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Radiation and Checkpoint Inhibitor Immunotherapy Lead to Long Term Disease Control in a Metastatic RCC patient With Brain Metastases.

ABSTRACT: Renal cell carcinoma (RCC) comprises 4.2% of all new cancer cases in the United States and 30% of cases are metastatic (mRCC) at diagnosis. Brain metastatic RCC historically has poor prognosis, but the development of immune checkpoint inhibitors has revolutionized their care and may be successfully combined with SBRT to improve prognosis. Here, we present a case of a patient with mRCC who had brain metastases treated with concurrent immune checkpoint inhibitors and SBRT. He continues to survive with good functional status years following his initial diagnosis. We discuss the relevant history regarding treatment approach in patients with brain metastatic RCC, ongoing trials focusing on the combination of immunotherapy and radiation, and the potential and promise of the abscopal effect.

SUBMITTER: Levitin M

PROVIDER: S-EPMC7539115 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Radiation and Checkpoint Inhibitor Immunotherapy Lead to Long Term Disease Control in a Metastatic RCC patient With Brain Metastases.

Levitin Maria M Ofori Joel J Shin Woo Jae WJ Huang Jiayi J Daly Mackenzie M Cao Dengfeng D Pachynski Russell R

Frontiers in oncology 20200923

Renal cell carcinoma (RCC) comprises 4.2% of all new cancer cases in the United States and 30% of cases are metastatic (mRCC) at diagnosis. Brain metastatic RCC historically has poor prognosis, but the development of immune checkpoint inhibitors has revolutionized their care and may be successfully combined with SBRT to improve prognosis. Here, we present a case of a patient with mRCC who had brain metastases treated with concurrent immune checkpoint inhibitors and SBRT. He continues to survive ...[more]

PMID: 33072598

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Project description:Abstract Background Background: It is estimated that a significant number of patients presenting with metastatic RCC are either ineligible, not recommended for, or refuse surgery. There remains no well-established method for addressing the primary tumor in such patients. Stereotactic ablative radiotherapy (SABR) is a highly effective modality for the treatment of the primary tumor in RCC. Our study seeks to evaluate SABR as an alternative approach to treat the primary tumor in patients with metastatic RCC receiving immunotherapy, who are not recommended for surgery, or who decline surgery. The primary objective of the study is to determine whether the addition of SABR to the primary tumor in combination with immunotherapy improves outcomes compared to immunotherapy alone in patients with metastatic, unresected, renal cell carcinoma (RCC). The primary endpoint is nephrectomy and radiographic progression-free survival (nrPFS) with progression determined as per iRECIST criteria. Patients are eligible if they are not recommended for upfront surgery, have a primary tumor treatable with SABR, and are candidates for immunotherapy. Immunotherapy is physician’s choice and will include either two different immunotherapy regimens (IO-IO) or immunotherapy in combination with a VEGF inhibitor (IO-VEGF). Methods 240 patients will be randomized in a 2:1 ratio favoring SABR plus immunotherapy (n=160) as compared to standard of care immunotherapy alone (n=80). The sample size will provide 90% power at a one-sided alpha level of 0.05 to detect a hazard ratio for nrPFS of 0.61, i.e., a 40% reduction in the rate of events. One-year PFS in the nivolumab plus ipilmumab arm was 50% (n=550, intermediate/poor risk population). Checkmate 9ER (Choueiri 2021) showed a one-year PFS rate in patients receiving nivolumab plus Cabozantinib (n=323) of 45-58% (intermediate/poor risk population). We have therefore estimated a one-year nrPFS rate of 50% in the control (immunotherapy alone) arm for SAMURAI. We expect nephrectomies to contribute only a small fraction to the total nrPRS events. To detect a hazard ratio of 0.62, which corresponds under exponential distribution assumptions to an absolute 15% improvement in one-year nrPFS from 50% in the control group to 65% in the experimental arm (SABR plus immunotherapy), a total sample size of 240 patients will be enrolled. This design will provide 90% power, based on a one-sided logrank test at the 0.05 alpha level, with three years of accrual and two further years of follow-up. The expected number of nrPFS events is E=175. The calculations allow for a 10% non-eligible/early dropout rate. The trial is currently open and accruing through the NRG oncology cooperative group (NCT05327686).

Project description:BACKGROUND:There is an unmet need to determine factors predictive of clinical benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC). We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as predictors of response rate, progression free survival (PFS) and overall survival (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:Regulatory approval was obtained. A single center retrospective chart review of mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics, smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria), NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF therapy ?6 months or <6. RESULTS:42 patients were evaluated with median age of 61 years (range, 24-85). Pretherapy NLR < 3 and ?3 was seen in 19 (45%) and 23 (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF inhibitors for a duration of ?6 months and <6 months, respectively. 12 (29%), 22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease based on Heng criteria, respectively. Multivariable analysis showed pretherapy NLR ?3 was predictive of shorter PFS and OS when treated with ICI with median 3.08 months and 13.50 months, respectively, versus 15.57 months and not reached for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF therapy <6 months was predictive of increased likelihood of benefit from ICI therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months, respectively, in cases with prior anti-VEGF therapy for ?6 months and <6 months. CONCLUSION:Pretherapy NLR <3 and duration of prior anti-VEGF therapy of <6 months, are independent statistically significant predictors of longer PFS and OS with ICI therapy in mRCC. Validation is required in a larger sample size with multi-institutional collaboration.

Project description:Background Neoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in patients with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting. We hypothesize that neoadjuvant CPI is a safe and feasible approach for patients with resectable MM. Method Under an institutionally approved protocol, we identified adult MM patients with resectable disease who received neoadjuvant anti-PD1 +/- anti-CTLA4 between 2015 to 2019 at our institution. Clinical information include age, gender, presence of nodal involvement or satellitosis, functional status, pre-treatment LDH, tumor mutation status, and treatment data was collected. Outcomes include event free survival (EFS), overall survival (OS), objective response rate (ORR), pathologic response rate (PRR), and grade ≥3 toxicities. Results We identified 36 patients. Median age was 62; 58% were female. Seventy-eight percent of patients received anti-PD1 + anti-CTLA4. Node positive disease or satellite lesions was present at the time of treatment initiation in 47% of patients. Primary sites of disease were anorectal (53%), urogenital (25%), head and neck (17%), and esophageal (6%). A minority of patients did not undergo surgery due to complete response (n=3, 8%) and disease progression (n=6, 17%), respectively. With a median follow up of 37.9 months, the median EFS was 9.2 months with 3-year EFS rate of 29%. Median OS had not been reached and 3-year OS rate was 55%. ORR was 47% and PRR was 35%. EFS was significantly higher for patients with objective response and for patients with pathologic response. OS was significantly higher for patients with pathologic response. Grade 3 toxicities were reported in 39% of patients. Conclusion Neoadjuvant CPI for resectable MM is a feasible approach with signs of efficacy and an acceptable safety profile. As there is currently no standard approach for resectable MM, this study supports further investigations using neoadjuvant therapy for these patients.

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Radiation and Checkpoint Inhibitor Immunotherapy Lead to Long Term Disease Control in a Metastatic RCC patient With Brain Metastases.

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Radiation and Checkpoint Inhibitor Immunotherapy Lead to Long Term Disease Control in a Metastatic RCC patient With Brain Metastases.

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