Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy

Abstract

Importance: Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non-small cell lung cancer (NSCLC) are unknown.

Objectives: To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD.

Design, setting, and participants: In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required.

Interventions: The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%.

Main outcomes and measures: The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy.

Results: Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350]; P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69]; P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD.

Conclusions and relevance: Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Audigier-Valette reported serving in a consulting/advisory role for Bristol-Myers Squibb and Merck Sharp & Dohme. Dr Mazieres reported serving in a consulting/advisory role for Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, and Eli Lilly and reported receiving research funding from Roche, Bristol-Myers Squibb, and AstraZeneca. Dr Duchemann reported serving in a consulting/advisory role for Roche and Bristol-Myers Squibb and reported receiving travel/accommodation funding from Roche. Dr Westeel reported serving in a consulting/advisory role for Bristol-Myers Squibb, Merck Sharp & Dohme, and AstraZeneca; reported receiving honoraria from Bristol-Myers Squibb and AstraZeneca; reported serving on speakers bureaus for Bristol-Myers Squibb and Merck Sharp & Dohme; and reported receiving travel/accommodation funding from Bristol-Myers Squibb, Roche, and AstraZeneca. Dr Remon reported receiving travel/accommodation funding from Merck Sharp & Dohme and OSE Pharma. Dr Adam reported serving in a consulting/advisory role for Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and AstraZeneca. Dr Bria reported receiving speakers fees from Bristol-Myers Squibb, Novartis, AstraZeneca, Merck Sharp & Dohme, Celgene, Pfizer, Helsinn, Eli Lilly, and Roche and reported receiving research funding from AstraZeneca, Roche, Open Innovation, Italian Association for Cancer Research (AIRC), and Cariverona Foundation. Dr Soria reported serving in a consulting/advisory role for Roche, AstraZeneca, and Pfizer. Dr Besse reported receiving research funding from GlaxoSmithKline, Roche/Genentech, Clovis Oncology, Pfizer, Boehringer, Eli Lilly, Servier, Onxeo, Bristol-Myers Squibb, Merck Sharp & Dohme, OSE Pharma, Inivata, and AstraZeneca. No other disclosures were reported.

Figures

Figure 1.. Hypothetical Tumor Volume Variation and Definition of Hyperprogressive Disease (HPD) in the Immunotherapy Cohort

Variation of tumor growth rate (TGR) volume per month was calculated both before the start of programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitor therapy and during PD-1/PD-L1 inhibitor therapy. Hyperprogressive disease was defined as Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 progressive disease at the first computed tomography (CT) scan during PD-1/PD-L1 inhibitor therapy and an absolute increase in the TGR exceeding 50% per month.
aNew lesions and nonmeasurable disease not included in the TGR.
bThe baseline CT scan performed within 6 weeks before PD-1/PD-L1 inhibitor therapy initiation.

Figure 2.. Scatterplots With Response According to Delta Tumor Growth Rate (TGR) in the Immunotherapy and Chemotherapy Cohorts

A, Light blue spots show 266 patients with regressing or stable tumors, dark blue spots show 78 patients with progressing tumors, and orange spots show 62 patients with accelerated tumor growth during programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitor therapy. B, Light blue spots show 47 patients with regressing or stable tumors, dark blue spots show 9 patients with progressing tumors, and orange spots show 3 patients with accelerated tumor growth during chemotherapy. Diagonal lines separate patients with delta TGR exceeding 50% from patients with delta TGR of 50% or less.

Figure 3.. Case Study of a Patient With Non–Small Cell Lung Cancer With Hyperprogressive Disease During Treatment With a PD-1 Inhibitor

Shown are computed tomographic scans before baseline (A), at baseline about 3 weeks later (B), and during programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitor therapy 1 month later (C) in a man in his mid-50s with stage IV (lung, liver, and bone metastases) HER2-amplified lung adenocarcinoma treated with anti–PD-1 therapy in the third line. After 2 administrations, there was evidence of extensive lung, liver, and peritoneal progression. Arrowheads show lung and liver metastases before and during anti–PD-1 treatment.

Figure 4.. Overall Survival for Hyperprogressive Disease (HPD) Compared With Progressive Disease Without Hyperprogression in the Immunotherapy and Chemotherapy Cohorts (6-Weeks Landmark Analysis)

A, Fourteen patients and 2 patients with pseudoprogression were excluded from the progressive disease without hyperprogression and HPD cohorts, respectively. The median overall survival is shown for 138 patients with progressive disease without hyperprogression at the first evaluation vs for 23 patients with diagnosed HPD within the first 6 weeks of treatment. B, The median overall survival is shown for 18 patients with progressive disease without hyperprogression at the first evaluation vs for 3 patients with diagnosed HPD within the first 6 weeks of treatment.