Hyperprogressive Disease in Patients With Advanced Non–Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy
Open accessAbstract
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.
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Only a minority of patients, about 35%, obtain sustained benefit from immune checkpoint inhibitors.
“However, only a minority (35%) of patients benefit from sustained response to ICI 8 .”
From Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer (2022) · cites this paper as [8]
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- Authors
- Ferrara, R., Mezquita, L., Texier, M., Lahmar, J., Audigier-Valette, C., Tessonnier, L., Mazieres, J., Zalcman, G., Brosseau, S., Le Moulec, S., Leroy, L., Duchemann, B., Lefebvre, C., Veillon, R., Westeel, V., Koscielny, S., Champiat, S., Ferté, C., Planchard, D., Remon, J., Boucher, M.-E., Gazzah, A., Adam, J., Bria, E., Tortora, G., Soria, J.-C., Besse, B., & Caramella, C.
- Affiliations
- Institut Gustave Roussy (FR)
- Pneumology Department, Centre Hospitalier Toulon Sainte-Musse, Toulon, France
- Nuclear Medicine Department, Centre Hospitalier Toulon Sainte-Musse, Toulon, France
- Pneumology Department, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France
- Thoracic Oncology Department, Hôpital Bichat-Claude Bernard, Université Paris-Diderot, Paris, France
- Hôpital Bichat-Claude-Bernard (FR)
- Medical Oncology Department, Institute Bergonié, Bordeaux, France
- Institut Bergonié (FR)
- Hôpital Avicenne (FR)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Service des Maladies Respiratoires, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
- Centre Hospitalier Universitaire de Besançon (FR)
- Drug Development Department (DITEP), Gustave Roussy, Villejuif, France
- Cancer Medicine Department, Gustave Roussy, Villejuif, France
- Università Cattolica del Sacro Cuore (IT)
- University of Verona (IT)
- Université Paris-Sud (FR)
- Corresponding author
- Besse, Benjamin
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2018-11-01
- Volume
- 4
- Issue
- 11
- Pages
- 1543
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC6248085
- OpenAlex
- W2891266481
- Cited by
- 720
- References
- 45
- Citations by year
- 2026: 31 · 2025: 37 · 2024: 82 · 2023: 67 · 2022: 92 · 2021: 135 · 2020: 162 · 2019: 108 · 2018: 6
- FWCI
- 38.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- hyperprogressive disease, non-small cell lung cancer, PD-1/PD-L1 inhibitors, immune checkpoint inhibitors, single-agent chemotherapy, tumor growth rate, pseudoprogression, overall survival, second-line therapy, prognostic factors, PD-L1 expression, PD-1 expression, immune-related adverse events, advanced non-small cell lung cancer
- MeSH terms
- Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Retrospective Studies, Programmed Cell Death 1 Receptor
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