Nivolumab Therapy Research Articles

Nivolumab as second-line treatment of patients with metastatic renal cell carcinoma with high or normal fibrinogen levels: A prospective, cohort study.

e16510 Background: In a number of coagulation-related studies, elevated fibrinogen levels were found in patients with renal cell carcinoma (RCC) and correlated with more advanced disease. The impact of hyperfibrinogenemia on the clinical outcomes of immunotherapy remains uncertain. Methods: In this prospective cohort study, fibrinogen levels were measured one week prior to the second-line nivolumab therapy (240 mg or 480 mg every 2 or 4 weeks) and then monthly until disease progression or unacceptable toxicity. High fibrinogen level was defined as ≤5 g/L. Key eligibility criteria included metastatic clear cell RCC resistant to the first-line targeted therapy, ≤3 MSKCC risk factors, ECOG PS 0-2, platelet count <400×10(9)/L, no heart diseases, no anticoagulation therapy, and age 40-65 years. The primary endpoint was overall survival (OS) in cohorts with high (H) and normal (N) fibrinogen levels. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and fibrinogen levels during therapy. Results: Between November 2018 and January 2021, 82 patients were enrolled, of whom 41 and 41, respectively, were recruited in H and N cohorts. The groups were well balanced at baseline. The median follow-up time was 32.4 months. Compared to patients in N cohort, patients in H cohort had shorter OS (P=0.001), shorter PFS (P<0.01), and lower ORR (P=0.012). In H cohort, a below-median fibrinogen level was associated with longer observed OS (median, 23.7 vs. 19.4 months; P=0.03). In N cohort, 6 (15%) patients with stable disease had an increase in fibrinogen levels during nivolumab therapy. Patient characteristics and clinical outcomes are summarized. Conclusions: High fibrinogen levels affect the clinical outcomes in patients with metastatic renal cell carcinoma treated with second-line nivolumab. These findings require large-scale prospective validation. Clinical trial information: KCRB0181209 . [Table: see text]

T cell CD62L expression following nivolumab therapy is associated with response to rituximab‐nivolumab in treatment naïve follicular lymphoma: the 1st FLOR study

Introduction: Inter-tumoral T cell dysfunction and efficacy of immune checkpoint inhibitors (ICI) in follicular lymphoma (FL) has been well described. However, few studies have examined peripheral blood immunity at diagnosis or the impact of frontline ICI on circulating immunity in FL. We hypothesised that immune dysregulation in peripheral blood would be present in treatment naïve FL and would correlate to response to frontline ICI. Methods: PBMC samples from 34 untreated FL patients receiving rituximab (R) and nivolumab (nivo) in the 1st FLOR trial (Hawkes JCO 2021) were collected at baseline, post 4 cycles of nivo and after 6 months of nivo±R. Immune profile was assessed using a single-tube 29 antibody FACS panel on a spectral flow cytometer and compared to the profile of 12 age matched healthy donors. Results were correlated with centrally determined PET response (Lugano criteria). Results: Compared to healthy donors, FL patients had increased proportions of TRegs (P < 0.0001) with decreased HLA-DR+ (P < 0.01) and increased PD-1+ (P < 0.01) populations. NK cells were increased (P < 0.05) with a 2-fold increase in TIM3 expression (P < 0.01). While total T cells were unchanged, expression of PD-1, TIM3, HLA-DR and 4-1BB were significantly increased in T cells from FL patients. Treatment with nivo significantly increased the populations of TRegs expressing 41BB, LAG-3, TIM3 or PD-L2 (P < 0.05) with a decreased PD-L1 positive population at PET-CT2. Expression of immune checkpoints on T cells was unchanged by therapy. To assess biomarkers of response, patients were stratified into sustained CR (CR achieved by PET-CT4 and maintained for 6 months without evidence of relapse, n = 15) vs. PR/PD (n = 21). At baseline, sustained CR was associated with a trend for increased proportions of Naïve CD4 and CD8 T cells and decreased TRegs and PD-L2 expressing TRegs. Baseline expression of PD-1 on T and NK cells did not correlate with sustained response. Most strikingly, expression of CD62L was significantly downregulated across total CD4 and CD8 T cells and TRegs at PET-CT2 in PR/PD patients (P < 0.05) and maintained at baseline levels in those patients who achieved a sustained CR. At this early timepoint final patient responses had not been established with most patients having either progressive or stable disease, suggesting that dysfunctional downregulation of CD62L in response to nivo may reflect the inability of patient’s T cells to activate and/or migrate to the tumour site and facilitate tumour clearance and long-term treatment responses. Conclusions: Grade 1-3A treatment naïve FL is associated with significant dysregulation of peripheral blood T and NK cells prior to therapy. Early downregulation of CD62L on T cells of patients treated with nivo was associated with the inability to achieve long term complete responses and may indicate aberrant T cell activation and/or function which impacts on long term response to therapy. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Bristol Myers Squibb Keywords: Basic and Translational Science, Diagnostic and Prognostic Biomarkers Conflicts of interests pertinent to the abstract. A. Barraclough Honoraria: Roche, Gilead G. Chong Consultant or advisory role: Bristol Myers Squibb Research funding: Bristol Myers Squibb, Merck Serono, Pharmacyclics, Regeneron, Bayer, Astra Zeneca, Amgen, Hutch Med, Incyte E. A. Hawkes Consultant or advisory role: Roche, Merck Sharpe & Dohme, Astra Zeneca, Gilead, Antigene, Novartis, Regeneron, Janssen, Specialised Therapeutics Research funding: Bristol Myers Squibb, Roche, Merck KgA, Astra Zeneca

Overall survival (OS) and pathologic response rate from a phase II clinical trial of neoadjuvant GVAX pancreas vaccine (with cyclophosphamide) in combination with nivolumab and stereotactic body radiation therapy (SBRT) followed by definitive resection for patients with borderline resectable pancreatic adenocarcinoma (BR-PDAC).

e16309 Background: The optimal management of BR-PDAC remains undefined due to the high rate of local progression and/or metastasis with upfront surgery alone. Given the limited activity of single agent PD-1 blockade in PDAC, combination strategies aimed at increasing high-avidity T-cells in the tumor microenvironment (TME) are under investigation. GVAX is an allogenic, whole cell, GM-CSF-secreting vaccine that activates T-cell immunity against tumor-associated antigens. Prior work has shown that GVAX in combination with low-dose cyclophosphamide (Cy) can inhibit T-regulatory cells and induce both PD-L1 expression and the formation of tertiary lymphoid aggregates. This multi-center phase II clinical trial evaluates the safety and clinical efficacy of the addition of GVAX/Cy/nivolumab and SBRT to neoadjuvant chemotherapy in patients with BR-PDAC. Methods: Patients received neoadjuvant mFOLFIRINOX or gemcitabine/abraxane if intolerant to mFOLFIRINOX. Two to six weeks after chemotherapy, the first dose combination immunotherapy with Cy (200 mg/m2), nivolumab (240mg) and GVAX (5 x 108 vaccine cells) was given. Three weeks later, patients received the second dose of combined immunotherapy concurrently with SBRT (6.6 Gy x 5 days) prior to surgical resection. The primary endpoint is CD8+ T-cell density (CD8) in surgical specimens compared with CD8 in historical control samples treated with neoadjuvant mFOLFIRINOX and SBRT only. Additional endpoints include pathologic response rates, adverse events (AEs) as graded by NCI CTCAE version 4.03, OS, and evaluation of immune changes to the TME. Results: 31 patients were enrolled from 2/2/2018 to 7/27/2021. Of these, 18 patients received at least one dose of combination immunotherapy. Following study treatment, one patient had progressive disease, three had occult intra-operative metastatic disease and 14 underwent definitive surgical resection (13 R0 resections and one R1 resection). The major pathologic response rate was 35% (defined as &lt;10% residual viable tumor), including one pathologic complete response (pCR). At a median follow-up of 20.5 months, median OS was 20.4 months (95% CI 18.2, NA). There were two grade 3 or higher AEs (one case of nivolumab-related autoimmune hepatitis and one case of SBRT-related pancytopenia). Conclusions: The addition of combined immunotherapy and SBRT to chemotherapy was safe and feasible in BR-PDAC. Observed median OS, pCR and R0 resection rates were comparable to contemporary studies administering neoadjuvant mFOLFIRINOX and SBRT. Additional immune correlative data will be available and reported at the time of the conference, guiding future applications of novel vaccine approaches. Clinical trial information: NCT03161379 .

LBP-25 - Concurrent nivolumab and external beam radiation therapy for patients with advanced hepatocellular carcinoma with vascular invasion: a phase 2, single-arm NEXTRAH trial

LBP-25 - Concurrent nivolumab and external beam radiation therapy for patients with advanced hepatocellular carcinoma with vascular invasion: a phase 2, single-arm NEXTRAH trial

A phase II trial of neoadjuvant nivolumab, docetaxel, and cisplatin therapy followed by surgery and radiation therapy for resectable high-grade salivary gland carcinoma.

TPS6110 Background: Salivary gland carcinomas (SGCs) are rare entities that contribute to approximately 5% of head and neck malignancies. The current standard therapy for resectable SGC is complete surgical resection with adjuvant radiotherapy or chemoradiotherapy. However, the patients with high-grade histological subgroup tumors have the highest risk of regional and distant metastasis as the primary cause of treatment failure.. The previous evidence demonstrates that neoadjuvant chemotherapy showed a statistically significant advantage in survival for patients with head and neck cancer. Based on the success of neoadjuvant immune checkpoint inhibitors (ICI) in preventing disease recurrence and achieving pathologic complete response (pCR) in different types of cancer, we designed this study by incorporating nivolumab combined with neoadjuvant cytotoxic chemotherapy in patients with potentially resectable high-grade SGCs. Methods: This study is the phase II, open-label, single-center study of nivolumab in combination with docetaxel, and cisplatin as a neoadjuvant therapy in high-grade resectable SGCs. All the patients must be confirmed with pre-defined high-grade histology and clinically node-positive. As the representative inclusion/exclusion criteria, all the patients must not receive prior cancer therapy in advance to study enrollment, including another kind of immunotherapy, cytotoxic chemotherapy, or radiotherapy. Three cycles of nivolumab (360mg), docetaxel (60mg per m2), and cisplatin (60mg per m2) are applied every three weeks. Three weeks after the last treatment, the patient is re-evaluated for the surgery and will undergo surgery within seven weeks after the last treatment. Based on the surgical pathologic outcome, additional radiotherapy will be initiated between 4 to 8 weeks after the surgery per the following guidance; R0: 59.4Gy/25fx; R1 or R2: 59.4Gy/25fx with optional boost 6.6Gy/3fx. The primary objective is the major pathologic response rate defined by ≤ 10% of tumors composed of viable tumors. Complete resection rate, response rate, downstaging at pathologic staging, two-year distant metastasis free-survival, disease-free survival, overall survival, safety results, surgical outcomes of facial nerve function, completeness of post-neoadjuvant surgery will be analyzed as the secondary objectives. The sample size was calculated using H0 of mPR ≤25% and H1 of mPR ≥50%, according to the one-arm binomial model (power of 90% and one-sided alpha of 0.05). A total of 50 patients will be recruited, include 40 evaluable patients. This study is currently recruiting patients at Samsung Medical Center, South Korea. The first subject received treatment in Nov. 2022 and three patients received the treatment. The time point for the primary analyses is Q3.2025. (ONO-4538-X78). Clinical trial information: NCT05727410 .

EE268 Temporal Trends in Adverse Event Costs with Nivolumab + Relatlimab Combination Therapy or Nivolumab Monotherapy for Patients with Unresectable or Metastatic Melanoma

This study described hospitalization costs of grade 3/4 all-cause adverse events (AEs) and treatment-related AEs (TRAEs) of nivolumab plus relatlimab fixed-dose combination therapy (Nivo+Rela) and nivolumab monotherapy (Nivo) for unresectable or metastatic melanoma.

Neoadjuvant T-VEC + nivolumab combination therapy for resectable early metastatic (stage IIIB/C/D-IV M1a) melanoma with injectable disease: NIVEC trial.

9546 Background: Neoadjuvant systemic treatment with checkpoint inhibitors (ICI) has shown high response rates in patients with resectable metastasized melanoma. In patients with unresectable stage IIIB-IVA melanoma, intralesional treatment with talimogene laherparepvec (T-VEC) has also shown high and durable response rates. In this trial we investigated the safety and efficacy of neoadjuvant treatment with a combination of nivolumab and T-VEC in regionally metastasized melanoma. Methods: In this single arm phase II open-label trial (NCT04330430), 24 patients with resectable stage IIIB-IVA melanoma were included. Inclusion criteria were a RECIST 1.1 measurable lesion of ≥10mm and no prior systemic therapy. Treatment consisted of four doses of intralesional T-VEC (dose in ml according to the size of the lesions) and three doses of nivolumab 240 mg flat dose every two weeks, followed by surgery. The primary endpoint was pathological response rate according to the International Neoadjuvant Melanoma Consortium (INMC) criteria, secondary endpoints were delay or failure to perform surgery, event free survival (EFS) from time of randomization and safety. Results: Baseline characteristics are presented in the table. The overall pathological response rate was 74%, with a major pathological response (MPR = pathologic complete response (pCR) + near-pCR (max 10% viable tumor cells) in 15 patients (65%), a partial response in two patients (9%), a non-response in 4 patients (17%) and progression of disease (PD) in two patients (9%). In one patient the response was not evaluable because surgery was delayed due to a vena cava thrombosis. The two patients with PD had evidence of distant metastasis on preoperative imaging and therefore did not proceed to surgery as planned. Grade 2 treatment related adverse events (trAE) occurred in 7 patients (29%) and grade 3 in 2 (8%). There were no grade 4-5 trAEs. The 1-year EFS was 75% (95%CI 0.55-1). Conclusions: Neoadjuvant combination therapy of nivolumab and T-VEC for patients with regionally metastasized melanoma (satellite/in-transit +/- lymph node metastases) has an acceptable toxicity profile and has shown a significant major pathological response rate of 65%. Clinical trial information: NCT04330430 . [Table: see text]

Severe lichenoid eruption due to concomitant medications following nivolumab administration

AbstractRecently, immune checkpoint inhibitors have been administered for several cancers and have shown great efficacy. However, they are associated with various immune‐related adverse events. Here, we report a case with severe lichenoid eruption following nivolumab administration that improved after the withdrawal of concomitant medications and the patient could continue nivolumab therapy. While nivolumab has been reported to cause severe skin reactions, the current case suggests that severe cutaneous manifestations after nivolumab administration could also be caused by the acquisition of immunogenicity of concomitant medications, including the one that was safely administered before nivolumab treatment and discontinuation of them may enable the patient to continue nivolumab therapy.

Comparative cost-effectiveness of nivolumab first-line and second-line therapy for advanced esophageal cancer in Japan.

A model-based cost-effectiveness analysis comparing first-line and second-line nivolumab therapy for advanced esophageal cancer was performed to support public healthcare in Japan. A partitioned survival model was developed to predict costs and outcomes. Survival data were obtained from two phase 3 clinical trials (Attraction-3 and Checkmate-648), and direct medical costs were estimated from the perspective of the Japanese National Health Insurance payer. The time horizon for the model was set to 20years. Health outcomes were calculated and defined as quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were compared to those of control therapy. A sensitivity analysis was performed based on parameter settings and model uncertainties. A willingness-to-pay threshold of 15 million Japanese yen (JPY) was established. Compared to that of each control therapy, the ICER for nivolumab per QALY gained was 15,712,265 JPY (143,099 USD) for first-line combination therapy with chemotherapy in the overall population, 10,657,085 JPY (97,059 USD) in the population with ≥ 1% Programmed Death-Ligand 1 (PD-L1) expression, and 41,184,322 JPY (375,085 USD) for second-line nivolumab monotherapy. A probabilistic sensitivity analysis estimated that nivolumab was cost-effective as a first-line therapy for the overall population (61.5%) and for the population with ≥ 1% PD-L1 expression (76.5%), but not as second-line monotherapy (32.3%). Nivolumab is recommended as a first-line therapy in combination with chemotherapy owing to its cost-effectiveness, but not as a second-line monotherapy. Patient selection based on PD-L1 expression may help to improve the cost-effectiveness of using nivolumab as a first-line treatment.

Biomarkers of response to first-line nivolumab therapy in patients with advanced renal cell carcinoma (RCC) enrolled in the HCRN GU16-260 trial.

4549 Background: The HCRN GU16-260 study showed that nivolumab (nivo) monotherapy is active in treatment-naïve patients (pts) with RCC. Although efficacy correlated with tumor cell (TC) PD-L1 expression, more clinically relevant biomarkers are needed. We previously showed that levels of CD8+ tumor-infiltrating lymphocytes (TIL) expressing PD-1 but not TIM-3 and LAG-3 (CD8+ PD1+ TIM3- LAG3-) were associated with response to nivo in previously treated clear cell RCC (ccRCC) pts (Pignon, 2019; Ficial, 2021). Here, we sought to validate these findings in the first-line setting. Methods: Primary tumor tissues from pts with ccRCC (n= 67) and non-ccRCC (n= 13) were analyzed by multiparametric immunofluorescence (IF), and the density of CD8+PD-1+TIM-3-LAG-3- TIL was quantified by image analysis. The correlation of the log-transformed biomarkers with objective response rate (ORR) and progression-free survival (PFS) was assessed in the ccRCC cohort and the combined (ccRCC + non-ccRCC) cohort (n=80) using Cox or logistic regression analysis, or Chi-square/Fisher’s exact test (as appropriate) for statistical inference – alpha level was set at 5% (1-sided). Results: In both the ccRCC and the combined cohort, density of CD8+PD-1+TIM-3-LAG-3- TIL (IF biomarker) measured as continuous variable was associated with ORR (ccRCC: OR = 1.54, p = 0.017; combined: OR = 1.35, p = 0.040) and PFS (ccRCC: HR = 0.79, p = 0.015; combined: HR = 0.85, p = 0.016). At a cutoff optimized for maximum sensitivity for ORR, ccRCC patients with a high (61/67) vs low (6/67) IF biomarker had higher ORR (44.3% vs. 0% p = 0.039) and longer median PFS (10.9 months vs. 4.2 months, p = 0.016). Of note, when combined with the IF biomarker, TC PD-L1 expression (≥1%) further separated the clinical outcomes of ccRCC pts. Conclusions: High levels of CD8+ PD1+ TIM-3-LAG-3- TILs were associated with response to first-line nivo in pts with advanced RCC and the combination with TC PD-L1 status further separated the outcomes of pts with ccRCC, validating our previous findings. Further investigations into the role of myeloid inflammation as determinant of clinical outcome to nivo therapy are ongoing. Clinical trial information: NCT03117309 . [Table: see text]

Modified FOLFOX plus/minus nivolumab and ipilimumab vs FLOT plus nivolumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: The randomized phase 2 IKF-S628 Moonlight trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

4050 Background: FOLFOX plus nivolumab has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas (EGA). The AIO-STO-0417 trial (Moonlight) is a multi-cohort treatment optimization trial that evaluates the combination of FOLFOX alone (Arm B) vs FOLFOX plus nivolumab (nivo) and ipilimumab (ipi) administered in parallel (Arm A/A1) or sequentially (Arm A2) and FLOT plus nivolumab administered in parallel (Arm C) for 1L-treatment of metastatic or advanced inoperable Her-2 negative EGA. The aim is to generate signals whether a. dual checkpoint inhibition or b. a triplet chemotherapy is beneficial in the context of nivolumab therapy for this disease. Methods: Pts were randomized 1:1 to Arm A (mFOLFOX q2w plus nivo 240 mg q2w + ipi 1 mg/kg q6w administered in parallel) or B (mFOLFOX alone). In a subsequent phase pts were randomized 1:2 to Arm A1 (identical to Arm A) or A2 (three cycles of mFOLFOX followed by nivo q2w + ipi q6w, with optional repetition). In a final phase, all pts were allocated to single Arm C (FLOT q2w + nivo q2w). The primary endpoint was progression-free survival (PFS) based on the ITT population for Arm A vs Arm B and PFS rate at 6 months (PFS@6) for Arms A2 and C. Main secondary endpoints were PFS and ORR. Here, we present results for Arms A/A1, A2 and B. Results: A total of 262 pts were enrolled, Arm A (n=60), Arm B (n=60), Arm A1 (n=30), Arm A2 (n=60) and Arm C (n=52, results presented elsewhere). Baseline characteristics were comparable in all arms. Overall PD-L1 expression (CPS ≥1) was low with 41% and balanced between Arms A/A1, A2 and B. Analysis of pooled Arms A/A1 (n=90) showed an increase in toxicity (pts with AEs grade ≥3 88% vs 65% in Arm B and 75% in Arm A2, treatment related SAEs grade ≥3 A/A1 41% vs B 18% vs A2 17%) but not in activity. Arm A/A1 compared with Arm A2 was more effective in terms of PFS@6 (48% vs 30%), median PFS 5.8 vs 4.0 months and objective response rate (ORR) 46% vs 30%. Conclusions: Albeit the small number of pts in each cohort we conclude that in the first-line setting of metastatic EGA. a) Chemo plus dual checkpoint inhibition administered in parallel is associated with an increase in toxicity but not activity. b) Although associated with lower toxicity the use of sequential chemo followed by IO monotherapy is insufficient. The relatively low numbers of patients with PD-L1 CPS ≥1 may have impacted these results. Clinical trial information: NCT03647969 .

Real-world effectiveness of nivolumab and subsequent therapy in Japanese patients with metastatic renal cell carcinoma (POST-NIVO study): 36-month follow-up results of a clinical chart review.

To examine the long-term effectiveness of nivolumab monotherapy and following subsequent therapies for metastatic renal cell carcinoma (mRCC) in Japanese real-world settings. This was a multicenter, retrospective, observational study, with a 36-month follow-up, and conducted in Japanese patients with mRCC who initiated nivolumab monotherapy between 1 Feb 2017 and 31 Oct 2017. Endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Of the 208 patients, 36.5% received nivolumab monotherapy as second-line, 30.8% as third-line, and 31.7% as fourth- or later-line therapy. By 36 months, 12.0% of patients continued nivolumab monotherapy; 88.0% discontinued, mainly because of disease progression (66.7%). The median (m) OS was not reached irrespective of treatment line, with a 36-month OS rate of 54.3% (second-line, 57.4%; third-line, 52.6%; fourth- or later-line, 52.9%). The ORR was 24.2% and five patients achieved complete response. The OS from first-line therapy was 8.9 years. In the 95 patients receiving therapy after nivolumab, 87.4% received vascular endothelial growth factor receptor-tyrosine kinase inhibitors, with mOS and mPFS of 27.4 and 8.1 months, respectively. Irrespective of treatment line, the mOS was not reached in patients with International Metastatic RCC Database Consortium (IMDC) favorable or intermediate risk at mRCC diagnosis. This 36-month real-world follow-up analysis showed a survival benefit of nivolumab monotherapy for patients with mRCC. The long-term effectiveness of sequential therapy from first-line therapy to therapy after nivolumab was also demonstrated. Additionally, nivolumab monotherapy was beneficial for patients with favorable IMDC risk at the time of mRCC diagnosis.

Neoadjuvant Immune Checkpoint Inhibition in Metastatic Conjunctival Melanoma.

The development of immune checkpoint inhibitors (ICI) has transformed the treatment of advanced-stage cutaneous melanoma; however, most trials did not include patients with conjunctival melanoma. Herein the authors describe a patient with recurrent conjunctival melanoma who developed locally advanced, b-raf and v-raf murine sarcoma viral oncogene homolog B1-negative melanoma in her nasal cavity and extensive, metabolically active, bilateral lymphadenopathy in her thorax. Her nasal mass measured 4.3 × 1.7 cm and was determined to be unresectable. She was treated with 4 cycles of combination ipilimumab and nivolumab therapy followed by maintenance nivolumab. She experienced a dramatic treatment response with a reduction in the size of her nasal mass to 3.0 × 1.1 cm and a complete resolution of her adenopathy. She then underwent complete surgical resection of her residual mass (approximately 75% of her original tumor size) and remains melanoma-free at 1 year of follow-up. Given the underlying genetic similarities of conjunctival melanoma to cutaneous melanoma, providers should consider the use of neoadjuvant immune checkpoint inhibitors for patients with locally advanced or limited metastatic disease.

The effect of concomitant proton pump inhibitor use on survival outcomes of Nivolumab-treated renal cell carcinoma patients: a multicenter study.

We aimed to evaluate the effect of concomitant proton pump inhibitors (PPI) use with nivolumab on survival outcomes in metastatic renal cell carcinoma (mRCC) in second-line setting. The study was designed as a multicenter and retrospective involving patients with metastatic renal cell carcinoma receiving second-line nivolumab therapy. One hundred and nine patients with mRCC were divided into two groups based on whether they use PPI concomitantly with nivolumab: concomitant PPI users and non-users. Overall survival (OS) and progression-free survival (PFS) were compared between the groups with and without concurrent PPIs. Of 109 patients in our study, 59 were not using PPI concomitantly with nivolumab and 50 were using PPI concomitantly. The median PFS was 6.37 (5.2-7.5) months in the concomitant PPI group and 9.7 (4.5-15) months in the non-users (p = 0.03). The median OS was 14.6 (7.1-22.1) months in patients on PPI concurrently with nivolumab and 29.9 (17.1-42.7) months in the non-users (p = 0.01). Accordingly, PPI use for PFS (Non-use vs. Use = HR: 0.44, 95%Cl 0.28-0.96, p = 0.014) and PPI use for OS (Non-use vs. Use = HR: 0.68, 95%Cl 0.22-0.88, p = 0.01) were found to be as independent risk factors. Concomitant use of PPIs is associated with worse survival outcomes in patients with mRCC treated with nivolumab. Clinicians should carefully consider the concomitant use of PPIs in such patients.

Potential clinical implications of CD4+CD26high T cells for nivolumab treated melanoma patients

BackgroundNivolumab is an anti-PD1 antibody that has dramatically improved metastatic melanoma patients’ outcomes. Nevertheless, many patients are resistant to PD-1 inhibition, occasionally experiencing severe off-target immune toxicity. In addition, no robust and reproducible biomarkers have yet been validated to identify the correct selection of patients who will benefit from anti-PD-1 treatment avoiding unwanted side effects. However, the strength of CD26 expression on CD4+ T lymphocytes permits the characterization of three subtypes with variable degrees of responsiveness to tumors, suggesting that the presence of CD26-expressing T cells in patients might be a marker of responsiveness to PD-1-based therapies.MethodsThe frequency distribution of peripheral blood CD26-expressing cells was investigated employing multi-parametric flow cytometry in 69 metastatic melanoma patients along with clinical characteristics and blood count parameters at baseline (W0) and compared to 20 age- and sex-matched healthy controls. Percentages of baseline CD4+CD26high T cells were correlated with the outcome after nivolumab treatment. In addition, the frequency of CD4+CD26high T cells at W0 was compared with those obtained after 12 weeks (W1) of therapy in a sub-cohort of 33 patients.ResultsCirculating CD4+CD26high T cells were significantly reduced in melanoma patients compared to healthy subjects (p = 0.001). In addition, a significant association was observed between a low baseline percentage of CD4+CD26high T cells (< 7.3%) and clinical outcomes, measured as overall survival (p = 0.010) and progression-free survival (p = 0.014). Moreover, patients with clinical benefit from nivolumab therapy had significantly higher frequencies of circulating CD4+CD26high T cells than patients with non-clinical benefit (p = 0.004) at 12 months. Also, a higher pre-treatment proportion of circulating CD4+CD26high T cells was correlated with Disease Control Rate (p = 0.014) and best Overall Response Rate (p = 0.009) at 12 months. Interestingly, after 12 weeks (W1) of nivolumab treatment, percentages of CD4+CD26high T cells were significantly higher in comparison with the frequencies measured at W0 (p < 0.0001), aligning the cell counts with the ranges seen in the blood of healthy subjects.ConclusionsOur study firstly demonstrates that peripheral blood circulating CD4+CD26high T lymphocytes represent potential biomarkers whose perturbations are associated with reduced survival and worse clinical outcomes in melanoma patients.

Hemoglobin and neutrophil levels stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk predict the effectiveness of ipilimumab plus nivolumab in patients with advanced metastatic renal cell carcinoma.

To identify biomarkers associated with the effectiveness of ipilimumab plus nivolumab against advanced metastatic renal cell carcinoma. We retrospectively analyzed the data of 75 patients treated with ipilimumab plus nivolumab at seven hospitals between August 2018 and April 2021. Prognostic biomarkers were assessed prior to initiating treatment with ipilimumab plus nivolumab. Median overall survival and progression-free survival were examined using the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify predictors of disease progression. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors most important for predicting disease progression were determined using classification and regression tree analysis. Median overall survival and progression-free survival were longer in the intermediate IMDC risk group than in the poor IMDC risk group (overall: not reached vs. 18.3 months; progression-free: not reached vs. 13.5 months). The multivariate analysis identified poor IMDC risk as a risk factor for disease progression (hazard ratio 2.61, 95% confidence interval: 1.05-6.51). Based on the results of the classification and regression tree analysis, the cohort was divided into non-anemia, anemia + neutro-Low, and anemia + neutro-High groups. Median overall survival and progression-free survival were longer in the non-anemia and anemia + neutro-Low groups than in the anemia + neutro-High group (overall: not reached vs. 29.3 months vs. 4.3 months: progression-free: not reached vs. 29.0 months vs. 3.9 months). Hemoglobin and neutrophil levels may represent crucial biomarkers for predicting the effectiveness of ipilimumab plus nivolumab therapy in patients with renal cell carcinoma.

The safety profile of nivolumab plus ipilimumab combination therapy in Japanese patients with renal cell carcinoma: results from post-marketing surveillance.

Nivolumab and ipilimumab combination therapy is approved in Japan for unresectable or metastatic renal cell carcinoma. Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. The observation period was 13weeks. Safety data included treatment-related adverse events with a particular emphasis on the gastrointestinal-related (colitis, enteritis, diarrhoea and gastrointestinal perforation) and liver-related (hepatic failure, hepatic function abnormal, hepatitis and cholangitis sclerosing) treatment-related adverse events that are listed in the risk management plan for nivolumab and ipilimumab combination therapy. Of the 203 patients registered, safety data were available for 159 (119 males/40 females) with a median age of 67years (range 22-88). Seventy-one patients received nivolumab and ipilimumab combination therapy four times per usual clinical therapy, and 33 continued nivolumab monotherapy thereafter. Any-grade treatment-related adverse events were reported in 102 (64.2%) patients and grade≥3 in 63 (39.6%). Hepatic function abnormalities (13.2%), rash (8.8%) and interstitial lung disease (7.5%) were the most common treatment-related adverse events. Five patients died following treatment-related adverse events. Gastrointestinal-related and liver-related treatment-related adverse events occurred in 10 (6.3%; four with grade≥3 treatment-related adverse events) and 27 (17.0%; 19 with grade≥3 treatment-related adverse events) patients, respectively. This post-marketing surveillance in patients with unresectable or metastatic renal cell carcinoma revealed a safety profile for nivolumab and ipilimumab combination therapy consistent with CheckMate 214. Furthermore, no new safety concerns were identified including gastrointestinal-related and liver-related treatment-related adverse events.

The impact of nutritional status in nivolumab-treated patients with advanced esophageal cancer.

Although phase III trials have reported improved overall survival in patients with advanced esophageal squamous cell carcinoma following treatment with nivolumab, as compared with chemotherapy (paclitaxel or docetaxel), the treatment was effective only in a limited number of patients. Therefore, the aim of this study is to determine whether there is a correlation between nutritional status (Glasgow prognostic score, prognostic nutritional index, and neutrophil-to-lymphocyte ratio) and prognosis of advanced esophageal cancer in patients treated with taxane or nivolumab therapy. The medical records of 35 patients who received taxane monotherapy (paclitaxel or docetaxel), for advanced esophageal cancer between October 2016 and November 2018 (taxane cohort) were reviewed. The clinical data of 37 patients who received nivolumab therapy between March 2020 and September 2021 (nivolumab cohort) were collected. The median overall survival was 9.1 months for the taxane cohort and 12.5 months for the nivolumab cohort. In the nivolumab cohort, patients with good nutritional status had significantly better median overall survival than those with poor nutritional status (18.1 vs. 7.6 months, respectively, p = 0.009, classified by prognostic nutritional index, 15.5 vs. 4.3 months, respectively, p = 0.012, classified by Glasgow prognostic score), whereas the prognosis of the patients treated with taxane therapy was less affected by the nutritional status. This suggests that the pretreatment nutritional status of patients with advanced esophageal cancer is a key factor for successful outcomes, especially for treatment with nivolumab.

Impact of cytoreductive nephrectomy prior to combination therapy of ipilimumab plus nivolumab in metastatic renal cell carcinoma.

The efficacy of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs) has been suggested in the real-world setting. We retrospectively examined the efficacy of CN prior to nivolumab plus ipilimumab systemic therapy for synchronous mRCC. Synchronous mRCC patients who received nivolumab plus ipilimumab at Kobe University Hospital or five affiliated hospitals between October 2018 and December 2021 were included in this study. We compared the outcomes of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) between patients with CN prior to systemic therapy and without CN. In addition, patients were 1:1 matched by propensity scores accounting for factors associated with treatment assignment. Twenty-one patients received CN prior to nivolumab plus ipilimumab (Prior CN) and 33 received nivolumab plus ipilimumab alone (Without CN). PFS of the Prior CN group was 10.8 months (95%CI 5.5-NR) and 3.4 months (95%CI 2.0-5.9) for the Without CN group (p = 0.0158). OS of Prior CN was 38.4 months (95%CI NR-NR) and 12.6 months (95%CI 4.2-30.8) for Without CN (p = 0.0024). Univariate and multivariate analyses identified prior CN as a significant prognostic indicator for PFS and OS. Moreover, propensity score matching analysis showed significant improvements in PFS and OS in Prior CN. Patients who underwent CN prior to nivolumab plus ipilimumab systemic therapy for synchronous mRCC had a better prognosis than patients treated with nivolumab plus ipilimumab alone. These results suggest the efficacy of prior CN for synchronous mRCC with ICI combination therapy.

Nivolumab-Induced Harada-like Uveitis with Bacillary Detachment Mimicking Choroidal Metastasis.

To describe a patient with metastatic clear cell renal cell carcinoma in remission on maintenance nivolumab therapy who developed late-onset ocular toxicity manifesting as creamy chorioretinal lesions with exudative retinal detachment concerning for choroidal metastasis. Case report. Main outcome measures include ophthalmoscopic examination, fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, and B-scan ultrasonography. A 49-year-old woman with past medical history of metastatic clear cell renal cell carcinoma in remission for two years after immunotherapy with four cycles of ipilimumab and nivolumab followed by maintenance nivolumab infusions developed lesions concerning for choroidal metastases in her right eye. Optical coherence tomography of the lesions revealed a bacillary layer detachment containing possible fibrinous exudate organized into layers and underlying choroidal thickening with chorioretinal folds. Later, choroidal thickening and chorioretinal folds also occurred in the left eye. Given that pan-imaging detected no metastasis, and the posterior segment abnormalities resolved following cessation of nivolumab and treatment with systemic corticosteroids, the patient was diagnosed with nivolumab-induced Vogt-Koyanagi-Harada-like uveitis (nVKH). and Importance: This case expands on the clinical spectrum of nVKH, a condition that can also present with bacillary layer detachment mimicking an early choroidal metastasis, manifest asymmetrically in each eye, and develop after longstanding treatment.