Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non-Small Cell Lung Cancer

Abstract

Introduction: With expanding indications for programmed death 1 (PD-1) axis inhibitors in non-small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients.

Methods: Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune-related response criteria.

Results: Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2-year survival rate from AR was 70% (95% confidence interval: 0.53-0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with the same PD-1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD-1 axis inhibitor after local therapy. The 2-year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77-1).

Conclusions: Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression.

Keywords: PD-1; PD-L1; acquired resistance; immunotherapy; non–small cell lung cancer.

Figure 1.

Development and management of acquired resistance to programmed death 1 axis inhibitor therapy. Swimmer plot showing the time to resistance after initial response to PD-1 axis inhibitor therapy, and subsequent therapy, among 26 patients with advanced non–small cell lung cancer. Each bar represents one patient. Patient identification number preceding each bar corresponds to patient identification number provided in Table 2.

Figure 2.

Kaplan-Meier curves of overall survival from acquired resistance to programmed death 1 axis inhibitor therapy for all patients and the subset of patients who received local therapy to all sites of acquired resistance.

Figure 3.

Sites of AR. (A) Pie chart showing number of patients with one site (grey), 2 sites (yellow), or three or more sites (orange) of progressive disease. Site location provided for patients with progression limited to one or two sites. (B) Progression and ongoing response at time of AR by tumor site. Bar graph showing both sites of tumor growth and sustained tumor response at the time of AR to PD-1 axis inhibitor therapy. Thirteen patients had both progressing and responding lesions in the same organ site at the time of AR. AR, acquired resistance to PD-1 axis inhibitor therapy; LN, lymph node; PD-1, programmed death 1.

Figure 4.

Sites of AR by pre-treatment progressing sites. Donut chart showing sites of AR (LN and/or non-LN sites; outer ring) in patients grouped by pre–PD-1 axis inhibitor sites of progression (LN and/or non-LN sites; inner circle). AR, acquired resistance; PD-1, programmed death 1; LN, lymph node.