The present study investigated the pharmacokinetic profile and clinical outcomes of low-dose nivolumab (40 mg flat) compared to conventional dose (3 mg/kg) in a cohort of patients with heterogeneous solid tumors in real world scenario.

The pharmacokinetic analysis included measuring the geometric means of plasma nivolumab concentration–time profiles after the first dose of nivolumab at the two dose levels (Conventional dose vs. low-dose nivolumab). The pharmacokinetic analysis revealed that half-life (t1/2), volume of distribution (Vd) and clearance (Cl) were comparable across all the enrolled patients irrespective of dose of nivolumab administered (p > 0.05). Also, there were no statistically significant differences in the dose normalized Cmax (P = 0.10) and AUC0-t (P = 0.33) between patients receiving conventional and low-dose nivolumab. This can be explained by linear pharmacokinetics of nivolumab in the range of 0.3–10 mg/kg with a dose-proportional increase in Cmax and AUC0-t and with low to moderate inter-individual variability observed at each dose level (CV = 7 to 45%) [15]. The derived and estimated pharmacokinetic parameters of nivolumab in the present study were consistent with the findings from previously reported pharmacokinetic studies [16].

Moreover, receptor occupancy assays in peripheral blood coupled with flow cytometry analysis, supported the use of low-dose nivolumab. The study indicated that doses as low as 0.1 mg/kg might maintain efficacy, given plateau receptor occupancy of PD-1 by nivolumab are achieved at this concentration [2, 6, 7]. This indicate high affinity/avidity of the clinical antibody. Additionally, the concentration of nivolumab achieved after administration of conventional dose is 47.3 µg/ml and 9.06 µg/ml after low-dose nivolumab whereas the required concentration for activity is 1.2 µg/ml [6]. The present study’s results are encouraging as they demonstrate that low-dose nivolumab can achieve therapeutic levels in cancer patients and these levels are comparable to those achieved with the conventional dosing regimen. This supports the potential feasibility and effectiveness of utilizing lower doses of nivolumab.

The median PFS (4.3 months) observed in patients who received conventional dose was comparable with those in CheckMate 141 study (2.0 months) [1]. Moreover, median PFS between conventional and low-dose nivolumab did not significantly differ, with both groups exhibiting clinically relevant outcomes (4.3 months (1.46–7.07) vs. 5.8 months (3.39–8.26) (P = 0.31), respectively). Similarly, the objective response rate (ORR) was 18.2% in conventional dose group and 11.1% in low-dose group, which was comparable between the two studied groups. The results are in accordance with a study by Yoo et al., who demonstrated no significant difference in PFS or OS or ORR between standard dose and low-dose nivolumab [17]. More recently, Patil et al. reported improved 1 year survival from 16.3 to 43.4% (P = 0.0036) and median OS 6.7 months to 10.1 months (P = 0 0.0052) by adding nivolumab at low-dose of 20 mg flat dose Q3W to metronomic therapy [13]. The observed median PFS in the low-dose nivolumab patients (5.8 months) were comparable with the PFS of patients (6.6 months) receiving 20 mg Q3W nivolumab in combination with metronomic therapy for HNSCC patients [13]. Lepik et al. also showed that in patients with relapsed or resistant Hodgkin lymphoma, the median PFS observed with a flat 40 mg Q2W dosage regimen was comparable to that of patients receiving a conventional dosage regimen (18.4 vs. 14.7 months) [18]. Interestingly, a number of studies have shown that ORR is correlated with nivolumab clearance rather than nivolumab dosage [2, 19]. In a similar vein, Mallardo et al. demonstrated correlation between week 12 nivolumab concentration and patients’ outcomes in terms of survival and tumor response [20]. We did not look into the correlation between clearance and outcomes because the dose of nivolumab administered to the patients was variable. However, our findings agree with the observation made by Lepik et al. in that outcomes with a lower flat dose was comparable to conventional dose. The geometric means of clearance of conventional and low-dose nivolumab (393 vs. 417 mL/d) did not differ significantly in the current trial, and the ORRs of the two dosing sets of nivolumab (2/11 vs. 1/9) were also similar.

The study reported all the adverse event observed throughout the study period. Adverse events of grade ≥ 3 occurred in 28.57% of the patients who received conventional dose versus 0% who received low-dose nivolumab. There was no treatment discontinuation due to adverse events of nivolumab in any of the patients. The study strongly indicates that low-dose nivolumab has lower toxicity as compared to conventional dose. Thus, this study showed that the safety is definitely better with low-dose as compared to conventional dose whereas efficacy is comparable between the two doses.

Considering the overall benefit imparted by nivolumab, it becomes imperative to explore various strategies that enable its inclusion in the treatment regimen of HNC while simultaneously reducing its cost making it available to larger population. In this context, the concept of low-dose nivolumab emerges as a potential solution, offering improved access and affordability of nivolumab in LMICs. Our study indicates that low-dose nivolumab is a practical approach, in metastatic/recurrent HNC in resource limited settings such as LMICs in real world scenario.

There are a few limitations of the study. This was a pilot study, and therefore the smaller sample size was included. As it was not powered for response and toxicity assessment, external validity of these findings is limited. The study population included patients with heterogeneous solid tumors. However, 22 out 25 patients were diagnosed with head and neck cancer. Since our goal was to compare the pharmacokinetics of conventional dose and low-dose nivolumab, early sampling method was employed, even though nivolumab has a longer half -life. Majority of the patients died or had progression of the disease before they received the 5th cycle of nivolumab. Hence, the steady state levels of nivolumab couldn’t be determined. Further studies can estimate this in indications which has allow steady state sampling.

To conclude, in this mixed cohort of patients, we report that low-dose nivolumab leads to lower exposure as compared with conventional dose of nivolumab. However, the dose normalized exposure of low-dose nivolumab was comparable to conventional dose indicating linear pharmacokinetics. Low-dose was better tolerated, and clinical outcomes were comparable to conventional-dose indicating that low-dose nivolumab does not compromise efficacy and improves safety. These findings call for head-to-head comparison of low-dose and conventional doses of nivolumab across therapy areas to improve access, affordability and safety of the immunotherapy regimen.