Assessment of the safety profile of nivolumab in Indian patients: A focused study on renal cell carcinoma and non-small cell carcinoma

The incidence of cancer in India contributes to more than 1.4 million cases annually, with 0.9 million cancer-related deaths reported as of 2022.[1] The rising burden of malignancies has led to rapid evolution in treatment paradigm over the past decade, including the incorporation of targeted therapies and immunotherapy. It is, therefore, imperative to assess the toxicity profile of these newer agents, considering the increasing number of patients who will receive these therapies in both localized and advanced settings. The incidence of treatment-related adverse events (TRAEs) with the use of immunotherapy has been found to be lower than chemotherapy.[2] However, the profile of immunotherapy-associated TRAEs differs from that of chemotherapy, with a focus on immunologic toxicities, such as endocrinopathies, fatigue, and cutaneous side effects.[2] Two malignancies, where immunotherapeutic agents have been incorporated in curative and metastatic settings, are non-small-cell carcinoma (NSCLC) and renal cell carcinoma (RCC). Lung cancer is the most common malignancy among Indian males and the fourth most frequent cancer overall,[1] with NSCLC being the most prevalent subtype.[3] While RCC accounts for only 1.2% of annual cancer cases in India, it carries a high risk of mortality and significantly impacts the quality of life (QoL).[1,4] Nivolumab is approved for use in NSCLC in perioperative and advanced settings.[2,5,6] In RCC, nivolumab is used in the first-line setting in combination with cabozantinib or ipilimumab, and as monotherapy in the recurrent setting.[7-9] Real-world studies have elaborated on the incidence of TRAEs in patients with RCC and NSCLC.[10,11] However, data from the Indian population on the toxicity profile of nivolumab remain sparse. A recent prospective study specifically evaluated the spectrum of TRAEs in Indian patients with RCC and NSCLC receiving nivolumab, with a primary focus on safety and tolerability. This Phase IV prospective, multicenter, single-arm, open-label study enrolled patients with locally advanced or metastatic NSCLC and metastatic RCC who had undergone at least one prior line of therapy.[12] The primary aim was to assess the safety and tolerability of nivolumab, while secondary objectives included evaluating the frequency of TRAEs, serious adverse events (SAEs), and adverse events (AEs), leading to treatment discontinuation. Patients were enrolled for a treatment period of 26 weeks, including 24 weeks of treatment with two-weekly 3 mg/kg nivolumab and two weeks of follow-up from the last study dose. The study population consisted of 100 patients, including 70 (70%) with locally advanced/metastatic NSCLC and 30 (30%) with advanced RCC. Among these, 95 (95%) reported AEs of all grades, including 25 (25%) TRAEs across both malignancies. A total of 40 TRAEs were recorded, with frequencies of 17 (24.3%) in NSCLC and 8 (26.7%) in RCC groups. Severe grade TRAEs were observed in 3 patients (4.3%) from NSCLC subset only. Prominent any-grade TRAEs included infusion-related reactions (6.1%), hypothyroidism (6.1%), and fatigue (4.2%). Severe events included lower respiratory tract infection (LRTI), dyselectrolemia, and pneumonitis, with the latter being classified as a Grade 5 TRAE. The authors describe select endocrine events in 9.6% of the cases, with hypothyroidism being the most common (6%). Immune-related adverse events requiring immunomodulators, such as corticosteroids, included two cases of pneumonitis (2.8% in NSCLC), hepatotoxicity (one case (1.4%) in NSCLC), and hypersensitivity reactions (one case (1.4%) and one case (3.3%) in NSCLC and RCC, respectively). This study highlights a manageable toxicity profile associated with nivolumab monotherapy in pretreated Indian patients with NSCLC and RCC. However, the incidence of TRAEs reported in this study was lower than globally conducted trials. For instance, any-grade fatigue was reported in 72 (17%) patients in a combined analysis of Checkmate 017 and 057 trials, in 140 (34.7%) patients in the Checkmate 025 trial but only 3 (4.2%) patients in this study.[13,14] Grade 3-4 electrolyte abnormalities, including hyponatremia, were reported in this study. Given that the median time to onset for primary adrenal insufficiency is approximately 120 days (ranging from 6 to 576 days) after starting immunotherapy,[15] routine serum cortisol monitoring could have captured more cases. As the authors prudently discuss, the study’s follow-up period of six months may have been insufficient to capture late-onset AEs or patient-reported symptoms that were missed in the initial part of treatment. Additionally, a more detailed description of serious TRAEs, particularly the clinico-radiological evaluations of the Grade 5 pulmonary events classified as pneumonitis and acute respiratory distress syndrome, would have been valuable. Although the study focused on AEs rather than clinical outcomes, additional assessment of QoL would have provided insights into the impact of TRAEs. Clinical outcomes were not analyzed keeping in view the single-arm design and short treatment duration. However, it would have been interesting to find if a higher frequency of TRAEs correlated with early radiological and/or metabolic response rates. The smaller proportion of patients with RCC leave a scope for further dedicated trials in the subset. Given the limited sample size of patients with RCC and the study being conducted only in the pretreated setting, the findings may not be truly applicable to the first-line settings involving combinations with tyrosine kinase inhibitors or ipilimumab. However, this Phase IV prospective study does confirm the safety profile of nivolumab with manageable toxicity in the Indian population. The manageable toxicity with nivolumab strengthens the clinician’s confidence in handling real-world adverse events, supporting its use in diverse settings. As per pooled cost-effective analysis from Checkmate 017 and Checkmate 057, the costs of TRAE management were higher with docetaxel than nivolumab.[16] Given no dose-response relationship in pharmacokinetics, future research into lower doses or extended dosing intervals could improve cost-effectiveness while maintaining its efficacy. Biosimilar options could further alleviate financial toxicity and expand access to immunotherapy to a wider population. In conclusion, this study confirms a favorable safety profile for nivolumab in the Indian population and further warrants the need for studies with larger sample sizes and longer follow-up durations to refine the management strategies of immune-related adverse events, particularly in the Indian population.