Nivolumab usage patterns combined with TKI for mRCC: Financial toxicity and clinical outcomes from self-paying patients in India—Is low dose an option when access is limited?
Authors: John Ajoy Oommen , Georgy Josh Thomas Thomas , Joel Anjana , Thumaty Divya Bala , Wisely Jerryes Pious , TJ Nirmal , Kumar Santosh , Chacko Raju Titus , Yadav Bijesh , Singh Ashish 
Published: June 2023

e16544

Background: Nivolumab with cabozantinib is an accepted treatment option for metastatic RCC (mRCC). Generic TKI access has improved, although nivolumab at currently licensed doses remains unaffordable in India. Immunotherapy is not reimbursable through national health insurance schemes, therefore patients pay out-of-pocket. We evaluated the practice patterns and clinical outcomes with low dose nivolumab combined with TKI in a tertiary academic hospital in India. Methods: We reviewed and abstracted clinical records of mRCC patients treated with nivolumab and TKIs between December 2019 and January 2022. Due to variations in nivolumab dosing frequencies, a metric of dose/Kg/28 days was used for comparative analysis. Patients also had treatment de-escalation in the form of decrease in dose or frequency of nivolumab. Those treated with such de-escalation strategies were noted along with reasons for de-escalation. PFS, OS were calculated as per standard definitions and adverse events graded as per CTCAE4.1. Results: We identified 53 patients who received nivolumab and TKI with 33(62.2%) IMDC intermediate and 12(22.6%) poor prognoses. The mean age was 54.9±8.5 years, predominantly male (83%), non-clear cell histology in 12(22.6%) and clear cell in the remaining. Site of metastases were: pulmonary 43 (81%), CNS 6 (11.3%), liver 16(30%), non-regional nodes 24(45%) and bone 18 (33.9%). Forty-three (81.1%) received no prior systemic therapy. The TKIs used were Lenvatinib (47.2%), cabozantinib(34%) and Axitinib (2%). Fourteen (26.4%) had a flat starting nivolumab dose of 40mg and the median dose of the cohort was 140mg (IQR, 40-240) every 21 days (IQR, 21-28) resulting in a median adjusted weight-based dosing of 2.2mg/kg/28days (IQR, 1.1- 4). Treatment de-escalation was undertaken in 36 (67.9%) due to financial toxicity 24(45.3%) or drug toxicity 10 (18.9%). Interval nephrectomy was performed in 9 (17%). At the median dose (2.2mg/kg/28days) 26 patients with low dose (LD) and 27 high dose (HD) nivolumab were compared. The median PFS of LD and HD groups were 17 (95% CI,10.8-23.1) months and 21 (95% CI,5.7-36.2) months respectively (P=0.75). The median OS of the LD and HD was NR and 21 (4.9-37) months respectively (P=0.017). The grade 3&4 adverse events were palmoplantar dysesthesia 7 (13.2%), hypertension 7(13.2%), arthritis in 3 (5.7%). One patient had Fournier’s gangrene and another had a pulmonary embolism. Primary hypothyroidism 28(52.8%) was the commonest grade 2 adverse event. Cost of 28 days of treatment was ₹ 87,280 ($1055.11 USD). Conclusions: Using LD nivolumab with TKI did not result in inferior survival and is less expensive than the currently approved dose. Treatment de-escalation due to financial toxicity was common and reflects reality in LMICs. Low dose strategies in mRCC warrant evaluation in prospective clinical trials.