AEs were reported. For 66 pts who stopped IPI+NIVO because of AEs, 1-yr survival probability was 76% (95%CI: 66-87) compared to 57% (95%CI: 47-69) for the remaining 85 (56%) patients treated with 1st-line IPI+NIVO. A total of 50 (33%) pts completed all 4 courses of IPI+NIVO and 44 (29%) pts received maintenance with NIVO. The 1- and 2-yr OS probabilities (95%CI) were 66% (58-74%) and 55% (46-65%). Probability of still being in 1st-line IPI+NIVO at 1- and 2-yrs was 50% (95%CI; 42-59) and 34% (95%CI; 25-45). Cumulative incidence for 2nd-line treatment and death at 1yr were respectively 24% (95%CI: 18-33) and 27% (95%CI: 20-34). Adjusted HR for ECOG PS of≥2, symptomatic brain metastases, liver metastases were respectively 3.1 (95%CI; 1.2-8.3), 2.0 (95%CI; 1.0-3.8), 2.2 (95%CI; 1.2-4.2). HR for BRAF-wildtype status was 0.5 (95%CI; 0.2-0.9). ConclusionsHalf of pts receiving 1st-line IPI+NIVO for MM had elevated LDH, one third brain metastases and a majority ECOG PS≤1. Nevertheless, OS is encouraging especially in pts who stopped treatment due to AEs. With appropriate patient selection in real-world, promising results can be achieved with 1st-line IPI+NIVO. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureA.J.M. van den Eertwegh: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen. A.C.J. van Akkooi: Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD - Merck; Advisory / Consultancy: MSD - Pfizer; Advisory / Consultancy: 4SC. J.W. de Groot: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck. G.A.P. Hospers: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck. E. Kapiteijn: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck. K.P.M. Suijkerbuijk: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Honoraria (institution): Roche. A.A.M. Van der Veldt: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Ipsen. J.B.A.G. Haanen: Advisory / Consultancy: Amgen; Advisory / Consultancy: AZ; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celsius Therapeutics; Advisory / Consultancy: GSK; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: AIMM; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Immunocore. All other authors have declared no conflicts of interest.

Two cases of anaphylaxis due to contrast media during administration of nivolumab and ipilimumab in metastatic renal cell carcinoma.

A combination therapy of nivolumab and ipilimumab is effective for advanced renal cell carcinoma, but there are concerns about immune-related adverse events. A 46-year-old man was hospitalized for metastatic renal cell carcinoma. On day 9, he received nivolumab and ipilimumab. On days 16 and 49, he presented with fever, skin rash, and hypotension after contrast-enhanced computed tomography. A 70-year-old man was hospitalized for metastatic renal cell carcinoma. On day 9, he received nivolumab and ipilimumab. On day 44, he presented with fever, skin rash, and hypotension after contrast-enhanced computed tomography. Both patients were diagnosed with anaphylaxis due to the contrast agent.

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibition Is the New Backbone in First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma

Recent randomised trials have demonstrated a survival benefit for a front-line ipilimumab and nivolumab combination therapy, and pembrolizumab and axitinib combination therapy in metastatic clear-cell renal cell carcinoma. The European Association of Urology Guidelines Panel has updated its recommendations based on these studies. Patient summaryPembrolizumab plus axitinib is a new standard of care for patients diagnosed with kidney cancer spread outside the kidney and who did not receive any prior treatment for their cancer (treatment naïve). This applies to all risk groups as determined by the International Metastatic Renal Cell Carcinoma Database Consortium criteria.

BIOLUMA: A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in lung cancer and to evaluate biomarkers predictive for response—Preliminary results from the NSCLC cohort.

e20550 Background: Patient selection, dosing regimens and resistance mechanisms for immune checkpoint inhibitor combination therapy remain unmet medical needs in lung cancer. Combining blockade of PD-1 and CTLA-4 can be more effective than monotherapy but is accompanied by an increase in toxicity. Thus, to circumvent unnecessary toxicity it is of great interest to identify patients who will benefit from PD-1/PD-L1 blockade alone and to add ipilimumab only in case of primary or secondary progression. We present interim data from the non-small-cell lung cancer (NSCLC) cohort of the ongoing BIOLUMA trial which evaluates efficacy and safety of nivolumab and ipilimumab in lung cancer with a broad translational program to identify potential biomarkers predictive of response and/or resistance including whole exome sequencing (WES) of serial biopsies, functional analysis of peripheral T-cells and gut microbiome analyses. Methods: BIOLUMA is a multicentre non-randomised phase II trial in 2nd line patients with non-squamous NSCLC. Patients are treated with nivolumab 240 mg until disease progression and subsequently with a combination therapy of nivolumab 3 mg/kg q2w and ipilimumab 1mg/kg q6w. Primary endpoint is overall response rate (ORR) after addition of ipilimumab to nivolumab treatment. Analysis of sequential tumor biopsies, blood and gut microbiome is performed at different timepoints. Results: To date, 26 patients have been enrolled and 9 patients were transferred to the combination therapy after progression on nivolumab monotherapy. Drop out rate between the treatment arms is high, mainly due to rapid disease progression and adverse events which don’t allow addition of ipilimumab. ORR is available for 8 of these patients: 6 patients (75%) had PD as best response, and 1 (12.5%) each had a stable disease and partial response, respectively. The patient who achieved a PR had experienced primary tumor progression on nivolumab monotherapy before. Toxicity rate was similar to what has been reported from other trials. Conclusions: In NSCLC, addition of ipilimumab to nivolumab in nivolumab refractory patients seems to be safe, but the response rate is low and the drop out between the treatment parts high. Given these data, early termination of this cohort is currently discussed. Clinical trial information: NCT03083691.

BIOLUMA: A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in lung cancer and to evaluate biomarkers predictive for response—Preliminary results from the SCLC cohort.

8563 Background: Patient selection, dosing regimens and resistance mechanisms for immune checkpoint inhibitor combination therapy remain unmet medical needs in lung cancer. We present interim data from the small-cell lung cancer (SCLC) cohort of the ongoing BIOLUMA trial which evaluates efficacy and safety of nivolumab and ipilimumab in lung cancer with a broad translational program to identify potential biomarkers predictive of response and/or resistance including whole exome sequencing (WES) of serial biopsies, functional analysis of peripheral T-cells and gut microbiome analyses. Methods: BIOLUMA is an investigator initiated, multicentre non-randomised phase II trial in 2nd line patients with SCLC. The initial all-comer SCLC cohort was recently amended for inclusion of patients with high tumor mutation burden (TMB) only. Patients are pre-screened for TMB by WES at the time of first diagnosis. After progression on platinum-based therapy, 4 cycles of nivolumab 1 mg/kg q3w in combination with ipilimumab 3 mg/kg q3w and subsequent nivolumab 240 mg flat dose as monotherapy are given. Primary endpoint is overall response rate (ORR) of the upfront combination therapy. Analysis of sequential tumor biopsies, blood and gut microbiome is performed at different timepoints. Results: The SCLC cohort was amended to include TMB high patients only, after two treatment-related deaths had occurred and emerging data indicated treatment benefit depends on high TMB status for the combination therapy. Both patients with treatment-related death had a CT-scan documented partial response (not confirmed according to RECIST due to death). One each died of pneumonitis and encephalitis. From the all-comer cohort, efficacy data are available for 18 patients. ORR was 38.8% with 7 partial and no complete responses. Stable disease occurred in 16.7% (n = 3) resulting in a DCR of 55.5%. TMB pre-screening for the amended cohort is currently ongoing. Conclusions: In the SCLC cohort, upfront combination therapy of nivolumab and ipilimumab shows remarkable ORR but is accompanied by high toxicity rates. In order to ensure a reasonable balance of risks and treatment benefit, only TMB high patients are included after an amendment of the cohort to improve the risk/benefit ratio. Clinical trial information: NCT03083691.

Risk of immune-related adverse events associated with ipilimumab-plus-nivolumab and nivolumab therapy in cancer patients.

PurposeThe aim of this study was to evaluate the risk of immune-related adverse events (irAEs) among cancer patients receiving nivolumab-plus-ipilimumab therapy and nivolumab monotherapy.Patients and methodsPubMed and Web of Science were searched for related studies from inception to June 2018. Eligible studies included randomized controlled trials comparing nivolumab-plus-ipilimumab with nivolumab alone in cancer patients reporting on all-grade (grade 1–4) and high-grade (grade 3/4) irAEs. Paired reviewers selected studies for inclusion and extracted data. The odds risk and 95% CI were calculated.ResultsA total of 2,946 patients from four studies were included in the meta-analysis. The underlying malignancies included lung cancer (two trials) and melanoma (two trials). Compared with nivolumab monotherapy, the nivolumab-plus-ipilimumab therapy was associated with a significantly higher risk of all- and high-grade irAEs such as pruritus, rash, diarrhea, colitis, alanine aminotransferase elevation, and pneumonitis.ConclusionThe combination therapy of nivolumab and ipilimumab increased the incidence of irAEs in patients with advanced cancer.

Gastrointestinal complications in patients treated with ipilimumab and nivolumab combination therapy or monotherapy.

Aim & methods: A retrospective study using the IBM Explorys Universe Database assessed the risk of gastrointestinal events (enterocolitis or diarrhea) among melanoma and lung cancer patients treated with ipilimumab and nivolumab combination or monotherapy. Results & conclusion: There were 904 melanoma patients (607 ipilimumab, 140 nivolumab and 157 combo) and 1641 lung cancer patients (68 ipilimumab, 1542 nivolumab and 31 combo). Approximately, 37% of lung patients and 46% of melanoma patients experienced at least one adverse event. After adjusting for covariates, patients receiving combination therapy were more likely to have a gastrointestinal event compared with ipilimumab monotherapy patients (melanoma hazard ratio: 1.54; 95% CI: 1.06-2.25; lung hazard ratio: 2.93; 95% CI: 1.09-7.89).

Paraneoplastic hyperleucocytosis in a melanoma patient after initiation of ipilimumab and nivolumab combination therapy

BackgroundParaneoplastic hyperleucocytosis (PH) is sporadically seen in patients with advanced solid tumors.Case presentationWe report a female patient with disseminated melanoma metastases. Two days after the first dosage of combined immunotherapy using the cytotoxic T lymphocyte antigen-4 (CTLA-4) blocker ipilimumab and the programmed death receptor-1 (PD-1) blocker nivolumab the patient developed asymptomatic hyperleucocytosis (over 120.000 leucocytes per μl) associated with elevated granulocyte colony-stimulating factor blood levels. Hematological and infectious disorders could be ruled out. Although paraneoplastic hyperleucocytosis spontaneously resolved she died from progressive disease about 60 days after start of treatment.ConclusionsPH is extremely rare in malignant melanoma, however, most patients who developed this complication had preceding immunotherapies such as interleukin-2. The latter observation and the fact that our patient developed PH rapidly after initiation of ipilimumab and nivolumab immunotherapy indicate an immune-mediated mechanism which may trigger PH under unknown circumstances. The development of paraneoplastic hyperleucocytosis indicates a very poor prognosis.

Phase II study of a combination therapy of nivolumab, bevacizumab and paclitaxel in patients with HER2-negative metastatic breast cancer as a first-line treatment (WJOG9917B, NEWBEAT trial).

TPS1110Background: In recent years, an immune checkpoint inhibitor, anti-PD-1 antibody, has been developed for various cancer types including breast cancer. The synergic effect of combination of ni...

Regorafenib and nivolumab combination therapy for advanced and metastatic solid tumors: Phase I clinical trial (EPOC1603).

TPS3124Background: Immune checkpoint inhibitors (CPIs) have shown promising efficacies in several types of malignancies. However, still around half of patients with most tumor types experienced dis...

Incidence of Thyroid Function Test Abnormalities in Patients Receiving Immune-Checkpoint Inhibitors for Cancer Treatment.

With the advent of immune-checkpoint inhibitor (ICI) therapy (anti-CTLA-4, anti-PD-1), immune-related adverse events such as thyroid function test abnormalities (TFTAs) are common, with a reported incidence range of 2%-15% depending upon the ICI used. The aim of this study is to describe the incidence of TFTAs retrospectively in patients who received ICI therapy. A total of 285 patients were reviewed (178 male, 107 female; 16-94 years of age), of whom 218 had no baseline TFTAs, 61 had baseline TFTAs, and 6 had a history of thyroidectomy (excluded). At least one dose of ipilimumab and/or nivolumab or pembrolizumab was administered. Post-ICI therapy TFTAs were classified according to standard definitions of thyroid conditions when possible. A total of 35% (76/218) patients had new-onset TFTAs on ICI therapy. Of note, 70.5% (43/61) had baseline TFTAs that were exacerbated by ICI therapy. The median times to new-onset or exacerbated baseline TFTA were 46 and 33 days, respectively. Of note, 64.5% (20/31) of patients on both ipilimumab and nivolumab had new-onset TFTAs, compared with 31.3% (15/48) on ipilimumab, 31.5% (28/89) on nivolumab, and 26% (13/50) on pembrolizumab. The incidence of TFTAs with ICI therapy was higher than previously reported. Patients with baseline TFTAs and/or who were receiving ipilimumab and nivolumab combination therapy had a higher incidence of TFTAs than patients receiving single-agent ICI therapy. We recommend more frequent evaluation of thyroid function in the first 8 weeks, especially in patients with baseline TFTAs. Increased use of immune-checkpoint inhibitors in cancer treatment has highlighted the importance of monitoring for and treating immune-related adverse events. This study was conducted to assess the incidence of thyroid function test abnormalities retrospectively in patients with cancer on immune-checkpoint inhibitors, which is not known exactly. This study is unique in that it included patients with a variety of histologic subtypes of cancer and also followed the clinical course of patients with baseline thyroid function test abnormalities. This study can help make oncologists aware that the incidence of thyroid function test abnormalities is higher than anticipated. Early identification and timely treatment can help ameliorate symptoms for patients and improve their overall quality of life.

Successful Combination Therapy of Nivolumab and Radiation for Massive Mucosal Melanoma in Patient with Autoimmune-Myasthenia Gravis, Systemic Lupus Erythematosus and Rheumatoid Arthritis

A 58-year-old woman complicated with autoimmune diseases of myasthenia gravis (MG), rheumatoid arthritis, and systemic lupus erythematosus noticed an irregular black macule on her bilateral major labia, which was diagnosed as malignant melanoma. The melanoma lesion involving the vagina, uterus, and ventral side of rectum was not operable and was treated with nivolumab and concurrent radiotherapy with good control of the MG. This resulted in remarkable tumor shrinkage, possibly due to synergistic effects of both treatments. To our knowledge, few reports have described the effectiveness of combination therapy with nivolumab and radiation for malignant melanoma. The present case showed an enhanced anti-tumor effect with combination therapy.

Abstract CT065: KEYNOTE 029: A phase I/II randomized trial of pembrolizumab (pembro) plus 2 dose regimens of ipilimumab (ipi) for advanced melanoma

Abstract Background: Combination therapy of nivolumab plus full-dose ipi (3 mg/kg) provided greater efficacy than either inhibitor alone but with increased toxicity (55% treatment-related adverse events [TRAEs]). Results from part 1B of the phase I/II KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) showed preliminary efficacy in pts with melanoma treated with standard-dose pembro (2 mg/kg every 3 weeks [Q3W]) + reduced-dose ipi (1 mg/kg Q3W for 4 doses). This combination appeared superior to historical studies with single-agent anti-PD-1, but 42% of pts had TRAEs. Part 1C of KEYNOTE-029 will explore 2 additional dosing regimens of this combination to further investigate efficacy and minimize the occurrence of the toxicity observed in part 1B. Methods: Eligibility criteria include age ≥18 yr; histologically confirmed unresectable stage III/IV melanoma not amenable to local therapy; no prior treatment ([neo]adjuvant treatment, excluding PD-1/PD-L1 or BRAF/MEK inhibitors is allowed, provided pts did not discontinue for TRAEs, all related AEs returned to baseline or stabilized, and relapse did not occur during or within 6 mo of treatment discontinuation for anti-CTLA-4 therapy); measurable disease per RECIST v1.1; ECOG performance status 0 or 1; no active brain metastases (baseline brain MRI required); and no active autoimmune disease requiring systemic therapy within the past 2 yr or history of pneumonitis requiring steroids. In part 1C, ~100 pts are to be randomly assigned 1:1 to receive pembro 200 mg Q3W + ipi 50 mg Q6W (arm 1) or ipi 100 mg Q12W (arm 2). Combination treatment will continue for ≤24 wk in arm 1 and ≤48 wk in arm 2, followed by pembro monotherapy for ≤24 mo or until progressive disease (PD), intolerable toxicity, patient withdrawal, or physician decision to discontinue. Tumor imaging will be performed every 6 wk until wk 24, then every 12 wk thereafter. Response will be assessed per RECIST v1.1 by independent central review (for efficacy) and modified RECIST v1.1 by investigator review (for treatment decisions). Survival follow-up will occur every 12 wk. AEs will be graded throughout the study and for 30 d thereafter per NCI CTCAE v4.0. Pts with investigator-determined, confirmed complete response (CR) who received ≥24 wk of pembro and ≥2 doses of pembro after initial CR may discontinue pembro; pts with investigator-determined, confirmed CR or very good partial response (percentage change from baseline in tumor size >60%) who received ≥1 ipi dose may discontinue ipi. Pts experiencing stable disease or better who subsequently experience PD may be eligible for a second treatment course with pembro + ipi or pembro monotherapy (maximum 17 doses of pembro and 4 doses of ipi). Eligible pts with PD may remain on treatment until a confirmatory scan ≥4 wk later. Primary end points are safety and ORR; secondary end points include PFS, OS, and duration of response. Citation Format: Michael B. Atkins, Matteo S. Carlino, Andrew G. Hill, Catriona M. McNeil, Georgina V. Long, Victoria Atkinson, Jonathan S. Cebon, Michael B. Jameson, Wen-Jen Hwu, John A. Thompson, James Anderson, Blanca Homet Moreno, Nageatte Ibrahim, Antoni Ribas. KEYNOTE 029: A phase I/II randomized trial of pembrolizumab (pembro) plus 2 dose regimens of ipilimumab (ipi) for advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT065. doi:10.1158/1538-7445.AM2017-CT065

A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors.

e14040 Background: NKTR-214 is a CD-122-biased agonist that targets the IL-2 pathway and is designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over T regulatory cells within the tumor microenvironment. In a phase 1 monotherapy trial, pts treated with NKTR-214 demonstrated a substantial increase in CD8+ T and NK cells within the tumor microenvironment even when pretreated with multiple prior immunotherapeutic agents (abstract submitted). Based on this biomarker data and a favorable safety profile, a trial combining NKTR-214 and nivolumab was initiated. Methods: This is an on-going phase 1/2 study of NKTR-214 plus nivolumab in Pts with either melanoma (Mel), NSCLC, renal, bladder, or TNBC. Pts who are immunotherapy naïve or checkpoint therapy relapse/refractory are being studied separately. NKTR-214 and nivolumab are administered IV on a q2w or q3w schedule. Cohort 1 received NKTR-214 0.006 mg/kg q3w with nivolumab 240 mg q2w. Blood and tumor tissue were collected to measure immune activation using flow cytometry, immunohistochemistry, T cell clonality and gene expression analyses. Results: As of February 7, 2017, 5 Pts have been treated with the combination and all Pts were naïve to checkpoint inhibitors. There have been no dose limiting toxicities, no drug-related or immune related grade 3-5 adverse events (TRAEs) and no Pts have discontinued treatment. The most common TRAEs were pruritis and rash. Radiographic scans were available for 2 Pts. On treatment, Pt 1 with Mel had a mixed radiographic response at 1st scan, a ~40% decrease in LDH and a robust tumor immune cell infiltrate at week 3 the majority being newly proliferating CD8+ T cells expressing PD-1. Pt 2 with Mel had an unconfirmed complete response per RECIST 1.1 after 6 weeks of treatment; follow up tumor response data will be presented. Conclusions: Preliminary data demonstrate that NKTR-214 and nivolumab combination therapy is well tolerated with early evidence of clinical activity. Updated safety, pharmacokinetics, tumor response and biomarker data will be presented. Clinical trial information: NCT02983045.

Paraneoplastic acral vascular syndrome in a patient with metastatic melanoma under immune checkpoint blockade

BackgroundParaneoplastic acral vascular syndrome (PAVS) is a rare phenomenon which is observed in patients with adenocarcinomas and other malignancies. Various potential pathogenic mechanisms such as tumour invasion of sympathetic nerves, hyperviscosity, hypercoagulability, vasoactive tumour-secreted substances, and immunological mechanisms have been suggested.Case presentationWe report a 60-year-old Caucasian male attended our hospital with a bulky lymph node mass in the right axilla. Extirpation of a lymph node conglomerate revealed 5 melanoma lymph node metastases. Computed tomography showed a liver metastasis (diameter: 3.8 cm), several retroperitoneal metastases, bilateral metastases in the lung hilus, and prepectoral subcutaneous metastases (Stage IV; pTx, N3, M1c). Lactate dehydrogenase and S100B were slightly elevated. Combination therapy of nivolumab (1 mg/kg BW) and ipilimumab (3 mg/kg BW) was started. Three weeks after the first combination therapy he developed progressive erythema, paraesthesia and pain on the fingertips of both hands. Both cold and warmth was not well tolerated by the patient. Complete work-up excluded associated conditions or factors such as haematological disorders, rheumatologic disorders, hypertension, diabetes or smoking. Treatment was initiated with prostacyclin 20 μg twice daily and oral prednisolone 50 mg in tapering dosage. However, prostacyclin was stopped after the first applications because the pain increased during infusion. The second course of nivolumab and ipilimumab was administered. About 2 weeks later, the patient presented with increased pain and small subungual necrosis. We treated the patient with oral analgetics and intravenous prednisolone 500 mg in tapering dosage. On digital substraction angiography occlusion of all arteries of the fingers was demonstrated. Further rheologic and anti-melanoma treatments were refused by the patient. About 2 months after the second course of nivolumab and ipilimumab combination therapy several fingers showed severe gangrene which finally led to amputations of end phalanges of several fingers. Histopathology did not reveal evidence for vasculitis or other primary vascular pathologies. During the following 2 months the patient experienced dramatic progress of his metastatic disease and finally died at multi-organ failure.ConclusionPresence of rapidly progressive digital ischemia in an elderly patient with cancer should always raise clinical suspicion of a paraneoplastic phenomenon when other possible causes have been excluded. In patients treated with immune checkpoint inhibitors such as CTLA-4 and PD-L1 blockers PVAS-like events have not been reported so far. However, it is debatable whether immune checkpoint blockade may play a pathogenetic role in the development of PAVS in patients with malignancies.

Polymyalgia Rheumatica and Temporal Arteritis*

<h3>Background</h3> Metastatic sarcomatoid renal cell carcinoma (sRCC) is an aggressive variant of RCC with generally poor prognosis. Treatment with vascular endothelial growth factor inhibitors or chemotherapy generates only short-lived responses....