Safety Of Nivolumab In Combination Research Articles

Long-term comparative efficacy and safety of nivolumab plus ipilimumab relative to other first-line therapies for advanced non-small-cell lung cancer: A systematic literature review and network meta-analysis

ObjectivesTo quantify the long-term comparative efficacy and safety of nivolumab in combination with ipilimumab (NIVO + IPI) relative to other immunotherapy (IO)-based regimens and chemotherapy in patients with first-line advanced non-small cell lung cancer (aNSCLC). MethodsPhase 3 randomized controlled-trials (RCTs) with minimum 3-year follow-up evaluating IO-based regimens approved for first-line aNSCLC were identified via systematic literature review. Analytic populations were defined by levels of PD-L1 expression and histology. Due to presence of proportional hazards violations, time-varying hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were estimated via Bayesian fractional polynomial network meta-analysis. For safety endpoints, odds ratios (ORs) were estimated using indirect treatment comparisons (ITCs). ResultsCheckMate 227, KEYNOTE-189, KEYNOTE-407, KEYNOTE-024, KEYNOTE-042, and IMpower150 were included in the base case analysis. For OS and PFS, HRs of NIVO + IPI relative to other IO-based regimens trended downward over time across analytic populations. The 36-month OS HRs of NIVO + IPI versus comparators were: 0.69 (95 % credible interval: 0.47, 1.00) versus pembrolizumab + chemotherapy and 0.65 (0.45, 0.93) versus atezolizumab + bevacizumab + chemotherapy in the non-squamous and PD-L1 all-comers population; 0.73 (0.53, 1.02) versus pembrolizumab + chemotherapy in the squamous and PD-L1 all-comers population; and 1.05 (0.83, 1.32) versus pembrolizumab in the mixed histology and PD-L1 ≥ 50 % population. For PFS, 36-month HR point estimates ranged from 0.46 to 0.85 (only statistically significant versus pembrolizumab + chemotherapy in the squamous population; 0.46 [0.31, 0.69]). Adverse events (AEs) leading to discontinuation were not statistically significantly different between NIVO + IPI and pembrolizumab + chemotherapy, nor between NIVO + IPI and pembrolizumab monotherapy, although treatment-related grade ≥ 3 AEs were higher with NIVO + IPI than pembrolizumab monotherapy (OR = 2.21 [1.30, 3.75]). ConclusionsThis study indicates trends towards long-term benefit with NIVO + IPI compared with other IO-based combinations, with manageable toxicities.

Phase II study of nivolumab in combination with FOLFOXIRI/bevacizumab as first-line treatment in patients with advanced colorectal cancer RAS/BRAF mutated (mut): NIVACOR trial (GOIRC-03-2018).

3509 Background: FOLFOXIRI plus bevacizumab (BEV) represents standard chemotherapy in first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC). The NIVACOR study evaluates the addition of nivolumab (NIV) to FOLFOXIRI/BEV as first-line therapy in mCRC RAS/BRAF mut pts regardless of MSS/MSI status. Methods: This is a single-arm, multicenter, open-label, phase II trial in first-line treatment of pts with mCRC RAS/BRAF mut. Pts received NIV at a flat dose of 240 mg q14 days, FOLFOXIRI (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and 5-fluorouracil CI 3,200 mg/m2 for 48 hours) in combination with BEV at the dose of 5 mg/kg IV q14 days for eight cycles and then, the maintenance with BEV/NIV until PD or unacceptable toxicities. The primary endpoint was the ORR according to RECIST 1.1 Criteria. All images are reviewed by Independent Data Monitoring Committee. According to Fleming’s design with alpha and beta levels of 0.05 and 0.2 respectively, in a sample size of 73 pts (comprehensive of a 10% drop-out rate), at least 56 responses were necessary to not reject the alternative hypothesis of an ORR=0.80. Results: From October 2019 to March 2021, 73 pts were enrolled in 9 Italian centers. The median age was 60 (51-65) years and 50.7% were male; the main primary tumor side was right (50.7%). The molecular characterization was: 87.7% RAS mut, 16.2% BRAF mut, and 4.5% both RAS and BRAF mut; 10/62 were MSI (16.1%), 52/62 (83.9%) MSS, and 11 pts not assessed. Liver metastases were present in 56.2% pts. The median follow-up was 14.3 (IQR 11.5-16.5) months on December 31, 2021. The median (m) duration of treatment was 12 (8-17) cycles. The ORR was 76.7%, with 7(9.6%) CR and 49(67.1%) PR. SD were 15(20.6%) with a DCR of 97.3%; 2(2.7%) pts were not evaluable. The mDOR was 8.4 (95%CI, 7-NE) months. The mPFS was 10.1 months (95%CI, 9.4-NE) and 12-months PFS was 53.4%. At data cut-off, 65 (89.1%) pts are still alive. In subgroups analysis of MSS pts the ORR was 78.9% with a mDOR of 7.59 (95% CI 6.21 -11.43) months, DCR of 96.2%, and mPFS of 9.8 (95%CI 8.18-15.24) months. The surgery of the primary tumor, metastases, or both was performed in 6(8.2%), 9(9.6%), and 5(6.9%) of pts, respectively. The main grade (G) 3 -4 toxicities were: neutropenia (G3 21.9%, G4 15.1%), diarrhea (G3 17.8%, G4 1.4%), hypertension G3 (6.8%), fatigue G3 (6.8%), and febrile neutropenia G4 (4.1%). Conclusions: The primary endpoint ORR was met. These results show the preliminary efficacy and safety of NIV in combination with FOLOXIRI/BEV as first-line therapy in pts with mCRC RAS/BRAF mut. Also, promising activity was observed in MSS subgroup pts. These data support the conduction of phase III randomized-controlled study. Research Sponsor: Bayer, Bristol Myers-Squibb. Clinical trial information: NCT04072198.

Phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (cKS)

Classical Kaposi sarcoma (cKS) is a rare human herpesvirus 8-associated sarcoma with limited treatment options. We evaluated the efficacy and safety of nivolumab in combination with ipilimumab in patients with previously treated progressive cKS. cKS patients with progressive disease after one or more lines of systemic therapy and measurable disease by positron emission tomography/computed tomography and/or physical examination received nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until progression or toxicity for a maximum of 24 months. The primary endpoint was overall response rate; secondary endpoints included 6-month progression-free survival (PFS) rate and safety. Immune correlates were explored using immunohistochemistry, DNA sequencing (596/648 genes) and RNA sequencing (whole transcriptome hybrid capture) of tumor specimens and matched blood. Eighteen male patients (median age 76.5 years) were enrolled between April 2018 and December 2020. At a median follow up of 24.4 months, overall response rate by RECIST v1.1 was 87%. Metabolic complete response as assessed by positron emission tomography/computed tomography was observed in 8 of 13 (62%) assessable patients. Some 6/13 achieved pathological complete response after treatment. In two patients, palliative limb amputation was prevented. Median PFS was not reached. The 6- month and 12-month PFS rate was 76.5% and 58.8%, respectively. Only four patients (22%) experienced grade 3-4 adverse events. The most frequent genomic alteration was biallelic copy number loss of the FOX1A gene. The majority of tumors carried a low tumor mutational burden, were microsatellite stable, mismatch repair proficient, did not express programmed death-ligand 1, and displayed only low lymphocytic infiltrates, rendering them immunologically 'cold'. This prospectively designed phase II study of nivolumab and ipilimumab demonstrates promising activity of this combination in progressive cKS representing a new treatment option in this population.

A phase II study of nivolumab in combination with modified FOLFIRINOX for metastatic pancreatic cancer.

553 Background: Although FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of unresectable pancreatic cancer patients, high unmet medical needs still exist for the treatment of this cancer. Nivolumab has shown efficacy for multiple cancer types in not only its monotherapy but also combinations with conventional chemotherapies. This study aimed to assess the efficacy and safety of nivolumab in combination with modified FOLFIRINOX, which is one of the first line chemotherapy for pancreatic cancer. Methods: Thirty-one treatment-naïve patients with metastatic, unresectable/recurrent pancreatic cancer patients received nivolumab (480 mg, every 4 weeks) plus modified FOLFIRINOX (oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, irinotecan 150 mg/m2 and fluorouracil 2400 mg/m2, every 2 weeks). The primary endpoint was objective response rate (ORR) (central assessment). Secondary endpoints were overall survival (OS), progression-free survival (PFS) (central assessment), safety etc. Results: The median duration of follow-up was 13.40 months. ORR was 32.3% (CR: 0.0%, PR: 32.3%) and the median duration of response was 7.36 (range 3.5-20.1+) months. Median OS and PFS were 13.40 (90% CI 10.87-15.24) months and 7.39 (90% CI 3.88-7.59) months, respectively. The 1-year survival rate was 54.8 (90% CI 39.1-68.1) %. The most frequently reported grade 3-4 drug-related adverse events were neutrophil count decreased (38.7%), decreased appetite (16.1%), hypokalemia (12.9%), febrile neutropenia (9.7%), nausea (9.7%) and white blood cell count decreased (9.7%). Adrenal insufficiency (3.2%) was observed as immune mediated adverse event. Conclusions: Nivolumab in combination with modified FOLFIRINOX had a manageable safety profile in patients with metastatic pancreatic cancer. Additional work is needed to determine the population who can benefit from the combination. Clinical trial information: JapicCTI-184230.

FOLFOXIRI/Bevacizumab Plus Nivolumab as First-Line Treatment in Metastatic Colorectal Cancer RAS/BRAF Mutated: Safety Run-In of Phase II NIVACOR Trial.

The NIVACOR trial is a phase II study assessing the efficacy and safety of nivolumab in combination with FOLFOXIRI/bevacizumab in first-line setting in patients affected by metastatic colorectal cancer (mCRC) RAS/BRAF mutated. We report safety run-in results in the first 10 patients enrolled. Patients received triplet chemotherapy with FOLFOXIRI scheme plus bevacizumab, in association with nivolumab every 2 weeks for 8 cycles (induction phase) followed by bevacizumab plus nivolumab every 2 weeks (maintenance phase), until progression of disease or unacceptable toxicities. The first ten patients were evaluated: 7 experienced at least one adverse event (AE) related to FOLFOXIRI/bevacizumab and 2 related to nivolumab. The most frequent grade 1–2 AEs related to FOLFOXIRI/bevacizumab were diarrhea and fatigue (71%), nausea and vomiting (57%); 3 (43%) had grade 3–4 neutropenia, and 2 (20%) patients developed grade 1–2 AEs nivolumab related: skin rash and salivary gland infection. Two patients delayed the dose because of serious AEs, proteinuria and salivary gland infection; one patient discontinued experimental treatment due to the ileo-urethral fistula and concurrent Clostridium infection diarrhea. No treatment- related death occurred. The safety run-in analysis of NIVACOR trial reassured using co-administration of FOLFOXIRI/bevacizumab and nivolumab was well tolerated with an acceptable toxicity profile.Clinical Trial Registration https://clinicaltrials.gov/, (NCT04072198).

A protocol for phase II study investigating the safety and efficacy of TM5614 in combination with nivolumab in the treatment of unresectable malignant melanoma

Abstract Introduction: Plasminogen activating inhibitor-1 (PAI-1) plays a significant role in the development of various cancers, including melanomas, and modulation of tumor-associated inflammation is one of the key anti-tumor functions of PAI-1. A recent report suggested that PAI-1 inhibitors suppress the expression of programmed cell death 1 ligand 1 (PD-L1) on tumor-associated macrophages (TAMs), suppressing the induction of regulatory T cells and promoting anti-melanoma immune responses. Methods and analysis: This is a single-arm, open-label, multi-institutional, phase 2 clinical trial to assess the efficacy and safety of nivolumab in combination with TM5614 (pPAI-1 inhibitor) in patients with advanced malignant melanoma. Nivolumab will be administered every 4 weeks, and TM5614 will be administered daily for 8 weeks. For the first-line cohort, assuming the null hypothesis of a response rate of 22.2% and an alternative hypothesis of 40%, a minimum of 22 patients are required to achieve a two-sided, type I error of 5% and power of 70% based on the exact binomial distribution. For the second-line and beyond cohorts, assuming the null hypothesis of a response rate of 5% and the alternative hypothesis of 22.2%, a minimum of 18 patients are required to achieve a two-sided, type I error of 5%, and power of 70% based on the exact binomial distribution. Discussion: This study will contribute to the development of novel combination therapy for anti- programmed cell death 1 antibodies-resistant advanced melanoma patients, which remains an unmet clinical need. Trial registration: Trial registration number: jRCT2021210029

819TiP COLIBRI trial (GINECO-CE108b): A multicenter, window study evaluating immune impact and safety of nivolumab in combination with ipilimumab before initial radio-chemotherapy (RTCT) treatment for locally advanced cervix cancer

Cervical cancer is the fourth most frequent cancer in women with a survival rate <20% for advanced stages. It mainly results from chronic infection with human papillomavirus. Standard first-line therapy is RTCT for cervical cancer FIGO stage IB3 and more. Recent evidence in pretreated advanced disease reported combined use of ipilimumab (anti-CTLA-4) with nivolumab (anti-PD-1) may have complementary action, thus yielding a highest clinical efficacy but is explored in heavily pretreated patients where immune resources could be altered.

Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSé-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium

PurposeAcSé-ESMART is a European multicentre, proof-of-concept multiarm phase I/II platform trial in paediatric patients with relapsed/refractory cancer. Arm G assessed the activity and safety of nivolumab in combination with metronomic cyclophosphamide +/- irradiation. Experimental designFollowing a Phase II Simon two-stage design, nivolumab was administered intravenously at 3 mg/kg every 2 weeks of a 28-day cycle, oral cyclophosphamide at 25 mg/m2 twice a day, 1 week on/1 week off. The primary endpoint was objective response rate. Irradiation/radioablation of primary tumour or metastasis could be administered as per physician's choice. Biomarker evaluation was performed by tumour immunohistochemistry, whole exome and RNA sequencing, and immunophenotyping of peripheral blood by flow cytometry. ResultsThirteen patients were treated with a median age of 15 years (range: 5.5–19.4). The main histologies were high-grade glioma, neuroblastoma, and desmoplastic small round cell tumour (DSRCT). The safety profile was similar to those of single-agent nivolumab, albeit haematologic toxicity, mainly lymphocytopenia, was commonly reported with the addition of cyclophosphamide +/- irradiation. Two patients with DSRCT and ependymoma presented unconfirmed partial response and prolonged disease stabilisation. Low mutational load with modest intratumour CD3+ T-cell infiltration and immunosuppressive tumour microenvironment were observed in the tumour samples. Under combined treatment, no positive modulation of circulating T cells was displayed, while derived neutrophil-to-lymphocyte ratio increased. ConclusionsNivolumab in combination with cyclophosphamide was well tolerated but had limited activity in this paediatric setting. Metronomic cyclophosphamide did not modulate systemic immune response that could compensate limited T-cell infiltration and the immunosuppressive tumour microenvironment. ClinicalTrials.gov IdentifierNCT2813135.

Safety of nivolumab in combination with prior or concurrent radiation therapy in hepatocellular carcinoma

Nivolumab has been demonstrated to be effective for the treatment of unresectable hepatocellular carcinoma (HCC). While many patients may additionally benefit from radiation therapy (RT), the toxicity of combination nivolumab and RT is unknown. Patients who underwent liver-directed RT prior to or concurrent with nivolumab for HCC at our institution were reviewed. Toxicity was assessed by Common Terminology Criteria for Adverse Effects v5.0 criteria until disease progression, change in systemic therapy, additional liver-targeted locoregional therapy (LRT), or death. Prevalence ratios (PR) were compared for patients undergoing prior and concurrent RT. Childs-Turcotte-Pugh (CTP) and Albumin-Bilirubin (ALBI) scores at 1-, 3-, and 6-months were compared with baseline. We identified 55 patients with median follow-up 6.0 months; 34 (62%) received prior and 21 (38%) received concurrent RT. Grade 3+ toxicity occurred in 8 patients (17%). Grade 3+ toxicities did not differ between prior and concurrent RT cohorts on the univariable analysis (PR 1.91; 95% CI 0.42, 8.59) but were higher in the prior RT cohort on the multivariable analysis (PR 5.42; 95% CI 1.42, 20.67; p = 0.013). Mean CTP scores increased from baseline (6.33) at 1 month (7.04; 95% CI 6.80, 7.27) and 3 months (6.81; 95% CI 6.43, 7.19) and thereafter normalized; mean ALBI scores increased from baseline (− 1.93) at 1 month (− 1.75; 95% CI − 1.84, − 1.66) with no difference thereafter. Combination RT and nivolumab is generally safe in the management of unresectable HCC with a low rate of serious adverse events. Prospective trials investigating the efficacy of combination nivolumab and RT are warranted.

Study to Assess the Efficacy and Safety of Nivolumab in Combination With Paclitaxel in Subjects With Head and Neck Cancer Unable for Cisplatin-based Chemotherapy (NIVOTAX)

Study to Assess the Efficacy and Safety of Nivolumab in Combination With Paclitaxel in Subjects With Head and Neck Cancer Unable for Cisplatin-based Chemotherapy (NIVOTAX)

Abstract OT2-04-07: Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer (WJOG11418B, NEWFLAME trial)

Abstract Background: In this year, anti-programmed death-ligand 1 (PD-L1) antibody has been approved for PD-L1-positive metastatic triple-negative breast cancer by the U.S. Food and Drug Administration. The synergistic effect of the combination of anti-PD-L1 antibody, CDK4/6 inhibitor and endocrine therapy (ET) has been anticipated based on various preclinical data. A Phase Ib study (JPCE, NCT02779751) of abemaciclib plus pembrolizumab demonstrated manageable safety and promising anti-tumor activity in patients with HR-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Therefore, we initiated this investigator-initiated trial to evaluate the efficacy and safety of the combination of nivolumab, abemaciclib and ET (letrozole [LET] or fulvestrant [FUL]) as a first or second-line treatment in patients with HR+, HER2- MBC. Trial Design: This is a multicenter, multi-cohort, nonrandomized, open-label Phase II study to evaluate the efficacy and safety of nivolumab in combination with abemaciclib and ET (LET or FUL) in patients with HR+, HER2- MBC. Since there is no safety data of the combination of nivolumab, abemaciclib and ET, we evaluate safety and tolerability of the combination therapy in the first 6 patients with predefined dose-limiting toxicities. Patients will receive nivolumab 240 mg/body on day 1, 15, abemaciclib 150mg twice daily, and either LET 2.5mg once daily (LET cohort) or FUL 500mg on day1, day15 (FUL cohort) every 4 weeks until disease progression, unacceptable toxicity, or patient refusal. Pre- or perimenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligibility Criteria: Key eligibility criteria for the LET cohort are: postmenopausal HR+, HER2- MBC with ECOG PS≤1, measurable disease, no prior systemic therapy. ET in the adjuvant setting is permitted if the patient has a disease-free interval &amp;gt; 12 months from the completion of ET. Key eligibility criteria for the FUL cohort are: HR+, HER2- MBC with ECOG PS≤1, measurable disease, no more than one ET or any prior chemotherapy for MBC. Patients are required to have a disease that progressed while receiving adjuvant ET, ≤ 12 months after adjuvant ET, or while receiving ET for MBC. Specific Aims: The primary endpoint is the objective response rate (ORR) and key secondary endpoints include progression-free survival, overall survival, and the safety of the protocol treatment. Statistical Design: The threshold and expected ORR of LET cohort are 55% and 75%, respectively, and 16 patients are needed to ensure a statistical power of 80% (α=0.20). The threshold and expected ORR of FUL cohort are 45% and 60%, respectively, and 32 patients are needed to ensure a statistical power of 80% (α=0.20). Target Accrual: A total of 53 patients (LET cohort: 18, FUL cohort: 35) will be enrolled and duration of enrollment will be 1 year and 4 months. This trial opened to accrual in June 2019. Clinical trial information: JapicCTI-194782. Contact Information: Jun Masuda, Toranomon Hospital, Tokyo, Japan, masu-j@toranomon.gr.jp Citation Format: Jun Masuda, Junji Tsurutani, Norikazu Masuda, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Masato Takahashi, Hiroji Iwata, Tsutomu Iwasa, Toru Mukohara, Kenichi Yoshimura, Takayuki Ueno, Toshimi Takano. Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer (WJOG11418B, NEWFLAME trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-07.

A Study Comparing the Efficacy and Safety of Nivolumab in Combination With Bacillus Calmette-Guerin (BCG) Versus BCG Alone in Participants With High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC)

A Study Comparing the Efficacy and Safety of Nivolumab in Combination With Bacillus Calmette-Guerin (BCG) Versus BCG Alone in Participants With High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC)

Efficacy Analysis of Nivolumab in Combination with Gemcitabine and Cisplatin in Patients with Unresectable or Metastatic Biliary Tract Cancers

Background: Current chemotherapy for advanced biliary tract cancers has limited efficacy. This study aimed to determine the efficacy and safety of nivolumab in combination with gemcitabine and cisplatin and biomarkers for predicting response and prognosis. Methods: In this open-label, single-arm, phase Ⅱ trial, enrolled patients received gemcitabine 1000mg/m2 on day 1 and d 5, followed by cisplatin 75mg/m2 on day 1 and nivolumab 3mg/kg on day 3 in every 3-week treatment cycle. Responsive patients switched to maintenance therapy after a maximum of six cycles combination therapy. The primary outcome was objective response. Secondary outcomes included safety, disease control, progression free survival and overall survival. Findings: Between November 16, 2017, and December 31, 2018, 27 of 32 enrolled patients received a median of 4 cycles (IQR, 3-6) combination therapy with a median follow-up of 12.8 (95% CI, 10.8-14.8) months. 15 (55.6%) patients achieved objective response and the disease control was 92.6%. 2 of 6 (33.3%) response evaluable patients previously treated with gemcitabine- or cisplatin-based chemotherapy achieved 1 complete response and 1 partial response.13 of 21 chemotherapy-naive patients (61.9%) achieved objective response. Median progression free survival was 6.1 months (95% CI, 3.4 -8.2), and progression free survival at 6-month was 51.9 % (95% CI, 31.9-68.6). Median overall survival was 12.5 months (95% CI, 5.0-NR), and overall survival at 12-month was 54% (95% CI, 33.1- 70.9). The most common grade 3 or higher adverse events were thrombocytopenia (56%), and neutropenia (22%). PD-L1 was invalid for predicting response and prognosis. MSI and Fitness could predict response. TNB, sFASL and IFN-γ in serum may predict prognosis. Interpretation: Nivolumab in combination with gemcitabine and cisplatin had promising efficacy and manageable safety profile in unresectable or metastatic biliary tract cancers. Clinical Trial Registration: (NCT03311789). Funding Statement: This research was supported by the grants from the Natural Science Foundation of China (No. 81830002 and 31870873 to WDH, No. 81773248, 81572914 to Qian Mei), the National Key Research and Development Program of China (No. 2016YFC1303501 and 2016YFC1303504 to WDH). Declaration of Interests: There was no commercial funding in this study. All authors declared no competing interests. Ethics Approval Statement: The study protocol was approved by the institutional ethics committee and conducted in accordance with international standards of good clinical practice. Written informed consent based on Declaration of Helsinki principles was provided by patients or their representatives before study entry.

LBA52 - Efficacy and safety of nivolumab in combination with docetaxel in men with metastatic castration-resistant prostate cancer in CheckMate 9KD

LBA52 - Efficacy and safety of nivolumab in combination with docetaxel in men with metastatic castration-resistant prostate cancer in CheckMate 9KD

The Safety of Nivolumab in Combination with Prior or Concurrent Radiation Therapy Among Patients with Hepatocellular Carcinoma

The Safety of Nivolumab in Combination with Prior or Concurrent Radiation Therapy Among Patients with Hepatocellular Carcinoma

Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.

e13526 Background: Recurrence of high-grade glioma (HGG) (WHO grade III-IV) is a nearly universal phenomenon and necessitates the development of new therapeutic modalities. Two possible immunotherapeutic modalities are checkpoint blockade with agents such as nivolumab, a blocking antibody against the inhibitory checkpoint programmed cell death-1 (PD-1), and dendritic cell (DC) vaccination. We have shown in phase 1 and 2 trials that DC vaccination against the glioblastoma (GBM)-associated antigen human cytomegalovirus pp65-lysosomal-associated membrane protein (CMVpp65) is safe and possesses potential benefit. We hypothesized that nivolumab-induced immune checkpoint blockade could enhance efficacy of DC vaccination. Therefore, we undertook a phase 1 study to evaluate safety of nivolumab in combination with CMVpp65 mRNA pulsed DC vaccination in subjects with first or second recurrence of resectable HGG. Methods: We performed a phase 1, single-center, randomized study of nivolumab alone versus nivolumab + DC vaccination prior to planned surgical resection for both groups. We administered nivolumab 3 mg/kg IV q2weeks for 8 weeks followed by surgery and planned continuation of nivolumab. For the group receiving nivolumab + DC vaccination, we administered 3 vaccines before surgical resection with both groups receiving 5 planned post-resection DC vaccines. Primary endpoint was safety assessment using NCI-CTCAE 4.03. Results: We enrolled 6 subjects (4: GBM, 1: anaplastic astrocytoma, 1: anaplastic oligodendroglioma) with 3 receiving nivolumab alone and 3 receiving nivolumab + DC vaccination. Age range was 45-63 years subjects. We documented similar adverse events in both groups with most common grade 1-2 toxicities being fatigue (2 subjects, nivolumab alone) and thrombocytopenia (2 subjects, nivolumab + DC vaccine). Grade 4 toxicities included wound infection (2 subjects, nivolumab + DC vaccine) and meningitis (1 subject, nivolumab + DC vaccine). While we designed the study to enroll 66 subjects, we terminated the study early in light of CheckMate 143 phase III data showing nivolumab did not improve overall survival in recurrent GBM. Conclusions: Safety of nivolumab + DC vaccination in recurrent HGG is similar to nivolumab alone. Continued evaluation of new therapeutics including immunotherapy is underway for this patient population. Clinical trial information: NCT02529072.

Efficacy and safety of nivolumab in combination with ipilimumab in Japanese patients with advanced melanoma: An open-label, single-arm, multicentre phase II study

AimThe aim of the study was to evaluate the efficacy and safety of nivolumab combined with ipilimumab in treatment-naïve Japanese patients with advanced melanoma. MethodsIn this multicentre, single-arm study, treatment-naïve Japanese patients with unresectable stage III/IV or recurrent melanoma received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg). The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included overall survival (OS), progression-free survival (PFS), disease control rate and safety. ResultsThe subtypes of the thirty patients enrolled were: 12, mucosal; eight, non-acral cutaneous; seven, acral; two, uveal and one, unknown primary melanoma. The ORR was 43.3% (95% confidence interval [CI]: 25.5, 62.6) with central and local assessment. The centrally and locally assessed disease control rate (95% CI) were 73.3% (54.1, 87.7) and 86.7% (69.3, 96.2), respectively. At the median follow-up period of 14.1 months (range 5.2–27.7), median OS and centrally assessed PFS were not reached. OS (95% CI) at 6, 12, 18 and 24 months was 93.3% (75.9, 98.3), 83.3% (64.5, 92.7), 72.9% (50.0, 86.5) and 65.6% (40.4, 82.2), respectively. Treatment-related adverse events (AEs) occurred in all patients. Grade III–IV and serious AEs occurred, mostly during the combination phase, in 23 (76.7%) and 20 (66.7%) patients, respectively. No treatment-related deaths occurred. ConclusionsThis study confirmed the efficacy and safety of nivolumab plus ipilimumab in treatment-naïve Japanese patients with advanced melanoma including rare subtypes. Incidence rates for grade III–IV AEs were high but manageable with appropriate medical attention and treatment. Trial registrationJapicCTI-152869.

Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study

BackgroundCombination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented.MethodsPatients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint.ResultsArm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached.Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months.ConclusionsThe addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.Trial registrationClinicaltrials.gov identifier: NCT01472081. Registered 16 November 2011.