Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma

Abstract

Background: Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in metastatic cancers remains unclear. Many patients, especially those without radiologic complete remission, develop progressive disease after ICI discontinuation. Extending DoT with ICI may potentially improve efficacy outcomes but presents major logistical and cost challenges with standard frequency dosing (SFD). Receptor occupancy data supports reduced frequency dosing (RFD) of anti-PD-1 antibodies, which may represent a more practical and economically viable option to extend DoT.

Methods: We conducted a retrospective study of patients with metastatic melanoma and Merkel cell carcinoma (MCC), who received ICI at RFD administered every 3 months, after initial disease control at SFD. We evaluated efficacy, safety, and cost-savings of the RFD approach in this cohort.

Results: Between 2014 and 2021, 23 patients with advanced melanoma (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT was 1.1 years at SFD and 1.2 years at RFD. The 3 year PFS after start of RFD was 73% in melanoma and 100% in MCC patients, which compare favorably to historical control rates. In the subset of 15 patients who received at least 2 years of therapy, total savings amounted to $1.1 million in drug costs and 384 h saved despite the extended DoT (median 3.4 years), as compared to the calculated cost of 2 years at SFD.

Conclusions: ICI administration at RFD can allow extension of treatment duration, while preserving efficacy and reducing logistical and financial burden. RFD approach deserves further exploration in prospective clinical trials.

Keywords: Drug costs; Immunotherapy; Melanoma; Merkel cell carcinoma; Nivolumab; Pembrolizumab.

Fig. 1

Clinical course of each patient receiving standard-frequency anti-PD-1 therapy followed by reduced-frequency dosing. This swimmer’s plot portrays duration of treatment, best overall response, clinically significant immune-related adverse events, and disease progression or death in 23 patients who received standard frequency dosing of anti-PD-1 (SFD) then transitioned to reduced-frequency dosing (RFD). Each patient received SFD (dark gray) until objective response or disease control was achieved, followed by transition to RFD (light gray) guided by timing of disease response. The median duration of therapy at SFD was 13.1 months (range 2.3–26.0), and the median duration of RFD was 14.5 months (range 2.1–42.1). Abbreviations SFD—Standard frequency dosing, RFD—Reduced frequency dosing, CR—Complete response, PR—Partial response, SD—Stable disease, PD—Progressive disease

Fig. 2

Kaplan–Meier curve showing progression-free survival (PFS) for patients by disease type and by best overall response. PFS was measured from initiation of reduced-frequency dosing to disease progression or death, whichever occurred first. Patients without an event were censored (tick mark) at the last disease assessment date. A From time of initiating reduced frequency dosing, the estimated 36 month PFS for melanoma patients was 73% (95% CI 53–100). Median PFS for melanoma patients was not reached. B The estimated 36 month PFS was 100% (95% CI 48–100). Median PFS for MCC patients was 58.2 months. C By best overall response (BOR) in melanoma, the estimated 36 month PFS rate for CR, PR, and SD were 100% (95% CI 29–100), 89% (95% CI 71–100) and 50% (95% CI 22–100), respectively. D By BOR in MCC, the estimated 36 month PFS rate was 100% (95% CI 29–100) in patients with CR and 100% (95% CI 16–100) in PR. Abbreviations PFS—Progression free survival, MCC—Merkel cell carcinoma, CR—Complete response, PR—Partial response, SD—Stable disease, PD—Progressive disease, BOR—Best overall response

Fig. 3

Cumulative rate of delayed immune-related adverse events (irAEs) in all patients on reduced frequency dosing (RFD). A The cumulative incidence of irAE after initiation of RFD was 57% (N = 10 patients) for all grades and 28% (N = 4 patients) for grade 3 irAEs. Grade 3 events included colitis (2), hepatitis, and dermatitis. B Rates of irAEs on RFD developed at similar rates between patients with a prior irAE during standard-frequency (N = 11) and patients who had never experienced an irAE previously (N = 12). Of the 11 patients who experienced irAE on standard-frequency doses of immunotherapy, only one patient experienced a recurrence of a prior irAE. Thus, the majority of delayed irAEs that patients incurred on RFD were new toxicity events. Abbreviations irAE—Immune-related adverse event, RFD—Reduced frequency dosing

Fig. 4

Case study suggesting dependence on continuous PD-1 blockade for disease control (patient Melanoma-15 from Fig. 1) Adult male with metastatic melanoma was treated with pembrolizumab for 47 months (26 months at standard-frequency dosing (SFD) and 21 months at reduced-frequency dosing (RFD) before he electively discontinued ICI (panel A). 14 months after elective discontinuation, his disease progressed (panel B), suggesting potential role of prolonged PD-1 blockade in controlling his disease. Reintroduction of nivolumab at SFD has recaptured his disease response (panel C), which is ongoing at 35 months after restarting nivolumab. This case suggests the importance of continuous PD-1 blockade in maintaining immune equilibrium in patients with residual disease

Fig. 5

Savings with reduced-frequency dosing (RFD) A Among the subset of 15 patients with a total duration of therapy > 2 years (median 3.4 yr, range 2.0–5.0), we calculated savings from drug costs and patient-centered costs with the reduced-frequency approach (despite extended duration beyond 2 years) compared to the costs of 2 years of therapy at standard-frequency dosing (SFD). Additionally, the cost savings from drug costs and patient-centered costs were calculated for the entire cohort. B In a hypothetical model utilizing RFD after an initial 6 months of SFD, the total duration of treatment was extended to 84 months for pembrolizumab with reduced-frequency approach or 114 months with nivolumab with the reduced-frequency approach without incurring any additional costs. Abbreviations SFD—standard frequency dosing, RFD—Reduced frequency dosing