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Background: Nivolumab (NIVO), a programmed death-1 immune checkpoint inhibitor, has demonstrated clinical efficacy across patients with different tumor types, including clear cell renal cell carcinoma (ccRCC), when administered via IV infusion. As an alternative to IV infusion, subcutaneous (SC) administration alleviates the need for IV ports, thereby lowering the risk of associated complications such as infections and phlebitis. SC formulation also reduces the time for dose preparation and administration, which may decrease overall treatment burden and reduce patient time in the clinic, benefiting patients and healthcare providers and improving overall healthcare resource utilization. SC-administered NIVO consists of NIVO co-formulated with the recombinant human hyaluronidase PH20 enzyme (NIVO + rHuPH20), which aims to increase the dispersion and absorption of NIVO within the SC space. SC NIVO + rHuPH20 was shown to be safe and well tolerated in a phase 1/2 study, warranting further investigation (Lonardi S et al. J Clin Oncol 2021;39(suppl 15):2575). Methods: CheckMate 67T is a multicenter, randomized, open-label, phase 3 study that will evaluate the noninferiority of SC NIVO + rHuPH20 versus IV NIVO in patients with advanced or metastatic ccRCC who have progressed after receiving ≤ 2 prior systemic treatment regimens. Key inclusion criteria are age ≥ 18 years, histologically confirmed advanced or metastatic ccRCC, measurable disease by RECIST v1.1 within 28 days prior to randomization, and a Karnofsky performance status ≥ 70. Key exclusion criteria are untreated symptomatic metastases to the central nervous system, other malignancy, autoimmune diseases, HIV-positive status with AIDS-defining infection within past year or current CD4 count < 350 cells/μL, other serious or uncontrolled disorders including severe, acute SARS-CoV-2 infection, and prior treatment with immune checkpoint inhibitors, other T-cell-targeting antibody drugs, or live attenuated vaccines within 30 days of first study treatment. At least 454 eligible patients will be randomized to receive SC NIVO + rHuPH20 or IV NIVO. The primary objectives are to demonstrate pharmacokinetic (PK) noninferiority of SC NIVO versus IV NIVO, as measured by time-averaged serum concentration over the first 28 days (Cavgd28) and trough serum concentration at steady state (Cminss) (co-primary endpoints). Secondary endpoints include objective response rate by blinded independent central review, additional PK parameters, safety, efficacy, and immunogenicity of SC NIVO and IV NIVO. This study is currently enrolling patients globally.
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AIM: Endoscopic Ultrasound (EUS) is well-established mode of intervention for tissue acquisition in solid organs with rapid on-site evaluation (ROSE). In the Covid-19 era implementation of infection control mechanisms has led modified hybrid technique to get high diagnostic yield for tissue sampling. Combination of Covid-19 SOPs and tissue acquisition method outline this hybrid technique to get high diagnostic Yield.We share our initial experience of EUS cases performed with this approach without ROSE. METHODS: All 84 cases who underwent EUS guided biopsy from June 2020 till December 2021 were included. The Procedure was done in a negative pressure room with all SOPs as per institutional guidelines for patient and staff safety with a minimum number of persons during procedure. RESULTS: Among these cases, 55 were male, mean age 56 years (range 22-90), Mean duration of procedure 25 min mean (10-90 min). 63 came for organ targeted for malignant pathology include pancreas 35, liver 02, lymph nodes 17, subepithelial lesions 06, mediastinal lesions 08, common-bile duct/gall bladder 04. 17 cases had a multi-targeted biopsy for the additional staging of disease. The number of 'passes' with the needle was average 02 with single pass 17, two pass 39, three passes 11, multitarget single pass in 17. Needle size (Franseen design) used for procedures was 22G in 78 cases and 25G in 6. Common tissue diagnoses include pancreatic adenocarcinoma 26, neuroendocrine tumours 04, tuberculosis 05, gastrointestinal stromal tumours 02, leiomyoma 03, lymphoma 03, metastatic renal cell carcinoma 04, squamous cell carcinoma 04, cholangiocarcinoma/ gall bladder adenocarcinoma 07, Sarcoma 02 and solid pseudopapillary epithelial neoplasm of pancreas (SPEN) 01. There were no immediate or early complications in all cases. CONCLUSIONS: Hybrid EUS in Covid 19 Era has emerged as a useful/cost-effective and safe approach to get tissue yield without the need for ROSE.
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Introduction: Nivolumab is a PD-1 checkpoint inhibitor that restores the pre-existing antitumor immune response by selectively blocking the interaction between PD-1 receptors on T-cells and PD-1 ligands, PD-L1 and PD-L2, on tumor cells and antigen presenting cells. Nivolumab prolongs survival in patients with metastatic kidney cancer with a good safety profile as demonstrated in the CheckMate 025 clinical trial. Material And Methods: This retrospective data involved prospectively monitored patients (named patient programm) treated with second-line nivolumab for mRCC at the University Hospital Centre Zagreb from 2016 to 2018 and the treatment continued to be funded by the Croatian Health Insurance. Patients with metastatic kidney cancer (mRCC) received tyrosine kinase inhibitors (TKI), (29/30), one patient received mTOR inhibitor as first line therapy, and subsequently they initially received nivolumab 3 mg kg NPP every 2 weeks. Later we applied a monthly dose 480 mg. Nivolumab treatment was continued in patients who did not have disease progression or grade 3 and 4 toxicity. Patients were monitored every three momths with CT of the chest, abdomen and pelvis and laboratory tests (hemathology, biochemistry, T4, TSH). We also respected patients' preference in regard to cycle dynamic by stopping nivolumab therapy or introducing SBRT during nivolumab therapy. Results: We treated a total of 30 patients (22 men and 8 women) with mRCC, who initially received TKI or mTOR therapy with median age 60.2 ± 9.79 years at diagnosis of kidney cancer. Most patients belonged to intermediate-risk groups. Majority of patients (23/30) were treated with sunitinib as the first line treatment after nephrectomy. Six patients had CR (20%) but two of them died in 2021, one of COVID- 19 and one of haed and neck cancer. Currently, 6 (20%) are alive, ECOG=0, 4 (13.3%) have CR without therapy, expressed in months-23, 33, 35 and 53 (treatment-free survival). Median OS first line with TKI therapy was 34 months while median OS second line with nivolumab was 17 months. Patients with sarcomatoid component in pathohistology report have longer survival. Patients with bone metastases have shorter survival to patients with other metastases. Conclusion: Nivolumab demonstrated clinical efficacy in the CheckMate 025 clinical trial and in clinical practice as second line treatment after patients had previously received TKI. Our results show that six years after first cycle of nivolumab as second line therapy 6 out of 30 patient (20%) are alive, ECOG=0. Further research should show which sequence therapy would be the best for each patient. Research about potential immunotherapy biomarkers which would indicate who responds to the therapy and who does not is ongoing.
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INTRODUCTION AND OBJECTIVE: Nephrectomy and venous thrombectomy is a challenging procedure with potential morbidity and mortality. Despite the increasing use of immune checkpoint inhibitors (ICI) in the management of advanced renal cell carcinoma (RCC), data regarding the outcomes of venous thrombectomy following ICI is limited. We evaluated the feasibility and perioperative outcomes of nephrectomy and venous thrombectomy following ICIs. METHODS: Patients with locally advanced or metastatic RCC with venous thrombus undergoing nephrectomy following ICI therapy were evaluated in four high-volume US academic centers between June 2017 and June 2021. Clinical data, perioperative outcomes, and 90-day complications were recorded. RESULTS: Out of 79 patients who received post-ICI nephrectomy, 27 had venous thrombus. Median (IQR) age was 64 (55-71) years. ICI regimens were Nivolumab ± Ipilimumab (n=19), and Pembrolizumab± Axitinib (n=8). Nephrectomy was indicated following either a good clinical response to ICI (n=24) or as a palliative surgery (n=3). Venous thrombi levels are shown in Table-1. Among all patients, 26 (96%) underwent radical and 1 (4%) partial nephrectomy;12 (44.5%) open, 12 (44.5%) robotic and 3 (11%) laparoscopic. One robotic case converted electively to open. Vascular procedures included renal vein thrombectomy (n=6), IVC thrombectomy and primary repair (n=19), IVC patch repair (n=1), and suprarenal cavectomy (n=1). No intraoperative complications were reported. Nine patients showed no viable tumor in the thrombus, of whom 2 had complete response in the primary tumor as well (ypT0N0). 90-day complication rate was 33% (n=9), with 8 patients (30%) requiring readmission (Table-2). One death was reported within 90 days due to COVID-19 infection. CONCLUSIONS: Nephrectomy and venous thrombectomy following systemic immune checkpoint inhibitor therapy is feasible. One third of patients show no viable tumor in the thrombus. Larger studies are needed to predict pathological response.
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Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved over the last few years with several systemic anti-cancer therapies (SACT) licensed across different lines of treatment. A previous real world study in the UK had demonstrated a significant attrition rate between each line of therapy suggesting less than half of patients who received first line SACT then received second line therapy and less than a fifth of first line SACT patients reach third line. Methods: We conducted a retrospective analysis of all patients treated between January 2018 and end of June 2021 to see if advancement in treatment options had impacted on the drop-off rates. Data was collected from 5 UK sites. Patients were identified from electronic SACT database. All reimbursed treatment options including the COVID interim treatment guidelines options were included. Patients who received SACT as part of a clinical trial were also included. Patients who remained on the respective lines of treatment were censored. Results: Data for 515 patients (372 male: 143 female) who received first-line SACT for mRCC were included in the analyses. IMDC prognostic groups were 103 favourable, 236 intermediate, 127 poor (49 not available). On progression 69% of patients were able to receive second-line therapy and 34% were able to receive third-line therapy. Of the 515 first-line therapies, 24% of patients received frontline ipilimumab and nivolumab, 10% received TKI and IO combination and 63% received single agent VEGF TKI. Second-line nivolumab or cabozantinib (43% and 40% respectively) were the most commonly prescribed options. Third-line cabozantinib 61% and nivolumab 16% remain the most used options. Across all lines of therapy progressive disease was the primary reason for discontinuation. 5% switched treatment due to toxicity. Conclusions: These results suggest that, with more treatment options available, including combination/ immunotherapy therapies, more patients are able to receive second and third-line therapies. Despite this, nearly one third of patients only receive one line of treatment which highlights the need to deliver the most efficacious treatments first to optimise patient outcomes. Moreover, single agent TKI was the most commonly used first-line SACT despite advances in the management pathway. Data analysing the impact of COVID on treatment selection will be presented.
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Background: The efficacy and safety of pazopanib (PZP) have been evaluated in pivotal randomized, clinical trials Real-world evidence (RWE) is required to further assess its use, effectiveness and safety in mRCC in clinical routine practices. Methods: APOLON is a non-interventional, multicentric prospective study with mRCC patients who receive frontline PZP treatment. The study is designed to assess PZP Progression-Free Survival (PFS) (under treatment), Overall Survival (OS), Objective Response Rate (ORR) assessed by investigators, tolerability and subsequent post-pazopanib therapy sequences. Impact of COVID-19 on patient's care was also assessed. Eligible patients were recruited from Nov 2017 to Jan 2019 in 55 participant sites in France. This interim analysis presents results 30 months (mo) after last patient was enrolled in the study. Results: The 217 patients were 71.1% males, with a median age of 69.6 years and had mRCC with a favourable (27.1%), intermediate (52.1%) or poor (20.8%) IMDC risk score according to physician. ECOG-PS was 0, 1 and ≥2 in respectively 43.3%, 39% and 17.6% of patients. Metastases were mainly located in lungs (64.1%), bones (28.6%), mediastinal (18%)/abdominal (17.1%). Patients had an history of partial/total nephrectomy in 54.8% of cases and previous local treatments for metastases in 27.6%. Median PFS, assessed by investigator, was 10.5 mo (95%CI: 9-12.4), similarly in patients < 65-year-old (YO) with 11.3 mo (95%CI: 7-16.3) and in those ≥ 65 YO with 9.9 mo (95%CI: 8.9-12). When assessed according to the IMDC risk score, mPFS was 18.1 mo (95%CI: 9.9-23.3) in favourable, 11.5 mo (95%CI: 8.7-14.4) in intermediate and 6.2 mo (95%CI: 3.5-9.5) in poor mRCC. The median OS was 27.3 mo (95%CI: 24.3 - ND). Investigator-assessed ORR was 48.3% with a CR in 6 patients (3.5%) and a PR in 77 (44.8%). After a median treatment duration of 10.1 mo, 190 patients (87.6%) discontinued PZP and 67.9% received at least one post-PZP line. Second line post-PZP consisted in nivolumab (71.3%), cabozantinib (14.7%), sunitinib (7%) or other (7%). Adverse Event (AE) leading to PZP dose reduction and discontinuation were reported in 42% and 40.9% of patients and treatment-related serious AE in 22.2% of patients. No safety signal was newly identified. The impact of the Covid 19 pandemic was limited on patients' cares and study follow-up. Visits during the pandemic included 84.1% of tumour evaluation. For 29 patients (14.1%), follow-up visits were carried out as a teleconsultation. Few patients (5,7%) had no visits during the pandemic. Conclusions: The APOLON study confirms PZP effectiveness and safety in patients with mRCC in real-life setting. The efficacy of pazopanib remains significant in patients aged 65 years and older. It is highly associated with risk score. The COVID pandemics had limited impact on patients' cares.
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Background: Cabozantinib is an approved therapy for advanced RCC (in the USA) and in treatment-naive patients with intermediate/poor risk, as well as following VEGF-targeted therapy (in Europe). Trial design: Cabopoint (NCT03945773) is a phase II, open-label study of cabozantinib in adults with unresectable, locally advanced or metastatic clear-cell RCC, whose disease progressed after checkpoint inhibitor therapy with ipilimumab and nivolumab alone (cohort A) or in combination with VEGF-targeted therapy (cohort B). The primary endpoint is objective response rate. Secondary endpoints include time to response, duration of response, disease control rate, progression-free survival and overall survival. A target of 250 patients at 50 European sites will receive cabozantinib (60 mg once daily;self-administered at home) for ≤ 18 months after the last patient receives their first dose. Safety assessments will occur every 2 weeks up to week 4, then every 4 weeks. Patients may continue cabozantinib after disease progression if there is clinical benefit. During follow-up, patients who discontinue early will be contacted every 12 weeks to assess survival and subsequent therapy. Each cohort will have an interim analysis when 60% of patients reach 12 months of follow-up. Cabopoint has been adjusted to allow the trial to continue during the COVID-19 outbreak, protecting participants in compliance with the study protocol.1 Alternative arrangements include: study drug dispensation to the participant's home if they cannot attend the study site;safety assessments at the study site or remotely at a local health care provider, within the protocol defined window;tumour assessments at a local radiology facility if they cannot attend the study site. Enrolment is permitted if the patient can be managed in compliance with the protocol and alternative arrangements.1 The limitations, risks and impact on data privacy of such arrangements will be accounted for and documented.