Nivolumab Combination Therapy Research Articles

A Network Meta-Analysis of the Differences in Effectiveness and Safety between Nivolumab and Targeted Drug Therapy in Metastatic Renal Cell Carcinoma.

Objective Nivolumab plus other drugs have provided significant benefits in patients with metastatic renal cell carcinoma (mRCC), but most of the available comparisons were conducted with sunitinib, and differences in efficacy with targeted drugs were marginally reported. Thus, this study used a network meta-analysis to compare the difference in efficacy between nivolumab combination therapy and other targeted agents. Methods In this systematic review and network meta-analysis, we searched PubMed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) with the time set from database establishment to December 10, 2021, using programmed death factor 1 (PD-1) inhibitors, nivolumab, and sunitinib in the treatment of mRCC. Progression-free survival (PFS), overall survival (OS), response rate (RR), and adverse events (AEs) were collated and analyzed using the gemtc package in the R language. Results A total of ten studies satisfied the inclusion criteria, including 6568 RCC cases, 10 drugs, and 11 treatment protocols. The Ate_Axi protocol obtained similar PFS to the Niv_Cab protocol, which outperformed that of all other protocols. The Niv_Cab regimen showed better PFS benefits than the Niv_Ipi regimen (HR < 1, P < 0.05), and Niv_Ipi had superior PFS compared to the Ate, Eve, Paz, Sor, and Sun scheme. The regimens Cab, Niv_Cab, and Niv_Ipi were associated with the best PFS benefits, while Eve is the least favorable drug in terms of PFS. Niv_Cab showed better OS than Ate_Bev, Eve, Paz, Sor, and Sun. The patients given Ate_Bev, Eve, Paz, Sor, and Sun had inferior OS to those given Niv_Ipi. The Pem_Axi, Niv_Cab, and Niv_Ipi regimens had the best OS, and that of Eve is considered least promising. The Niv_Cab protocol showed significantly better RRs than the Eve, Paz, Sor, and Sun protocols, and the Ate_Bev, Eve, Paz, Sor, and Sun protocols presented superior RRs compared to the Niv_Ipi protocol. The Ate, Eve, and Niv_Ipi regimens had the lowest incidence of AEs, and the Sor regimen had the highest incidence of AEs. Conclusion Among the targeted treatment options for mRCC, both Niv_Cab and Niv_Ipi yield better efficacy and safety in the treatment of mRCC, with Niv_Cab providing more survival benefit but with a less favorable safety profile.

Nivolumab plus ipilimumab in second-line combination therapy for older patients with esophageal squamous cell cancer (AIO-STO-0117 trial).

303 Background: Overall survival of patients with advanced and refractory esophageal squamous cell carcinoma (ESCC) is poor. Most patients are 65 years or older, present with advanced and metastatic disease and suffer from extensive co-morbidity and decreased functionality. While approved therapies beyond first-line therapy have not been available for decades, just recently treatment with PD-1 antibodies has shown to improve progression-free and overall survival in this patient cohort. Thus, we assessed the combination of nivolumab and ipilimumab in this vulnerable and older patient population. Methods: In this multi-center, open-label phase II trial older patients with ESCC with progression or recurrence of disease following first-line therapy were treated with nivolumab and ipilimumab. Patients had to pass a brief geriatric assessment using the G8 screening tool in combination with the Deficit Accumulation Frailty Index (DAFI). A safety run–in phase was initiated with nivolumab (240mg fixed dose Q2W). Following a safety assessment, patients then went on to receive the combination therapy of nivolumab/ipilimumab (nivolumab 240 mg fixed dose Q2W; ipilimumab 1 mg/kg Q6W), in case safety was critical patients were allowed to continue with nivolumab monotherapy. The primary outcome was overall survival. Progression-free survival, quality of life and adverse events were also assessed. Results: In total 66 evaluable patients (16 female, 50 male) with ESCC were enrolled in this trial after successful geriatric assessment, median age was 70.5 years (range 55-84 years). 44 patients were treated with the combination therapy of nivolumab and ipilimumab, 22 patients with nivolumab only. The primary endpoint was met with a median OS of 7.2 months (95% CI, 5.7 to 12.4 months) (p &lt; 0.006; versus historical control treated with standard chemotherapy). Median PFS was 2.7 months (95% CI, 2.5 to 2.9 months). ORR was 18.2% (95% CI, 9.8 to 29.6), all cases were partial responses. Grade 3 or more treatment related adverse events were observed in ̃25% of patients. Conclusions: The combination therapy of nivolumab and ipilimumab demonstrates improved overall survival and sustained confirmed responses in the second line therapy of older European patients with ESCC. Geriatric assessment is feasible in the setting of a prospective immune therapy trial. Overall, the RAMONA trial confirmed efficacy and safety of combination checkpoint inhibitor therapy in G8 prescreened older patients with ESCC in Europe beyond first line therapy. Clinical trial information: NCT03416244.

Durable complete response to combination nivolumab and ipilimumab in metastatic renal cell carcinoma

Immune checkpoint inhibitors, which promote or suppress the anti-tumor immune response, are becoming the mainstay of cancer treatment. In 2018, CheckMate 214 study showed a higher response rate with ipilimumab and nivolumab combination therapy compared to conventional therapy for advanced renal cell carcinoma. We report a case of complete response and durable response for two years to ipilimumab and nivolumab combination therapy in a patient with postoperative renal cancer recurrence that caused immune-related adverse events such as interstitial pneumonia and hepatotoxicity.

POSC162 Cost Effectiveness Analysis of Nivolumab Plus Ipilimumab Therapy in Patients with Advanced Non-Small Cell Lung Cancer in Japan

This study aimed to evaluate the cost-effectiveness of combination therapy of nivolumab plus ipilimumab (NIV+IPI) for patients with advanced non-small-cell lung cancer (NSCLC), comparing with platinum-doublet chemotherapy in Japanese settings. A partitioned survival model was developed to predict costs and quality-adjusted life years (QALYs) in a NIV+IPI arm and a chemotherapy arm. Data on overall survival and progression-free survival was derived from the CheckMate 227 trial. Cost estimates were based on Japanese healthcare system perspective, by using real world data, JMDC claims database. Utilities were derived from published sources outside Japan. The incremental cost-effectiveness ratio (ICER) of NIV+IPI therapy compared with chemotherapy was estimated. A subgroup analysis on the level of PD-L1 expression (≥1% or not) was conducted. In addition, deterministic sensitivity analysis was performed to assess the uncertainty in parameter settings. Compared with chemotherapy, NIV+IPI therapy incurred an additional cost of USD166,984 and conferred an additional 0.81 QALY, which resulted in an ICER of USD205,141/QALY gained. Contrary to prior expectations, the ICER of patients with a PD-L1 expression level ≥1% was higher than that of patients with a PD-L1 expression level <1% (USD241,734/QALY and USD129,288/QALY, respectively). Sensitivity analyses showed a relatively robust result that the ICERs remined higher than a Japanese price adjustment threshold of USD75,000/QALY over the full range of model parameters. The combination therapy of nivolumab plus ipilimumab as first-line therapy would not be cost-effective under a willingness-to-pay threshold of USD75,000/QALY. However, a better cost-effectiveness was found in the subgroup with a PD-L1 expression level <1%, which needs further research to elucidate the heterogeneity and specific biological mechanisms.

59 Associations between KIR/KIR-ligand genotypes and clinical outcome for patients with advanced solid tumors receiving BEMPEG plus nivolumab combination therapy in the PIVOT-02 trial

BackgroundHigh-dose IL2 therapy has shown clinical benefit in metastatic melanoma and renal cell carcinoma, however only in a select subset of patients. Bempegaldesleukin (BEMPEG), a novel CD122-preferential IL2 pathway agonist, preferentially binds the heterodimeric IL2βγR predominantly expressed on NK and CD8 T cells and minimizes binding to the IL2αR expressed on immunosuppressive Tregs. BEMPEG monotherapy in Phase I clinical trials induced proliferation and activation of NK cells in the blood and tumor microenvironment.1 NK activation is dependent on the balance of inhibitory and excitatory signals transmitted by NK receptors, including Fc-gamma receptors (FCγRs) and killer immunoglobulin-like receptors (KIRs) along with their KIR-ligands. The repertoire of KIRs/KIR-ligands an individual inherits and the single-nucleotide polymorphisms (SNPs) of FCγRs can influence NK cell function and affect responses to immunotherapies.2–4 Thus, we sought to investigate whether distinct immunogenotypes are associated with clinical response of patients enrolled in PIVOT-02, a Phase II study of BEMPEG plus nivolumab.Methods200 patients with advanced solid tumors enrolled in PIVOT-02 who were not previously treated with immunotherapy (immunotherapy-naïve, ‘IO’) had DNA available for genotyping and clinical data for correlative analyses. All patients received 0.006mg/kg BEMPEG plus 360mg nivolumab every 3 weeks.5 KIR/KIR-ligand gene status was assessed by real-time SYBR green PCR melt-curve analyses and PCR-SSP. FCγR SNP status was determined using Taqman primers/probes for FCγR2A, and FCγR3A and FCγR2C were determined using RNaseH primers/probes.6 Clinical outcome parameters included objective response rate (ORR), progression-free survival (PFS), and tumor shrinkage (TS, defined as best objective response &lt;0% by RECIST). Preliminary statistical analyses were done using a chi-square test, log-rank test, and Wilcoxon rank-sum test, respectively.ResultsKIR2DL2+/C1+ IO patients observed significantly greater TS (p=0.015) and a trend towards improved ORR (p=0.060) and increased PFS (p=0.058) compared to IO patients who were not KIR2DL2+/C1+. IO patients who were KIR2DL2+/C1+/KIR3DL1+/Bw4+ showed significantly improved ORR (p=0.014) and greater TS (p=0.044) compared to IO patients who were not KIR2DL2+/C1+/KIR3DL1+/Bw4+, with no significance found for PFS in these patients. FCγR polymorphisms did not influence ORR/PFS/TS.ConclusionsNK cells may play an important role in the anti-tumor efficacy of BEMPEG plus nivolumab, and NK activation is influenced by certain immunogenotypes. Similar to previous findings,2–4 the status of KIR2DL2+/C1+ and KIR2DL2+/C1+/KIR3DL1+/Bw4+ was associated with the response to BEMPEG plus nivolumab treatment in the PIVOT-02 trial. The potential to utilize these genotypes in clinical decision-making for immunotherapy treatment requires further investigation.Trial RegistrationClinicalTrialsgov NCT02983045ReferencesBentebibel S-E, et al. A first-in-human study and biomarker analysis of NKTR-214, a Novel IL2βγ-Biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov 2019;9:711–21.Erbe AK, et al. Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab. J Immunother Cancer 2019;7(1):70.Erbe AK, et al. Neuroblastoma patients’ KIR and KIR-Ligand genotypes influence clinical outcome for dinutuximab-based immunotherapy: A report from the Children’s Oncology Group. Clin Cancer Res 2018;24(1):189–96.Erbe AK, et al. FCGR polymorphisms influence response to IL2 in metastatic renal cell carcinoma. Clin Cancer Res 2017;23(9):2159–68.Diab A, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: Phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov 2020;10:1–16.Erbe AK, et al. Genotyping single nucleotide polymorphisms and copy number variability of the FCGRs expressed on NK cells. Methods Mol Biol 2016;1441:43–56.Ethics ApprovalThe study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The Protocol (online only) was approved by independent ethics committees and the relevant institutional review board at each site. All patients provided written informed consent.

Myocarditis as an immune-related adverse event following treatment with ipilimumab and nivolumab combination therapy for metastatic renal cell carcinoma: a case report

BackgroundImmune checkpoint inhibitors are new immunotherapy drugs globally used for many malignancies, including renal cell carcinoma. Myocarditis as an immune-related adverse event is rare but highly fatal, suggesting that its frequency may be higher than reported. This paper describes a case of myocarditis that developed asymptomatically following ipilimumab and nivolumab combination therapy for renal cell carcinoma.Case presentationA 71-year-old Asian man who presented to hospital with fever, fatigue, and weight loss of approximately 10 kg within 2 months was diagnosed with Xp.11.2 translocation renal cell carcinoma. Computed tomography revealed multiple lung masses, mediastinal lymph node enlargement, and a level II tumor thrombus reaching the inferior vena cava (cT3bN0M1; International Metastatic Renal Cell Carcinoma Database Consortium, poor risk). Ipilimumab/nivolumab combination therapy was started as induction therapy. The patient experienced acute interstitial nephritis as an immune-related adverse event after treatment initiation; however, a good response to steroid therapy was observed. The antitumor effect of the immunotherapy was notable. Although he experienced pulmonary embolism, it seemed asymptomatic and harmless; thus, a second infusion was introduced. From the eighth day, he demonstrated rapidly worsening cardiogenic shock with asymptomatic electrocardiographic changes and drastic drop in cardiac biomarkers, and a diagnosis of myocarditis as an immune-related adverse event was made. Although immediate methylprednisolone mini-pulse therapy followed by tapered prednisolone prevented mortality, extensive myocardial fibrosis with marked ejection fraction decline persisted as a sequela. Consequently, follow-up without treatment was instituted; however, much of the tumor response initially observed was maintained over several months.ConclusionPhysicians treating patients with immune checkpoint inhibitors should be aware of their potentially life-threatening cardiotoxic effects. This study emphasized the importance of a high index of suspicion, prompt diagnosis, and early intervention in patients who present with cardiac abnormalities and possible myocarditis after receiving immunotherapy.

Hypopituitarism in patients with metastatic renal cell carcinoma treated with ipilimumab and nivolumab combination therapy.

We investigated the incidence of hypopituitarism in Japanese patients with metastatic renal cell carcinoma (mRCC) who received ipilimumab and nivolumab (I-P) therapy and compared patient characteristics and survival rates between patients with hypopituitarism and those without. Twenty-two patients with mRCC who received I-P therapy as first-line treatment were the subjects of this retrospective study. The diagnosis of hypopituitarism was based on the hormone loading test. Hypopituitarism occurred in 41% (9/22) patients who received I-P therapy. Median time of diagnosis was 12weeks (IQR: 9.5-20). Clinical symptoms, such as fatigue, weakness or fever, were observed in 7 patients, while 2 patients had no clinical presentation. The following deficiency patterns were observed: isolated ACTH in 4 patients, ACTH and GH in 2 patients, ACTH and TSH in 2 patients and triple deficiency (ACTH, GH and TSH) in 1 patient. All patients with hypopituitarism were in the IMDC intermediate group, while 46% of those without hypopituitarism were in the IMDC intermediate group. Other patient characteristics were not different between the two groups. Object response rate was 33% (3/9) in patients with hypopituitarism and 23% (3/13) in those without (P=0.5954). Progression free survival (PFS) was significantly longer in those with hypopituitarism than those without (median: 24.7 vs. 4.5months, P=0.0008), while overall survival did not differ (P=0.136). Compared with the clinical trial, the incidence of hypopituitarism was higher than expected. Patients with hypopituitarism tended to have longer PFS, which may suggest that optimal management of hypopituitarism results in better prognosis.

Expanding the immune armoury against myelodysplastic syndrome.

Expanding the immune armoury against myelodysplastic syndrome.

Nephrotoxicity of immune checkpoint inhibitor therapy: a pharmacovigilance study.

Immune checkpoint inhibitor (ICI) therapy has demonstrated impressive clinical benefits across cancers. However, adverse drug reactions (ADRs) occur in every organ system, often due to autoimmune syndromes. We sought to investigate the association between ICI therapy and nephrotoxicity using a pharmacovigilance database, hypothesizing that inflammatory nephrotoxic syndromes would be reported more frequently in association with ICIs. We analyzed VigiBase, the World Health Organization pharmacovigilance database, to identify renal ADRs (rADRs), such as nephritis, nephropathy and vascular disorders, reported in association with ICI therapy. We performed a disproportionality analysis to explore if rADRs were reported at a different rate with one of the ICI drugs compared with rADRs in the entire database, using an empirical Bayes estimator as a significance screen and defining the effect size with a reporting odds ratio (ROR). We found 2341 rADR for all examined ICI drugs, with a disproportionality signal solely for nephritis [ROR = 3.67, 95% confidence interval (CI) 3.34-4.04]. Examining the different drugs separately, pembrolizumab, nivolumab and ipilimumab + nivolumab combination therapy had significantly higher reporting odds of nephritis than the other ICI drugs (ROR = 4.54, 95% CI 3.81-5.4; ROR = 3.94, 95% CI 3.40-4.56; ROR 3.59, 95% CI 2.71-4.76, respectively). Using a pharmacovigilance method, we found increased odds of nephritis when examining rADRs associated with ICI therapy. Pembrolizumab, nivolumab and a combination of ipilimumab + nivolumab showed the highest odds. Clinicians should consider these findings and be aware of the increased risk of nephritis, especially in patients treated with pembrolizumab, when administering ICI therapy.

Pathology of durable stable disease in melanoma patients treated with ipilimumab, nivolumab, or ipilimumab, and nivolumab combination therapy.

9567 Background: As immunotherapy with checkpoint blockade becomes the backbone of melanoma treatment there is a need to better understand the biology associated with long term benefit. One particularly interesting set of patients are those with prolonged stable disease or response with residual findings on imaging. It is unknown if immunotherapy has led to scarring at the site of prior disease or if there are residual tumor cells being controlled by an ongoing immune response. Evaluating tissue from patients with prolonged responses provides a unique opportunity to determine the composition of residual lesions. Correlation with PET/CT helps determine if this is an accurate modality to reflect presence of residual viable tumor tissue. Methods: Metastatic melanoma patients that have attained long term stable disease after treatment with ipilimumab, nivolumab, or ipilimumab plus nivolumab were identified. Patients must have received ipilimumab, nivolumab or combination therapy 2+ years prior to enrollment and must have had stable disease for ≥ 6 months. Patients were consented and underwent PET/CT scans and biopsies of residual areas of stable disease. Pre- and post-treatment tissue samples underwent pathologic assessment to look at tumor cell content, fibrotic content, and inflammation. Results: Ten patients were consented for evaluation but only 7 met the screening criteria and underwent PET/CT and tissue biopsy. Six patients had FDG avid lesions on PET/CT which ranged in intensity from SUV 2.4-22. One patient had no FDG avidity in the areas of residual disease observed on CT. Biopsies from the residual stable lesions demonstrated predominantly necrosis and fibrosis with prominent pigment containing macrophages. One patient with an axillary nodal lesion with an SUV of 22 had active melanoma on pathology which was resected, and the patient has subsequently remained without progression of disease. Conclusions: Patients with durable stable disease after treatment with ipilimumab, nivolumab or ipilimumab and nivolumab combination therapy represent a unique population of melanoma patients treated with immune checkpoint inhibition. An examination of the residual lesions observed in these patients demonstrated predominantly necrosis and fibrosis consistent with resolving lesions. The presence of melanophages in these samples may suggest some ongoing immune surveillance. One patient did demonstrate residual melanoma suggesting the need for ongoing monitoring of this patient population.

Multiple endocrinopathies, hypercalcaemia and pancreatitis following combined immune checkpoint inhibitor use- case report and review of literature

BackgroundImmune checkpoint inhibitors (ICIs) are a novel class of oncological agents which are used to treat a number of malignancies. To date seven agents have been approved by the Food and Drug Administration (FDA) to treat both solid and haematological malignancies. Despite their efficacy they have been associated with a number of endocrinopathies. We report a unique case of hypophysitis, thyroiditis, severe hypercalcaemia and pancreatitis following combined ICI therapy.Case presentationA 46-year old Caucasian female with a background history of malignant melanoma and lung metastases presented to the emergency department with lethargy, nausea, palpitations and tremors. She had been started on a combination of nivolumab and ipilimumab 24 weeks earlier. Initial investigations revealed thyrotoxicosis with a thyroid stimulating hormone (TSH) of < 0.01 (0.38–5.33) mIU/L, free T4 of 66.9 (7–16) pmol/.L. TSH receptor and thyroperoxidase antibodies were negative. She was diagnosed with thyroiditis and treated with a beta blocker. Six weeks later she represented with polyuria and polydipsia. A corrected calcium of 3.54 (2.2–2.5) mmol/l and parathyroid hormone (PTH) of 9 (10–65) pg/ml confirmed a diagnosis of non-PTH mediated hypercalcaemia. PTH-related peptide and 1, 25-dihydroxycholecalciferol levels were within the normal range. Cross-sectional imaging and a bone scan out ruled bone metastases but did reveal an incidental finding of acute pancreatitis – both glucose and amylase levels were normal. The patient was treated with intravenous hydration and zoledronic acid. Assessment of the hypothalamic-pituitary-adrenal (HPA) axis uncovered adrenocorticotrophic hormone (ACTH) deficiency with a morning cortisol of 17 nmol/L. A pituitary Magnetic Resonance Image (MRI) was unremarkable. Given her excellent response to ICI therapy she remained on ipilimumab and nivolumab. On follow-up this patient’s thyrotoxicosis had resolved without anti-thyroid mediations – consistent with a diagnosis of thyroiditis secondary to nivolumab use. Calcium levels normalised rapidly and remained normal. ACTH deficiency persisted, and she is maintained on oral prednisolone.ConclusionThis is a remarkable case in which ACTH deficiency due to hypophysitis; thyroiditis; hypercalcaemia and pancreatitis developed in the same patient on ipilimumab and nivolumab combination therapy. We postulate that hypercalcaemia in this case was secondary to a combination of hyperthyroidism and secondary adrenal insufficiency.

A pilot trial of neoantigen DNA vaccine in combination with nivolumab/ipilimumab and prostvac in metastatic hormone-sensitive prostate cancer (mHSPC).

TPS192 Background: Despite robust advances in the use of immune checkpoint blockade (ICB) across multiple cancer types, responses in prostate cancer remain suboptimal. Overall response rates for single-agent ICB in prostate cancer are low, but recent modest gains have been made with ipilimumab and nivolumab combination therapy in metastatic castrate-resistant prostate cancer. Prostvac-VF Tricom is a therapeutic vaccine that incorporates DNA for the shared self-antigen PSA into the vaccinia (or fowlpox) virus strain. A large randomized phase III clinical trial recently showed no improvement in overall survival (OS) with Prostvac compared with placebo, suggesting that a combinatorial approach is warranted. Personalized neoantigen vaccines based on specific mutated epitopes may have the ability to overcome immunoresistance seen with self antigens. Even in low mutational burden tumors like prostate cancer, T cell responses against neoantigens are observed in patients with favorable clinical outcomes, supporting neoantigen vaccination as a promising therapeutic strategy. Improvements in computational genomics and predictive algorithms have allowed the incorporation of MHC class II neoepitopes and those from gene fusion events relevant in prostate cancer. We thus hypothesized that a strategy utilizing both shared antigen (Prostvac) and personalized MHC-I and MHC-II neoantigen vaccines combined with dual ICB would induce robust immune responses and improve clinical outcomes. To maximize tumor burden reduction and minimize tumor-mediated immunoresistence, we are evaluating this novel strategy in patients with metastatic hormone-sensitive prostate cancer (mHSPC) who have completed frontline docetaxel chemotherapy. Methods: This ongoing trial (NCT03532217) began accrual in September 2018. Eighteen of 20 planned patients have been enrolled to date. Eligible patients have histologically confirmed high risk/volume mHSPC defined as 4 or more sites of metastatic disease or visceral involvement. Patients receive continuous androgen deprivation therapy (ADT) and have completed upfront docetaxel chemotherapy. Patients begin treatment with Prostvac-VF in combination with ipilimumab (1 mg/kg every 3 weeks for 2 doses), and nivolumab (3 mg/kg every 3 weeks for 6 doses) within 60 days of the last dose of docetaxel. Subsequently, patients receive nivolumab 480 mg IV every 4 weeks in conjunction with a personalized neoantigen DNA vaccine administered monthly via intramuscular electroporation. The primary objective of this exploratory study is to assess the feasibility, safety/tolerability, and immune responses of this combination strategy. Key secondary objectives include failure-free survival and milestone survival at 2 years, PSA response, and radiographic progression-free survival. Clinical trial information: NCT03532217.

Abstract PS4-14: Immunological analysis of the combination therapy of nivolumab, paclitaxel and bevacizumab in patients with HER2-negative MBC in NEWBEAT trial (WJOG9917BTR)

Abstract Background: Synergistic antitumor effect of combined anti-PD-1 antibody and anti-VEGF agent has been expected, based on previous preclinical data. We have conducted NEWBEAT trial to evaluate efficacy of triple combination regimen of nivolumab + paclitaxel + bevacizumab in patients (pts)with HR+ HER2- MBC or metastatic TNBC, and clinical results were presented in SABCS 2019. A biomarker study (WJOG9917BTR) was conducted to evaluate the VEGF and immune status of these patients. Methods: HER2-negative breast cancer patients in the NEWBEAT trial were enrolled. To explore the biomarkers for the triple combination treatment, immune status and its dynamics were evaluated with multicolor flowcytometry, multiplex ELISA in peripheral blood before and after treatment. Results: Among the 57 patients who were enrolled to the NEWBEAT trial, 50 patients were registered to the biomarker study. The expression of Ki67 and inducible T-cell co-stimulator (ICOS) on T cells increased after treatment, indicating induction of the T cell proliferation and activation. In responder (defined as patients with progression-free survival longer than 1 year, n = 30), the number of naïve CD4+ T cells at pretreatment were higher and effector memory CD4+ T cells were lower than non-responder. On the other hand, CD86+ myeloid DC at pretreatment were lower in non-responder pts. The median concentration of VEGF-A in serum before treatment was 116.065 pg/ml (range: 0-740.23) and decreased below 37 pg/ml at day 8 after treatment. Although serum VEGF-A level is inversely correlated with clinical outcome of pts with anti-PD-1 antibody in previous reports, in this trial VEGF-A high subgroup had better objective response than VEGF-A low subgroup, suggesting that blockade of VEGF by bevacizumab may overcome immunosuppression via VEGF signaling. Interestingly, in recurrent pts , the number of VEGFR-2+ CD4+ T cells / Monocyte were higher, and PD-L1+ CD4+ T cells / Monocyte / myeloid Dendritic Cell tended to be higher than in de novo stage IV pts. These results suggested that immune status of recurrent pts were more immunosuppressive than de novo stage IV pts, and that it might be more effective by the combination therapy to block the VEGF and PD-1 pathways. Moreover, the changes of immune status and dynamics on CD8+ T cells were not observed, suggesting that the therapeutic strategy of breast cancer might require the re-activation of CD8+ effector T cells through the stimulation of antigen-presenting cells followed by modification of CD4+ helper T cells.Conclusions: Our analysis showed the different immune status depending stage, subtype and response in advanced breast cancer pts. The dynamic decrease of serum VEGF-A concentration and high expression of VEGFR-1 or VEGFR-2 in the immune suppressive cells in advanced breast cancer pts suggested that combination treatment with bevacizumab might clinically overcome the immune suppression via inhibition of VEGF-A. (UMIN000029590) Citation Format: Yukinori Ozaki, Shigehisa Kitano, Junji Tsurutani, Tsutomu Iwasa, Masato Takahashi, Toru Mukohara, Norikazu Masuda, Manabu Futamura, Hironobu Minami, Koji Matsumoto, Hidetaka Kawabata, Makiko Yamashita, Kenichi Yoshimura, Toshimi Takano. Immunological analysis of the combination therapy of nivolumab, paclitaxel and bevacizumab in patients with HER2-negative MBC in NEWBEAT trial (WJOG9917BTR) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-14.

Abstract PR007: Is sex an effect modifier for cancer immune checkpoint inhibitors? – A population-based study

Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized melanoma management and are now standard of care. While sex is associated with immune function and immune-related diseases, the interplay between sex and ICIs is under-studied. Therefore, we examined whether cancer immunotherapy effectiveness varied between female and male patients with advanced melanoma who are on either ipilimumab plus nivolumab combination therapy or anti-PD1 therapy, namely nivolumab or pembrolizumab. Methods: Adults (age: 65+) with a record of melanoma diagnosis from 1991-2015 in the SEER-Medicare linked database were considered for the study. Only Stage III or IV melanoma patients whose claims records showed ipilimumab plus nivolumab (ipi/nivo) combination therapy or anti-PD1 therapy (i.e., nivolumab or pembrolizumab) as their last type of ICI prescribed were included in the analyses. Survival was defined as time from the first date of combination therapy or anti-PD1 therapy administration to death or loss of follow-up. We employed a Cox proportional hazards model to examine effect modification of sex on ICI while adjusting for prior use of ipilimumab, age at ICI initiation, Charlson Comorbidity Index, cancer stage at the time of diagnosis, and autoimmune disease diagnosis. Results: We identified 165 advanced melanoma patients on ipi/nivo combination therapy and 1,204 advanced melanoma patients on anti-PD1 therapy (426 on nivolumab and 778 on pembrolizumab). More than 70% of the patient cohort were male, and approximately 10% of the cohort were diagnosed with at least one autoimmune disease. Compared to the anti-PD1 therapy patients, there were more patients at age &amp;lt;70 (25.83% vs. 44.85%) and with no comorbidities (68.11% vs. 85.45%) on combination therapy. While everyone on the combination therapy had a history of taking ipilimumab prior to starting the current therapy, 30% of the anti-PD1 therapy patients were on ipilimumab previously. Given the unequal distribution of ipilimumab history between the ICI groups, we further divided our patient samples into the following 3 sub-groups: anti-PD1 patients with history of ipilimumab, anti-PD1 patients without history of ipilimumab, and combination therapy patients with history of ipilimumab. The interaction term between this treatment group classification and sex was statistically significant (p=0.009). Mortality hazard for female combination therapy patients with history of ipilimumab was 2.06 times (95% Confidence Interval: 1.28-3.32) higher than their male counterparts, and the difference was statistically significant (p=0.003). No significant difference was observed in other sub-groups. Conclusions: This retrospective observational study showed that the risk of mortality among patients treated with ipi/nivo combination therapy may depend on the sex of the patient. Further studies are warranted to validate the study results. This abstract is also being presented as PO052. Citation Format: Se Ryeong Jang, Nikita Nikita, Joshua Banks, Krupa Gandhi, Jennifer M. Johnson, Melissa Wilson, Scott W. Keith, Grace Lu-Yao. Is sex an effect modifier for cancer immune checkpoint inhibitors? – A population-based study [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PR007.

Checkpoint Blockade in Melanoma Patients With Underlying Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is associated with immune dysfunction and an increased risk of melanoma. For patients with metastatic melanoma, immunotherapy with checkpoint blocking antibodies is a standard of care. In patients with concomitant CLL and metastatic melanoma, it is not known whether CLL might influence the antimelanoma efficacy or immune-related toxicities of immune checkpoint blockade. Fifteen patients with locally advanced or metastatic melanoma and a concomitant diagnosis of CLL who received pembrolizumab or ipilimumab with or without nivolumab for the treatment of their melanoma at Memorial Sloan Kettering Cancer Center between January 1, 2010, and January 1, 2017, were retrospectively identified. Clinical characteristics including absolute lymphocyte counts during therapy were recorded along with a response to treatment (objective radiographic response, progression-free survival, and adverse events) for each patient. Of 9 response-evaluable patients treated with ipilimumab, 3 (33%) had a partial response, 1 (11%) had stable disease, and 5 (56%) developed progressive disease. Objective tumor responses were also observed with single-agent therapy pembrolizumab and with combination therapy of nivolumab and ipilimumab. Grade 3 or 4 toxicity was observed in 6 of 15 patients (40%), including diarrhea, transaminitis, rash, and hemolytic anemia. Although our retrospective assessment was limited, there was no evidence that CLL responded to the checkpoint blockade. This case series demonstrates that ipilimumab, pembrolizumab, and combined ipilimumab and nivolumab therapies show clinical activity in patients with melanoma and concomitant CLL, at rates consistent with those previously reported. This population may warrant closer surveillance for hematologic immune-related toxicities such as autoimmune hemolytic anemia.

Nivolumab for the Treatment of Advanced Pediatric Malignancies.

Nivolumab is an immune checkpoint inhibitor with high antitumor activity in selected neoplasms. The aim of the study was to evaluate the efficacy and safety of nivolumab in pediatric patients with various types of highly malignant advanced tumors. Ten patients with a median age of 15.1 years were included in the study. The indications for treatment were: malignant skin melanoma (n=5), brain tumor (n=2), malignant melanoma of the brain (n=1), Hodgkin lymphoma (n=1) and soft tissue sarcoma (n=1). Complete disease remission was observed in 4 patients. Overall survival at 24 months from diagnosis for the entire group was 0.36. Two patients receiving combination therapy of nivolumab and ipilimumab did not achieve a remission. Adverse events of immunotherapy were observed in 4/10 patients. Nivolumab is a promising option in pediatric advanced malignancies. Treatment with immunotherapy was relatively well tolerated, and emerging side-effects were manageable.

Checkpoint Inhibitor-Induced Colitis: A Case Series

Abstract Introduction/Objective Checkpoint inhibitors are novel immune-stimulating antibodies that have revolutionized the management and prognosis of several malignancies. The primary targets are cytotoxic T-lymphocyte–associated antigen-4 (anti-CTLA-4; e.g. pembrolizumab) and programmed cell death-1 receptor (anti-PD-1; e.g. ipilimumab and nivolumab). In spite of the significant advantages, many immune-related adverse effects have been identified. One of which is checkpoint inhibitor-induced colitis (CIC). Although there is awareness of the histopathologic features of anti- CTLA-4 induced colitis, there is much to be discovered about the pathologic features of anti-PD-1 colitis. Methods We herein report three cases of CIC. There were two women and 1 male (age range, 50 to 73-years-old, mean 64-years-old) who presented with diarrhea and/or hematochezia after multiple cycles of pembrolizumab or ipilimumab/ nivolumab combination therapy. Endoscopic examination was abnormal in all of these cases. Results The histologic features were similar in two cases, with moderate active chronic colitis and one case with focal active colitis. Two of the three patient were given steroids in addition to their regular medications with symptom improvement. One patient was removed off all medications and enrolled into hospice due to disease progression. CIC has been an increasingly recognized immune-related adverse effect that has a wide spectrum of clinical presentations ranging from mild diarrhea and abdominal pain to severe colitis and intestinal perforation. However, it is thought to be underestimated. Histologically, CIC can mimic inflammatory bowel disease, microscopic colitis and active colitis. Our cases showed histopathologic features mimicking those of ulcerative colitis. Conclusion Awareness of CIC is crucial for the multidisciplinary management essential for these patients. The histopathologic pattern coupled with the clinical history can allow pathologists to confirm the diagnosis of CIC and facilitate timely diagnosis and treatment.

S1622 Rapid Onset Colitis Following Single Infusion of Combination Checkpoint Inhibitor Therapy

INTRODUCTION: Checkpoint inhibitors are becoming more prevalent due to a growing number of oncologic indications. Colitis due to ipilimumab and nivolumab are well described adverse effects, but onset and severity can vary. We present a case of severe checkpoint inhibitor induced colitis five days after infusion. CASE DESCRIPTION/METHODS: A 68-year-old man was admitted for diarrhea. Five days prior, he received his first dose of ipilimumab and nivolumab combination therapy for metastatic prostate cancer, as a part of a clinical trial. He described up to 10 watery bowel movements per day with abdominal pain. Flexible sigmoidoscopy confirmed severe colitis. Biopsies showed acute inflammation, crypt abscesses, and cryptitis consistent with checkpoint inhibitor induced colitis. He was treated with IV steroids and transitioned to oral before discharge. His diarrhea persisted and he was given high dose steroids. After two weeks with no improvement, he was given an infusion of infliximab. Despite this, he was readmitted to the hospital. He received IV steroids and a second dose of infliximab. Four days later, he developed severe abdominal pain with guarding. CT showed pneumoperitoneum, requiring emergent surgery for cecal perforation (Figure 1). Surgical pathology showed focal serositis, multifocal mucosal/submucosal inflammation and crypt microabscesses (Figures 2 and 3). Follow up sigmoidoscopy showed improved inflammation. After an extended steroid taper, he was discharged. DISCUSSION: Ipilimumab and nivolumab are immune checkpoint inhibitors used to treat metastatic melanoma and renal cell carcinoma, with ongoing trials for metastatic prostate cancer (1). Diarrhea and colitis are common adverse reactions of these medications, with an incidence of up to 44% (1). Average onset of colitis is 5-10 weeks after the third infusion for both ipilimumab and nivolumab (2). Management is based on symptom severity. Grade 1-2 diarrhea may only require interruption of infusions, whereas grades 3-4 diarrhea should be treated with IV steroids (1). Infliximab is effective for steroid refractory disease. Vedolizumab has recently been used in patients unresponsive to steroids and infliximab (3). To our knowledge, this case represents the earliest onset of colitis following immune checkpoint inhibitor therapy. Early diagnosis with endoscopy is key, as this allows for directed treatment, which may decrease the risk of complications. It is important for the physician and patient to be aware of these side effects to ensure prompt treatment.Figure 1.: CT abdomen with IV contrast showing pneumoperitoneum, with free air due to cecal perforation.Figure 2.: Surgical specimen following exploratory laparotomy with right hemicolectomy for cecal perforation.Figure 3.: Histology showing multifocal mucosal/submucosal inflammation and crypt microabscesses.

TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma

Treatment with tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (RCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile. We report final results from TiNivo, a phase Ib/II study of tivozanib combined with nivolumab. In phase Ib, patients with metastatic RCC received tivozanib 1.0 mg once daily (QD) for 21 days followed by 7 days off treatment (n= 3) or tivozanib 1.5 mg QD (n= 3) plus nivolumab 240 mg every 2 weeks. The maximum tolerated dose was determined to be tivozanib 1.5 mg, and 22 additional patients were enrolled at the maximum tolerated dose for phase II. Primary end points included safety and tolerability, with secondary end points of objective response rate, disease control rate, and progression-free survival. In total, 25 patients were treated with tivozanib 1.5 mg QD [12 (48%) treatment-naïve; 13 (52%) previously treated]. Treatment-related grade 3/4 AEs were reported in 20 patients (80%); 4 patients (17%) experienced AEs that led to dose reduction, and 8 (32%) discontinued due to AEs. The objective response rate was 56% (including one complete response) and disease control rate was 96%, with a median time to best response of 7.9 weeks. Twenty patients (80%) had tumor shrinkage. With a median follow-up of 19.0 months (range, 12.6-22.8), median progression-free survival was 18.9 months (95% confidence interval 16.4-not reached) in all patients and was similar in treatment-naïve and previously treated patients. Tivozanib plus nivolumab combination therapy showed a generally tolerable AE profile and promising antitumor efficacy. These results support further development of tivozanib combined with nivolumab as a treatment option in patients with treatment-naïve or previously treated metastatic RCC. NCT03136627.

Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells’ responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers.