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An Illustrative Case of Combination Cabozantinib/Nivolumab for Progressive Metastatic Renal Cell Carcinoma (mRCC).

ABSTRACT: We report a case using combination cabozantinib plus nivolumab to salvage disease control in a patient with refractory metastatic renal cell carcinoma. The patient had previously experienced disease progression from high-dose interleukin-2, sunitinib, pazopanib, cabozantinib, and nivolumab, all given sequentially. Combination cabozantinib plus nivolumab resulted in 22 months of disease control. Vascular endothelial growth factor inhibitors including cabozantinib have immunomodulatory effects when combined with immune checkpoint inhibitors, with multiple ongoing phase III trials exploring the cabozantinib plus nivolumab combination in the first-line setting. To our knowledge, this is the first reported case of progression on nivolumab and cabozantinib when given as sequential monotherapies but stable disease on combination cabozantinib plus nivolumab.

SUBMITTER: Kao C

PROVIDER: S-EPMC7930408 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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An Illustrative Case of Combination Cabozantinib/Nivolumab for Progressive Metastatic Renal Cell Carcinoma (mRCC).

Kao Chester C George Daniel J DJ Zhang Tian T

The oncologist 20201214 3

We report a case using combination cabozantinib plus nivolumab to salvage disease control in a patient with refractory metastatic renal cell carcinoma. The patient had previously experienced disease progression from high-dose interleukin-2, sunitinib, pazopanib, cabozantinib, and nivolumab, all given sequentially. Combination cabozantinib plus nivolumab resulted in 22 months of disease control. Vascular endothelial growth factor inhibitors including cabozantinib have immunomodulatory effects whe ...[more]

PMID: 33251710

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Project description:Renal-cell carcinoma (RCC) affects over 330,000 new patients every year, of whom 1/3 present with metastatic RCC (mRCC) at diagnosis. Most mRCC patients treated with a first-line agent relapse within 1 year and need second-line therapy. The present study aims to compare overall survival (OS) between nivolumab and cabozantinib from two recent pivotal studies comparing, respectively, each one of the two emerging treatments against everolimus in patients who relapse following first-line treatment. Comparison is traditionally carried out using the Bucher method, which assumes proportional hazard. Since OS curves intersected in one of the pivotal studies, models not assuming proportional hazards were also considered to refine the comparison. Four Bayesian parametric survival network meta-analysis models were implemented on overall survival (OS) data digitized from the Kaplan-Meier curves reported in the studies. Three models allowing hazard ratios (HR) to vary over time were assessed against a fixed-HR model. The Bucher method favored cabozantinib, with a fixed HR for OS vs. nivolumab of 1.09 (95% confidence interval: [0.77, 1.54]). However, all models with time-varying HR showed better fits than the fixed-HR model. The log-logistic model fitted the data best, exhibiting a HR for OS initially favoring cabozantinib, the trend inverting to favor nivolumab after month 5 (95% credible interval <1 from 10 months). The initial probability of cabozantinib conferring superior OS was 54%, falling to 41.5% by month 24. Numerical differences in study-adjusted OS estimates between the two treatments remained small. This study evidences that HR for OS of nivolumab vs. cabozantinib varies over time, favoring cabozantinib in the first months of treatment but nivolumab afterwards, a possible indication that patients with poor prognosis benefit more from cabozantinib in terms of survival, nivolumab benefiting patients with better prognosis. More evidence, including real-world observational data, is needed to compare effectiveness between cabozantinib and nivolumab.

Project description:BackgroundThe efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.MethodsIn this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.ResultsOverall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.ConclusionsNivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).

Project description:BackgroundNivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted.MethodsPatients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered "feasible" if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval.ResultsOf the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16-53) off therapy. No patients developed RECIST PD while off therapy.ConclusionsThis prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC.Trial registrationNCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331 ).

Project description:BackgroundMetastatic neuroendocrine carcinoma has an extremely poor prognosis, and no effective second-line treatment is available. Herein, we describe a case of multiple metastases after primary resection of esophageal neuroendocrine carcinoma successfully treated with nivolumab plus radiotherapy in a short time.Case presentationA man in his 70s presented to our hospital after an abnormality was detected on an upper gastrointestinal series. Upper gastrointestinal endoscopy revealed a type 2 tumor spanning the endothelial cell junction to the abdominal esophagus. Histopathological examination of the biopsy confirmed a diagnosis of esophageal neuroendocrine carcinoma. The patient had no distant metastases. Thoracoscopic esophagectomy with three-field lymph node dissection was performed. Histopathological examination confirmed a diagnosis of esophageal neuroendocrine carcinoma with features of adenoid cystic-like carcinoma and squamoid pattern (pT2 [MP], INF a, ly1, v1 [EVG], pIM0, pDM0, pRM0, pN1 [1/28], M0; Stage II), which was positive for synaptophysin. The postoperative course was good, with no complications. The patient was treated with 100 mg of irinotecan and 100 mg of cisplatin, administered every 4 weeks, as postoperative adjuvant chemotherapy. Grade 3 loss of appetite was observed, and adjuvant chemotherapy was discontinued after four cycles of first-line treatment. A positron emission tomography-computed tomography scan 3 years after surgery showed abnormal uptake in the subaortic, left hilar, and left axillary lymph nodes, and in a mass in the right lung apex. The patient was diagnosed with metastatic esophageal neuroendocrine carcinoma postoperatively. First-line treatment could not be repeated due to toxicity from the initial treatment. Nivolumab (240 mg every 2 weeks) was administered as second-line treatment, and radiotherapy was started (56 Gy delivered in 28 fractions to the local [subaortic and hilar] lymph nodes). After 10 cycles of nivolumab in combination with radiotherapy (56 Gy), a positron emission tomography-computed tomography scan showed disappearance of all lesions. A complete response was achieved. Maintenance therapy (240 mg of nivolumab) was continued. No recurrence has been observed for 42 months.ConclusionsWe experienced a case in which nivolumab in combination with radiotherapy was effective for metastatic esophageal neuroendocrine carcinoma after primary resection.

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An Illustrative Case of Combination Cabozantinib/Nivolumab for Progressive Metastatic Renal Cell Carcinoma (mRCC).

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An Illustrative Case of Combination Cabozantinib/Nivolumab for Progressive Metastatic Renal Cell Carcinoma (mRCC).

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