Hyperprogressive disease during anti-PD-1 (PDCD1) / PD-L1 (CD274) therapy: A systematic review and meta-analysis

Jong Yeob Kim, Keum Hwa Lee, Jeonghyun Kang, Edith Borcoman, Esma Saada-Bouzid, Andreas Kronbichler, Sung Hwi Hong, Leandro Fórnias Machado de Rezende, Shuji Ogino, Nana Keum, Mingyang Song, Claudio Luchini, Hans J. van der Vliet, Jae Il Shin, Gabriele Gamerith

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62 Citations (Scopus)


Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., prior to programmed cell death 1 [PD-1, PDCD1] / programmed cell death 1 ligand 1 [PD-L1, CD274] inhibitor therapy) patient factors associated with risks of developing HPD during PD 1/PD-L1 inhibitor therapy. We searched eight databases until 6 June 2019. We calculated the summary odds ratio (OR) and its 95% confidence interval (CI) using the random-e_ects model and explored between-study heterogeneity and small-study e_ects. A total of nine articles was eligible (217 HPD cases, 1519 cancer patients) for meta-analysis. There was no standard definition of HPD, and the incidence of HPD ranged from 1 to 30%. We identified twenty-three baseline patient factors, of which five factors were statistically significantly associated with HPD. These were serum lactate dehydrogenase (LDH) above the upper normal limit (OR = 1.89, 95% CI = 1.02–3.49, p = 0.043), more than two metastatic sites (OR = 1.86, 1.34–2.57, p < 0.001), liver metastases (OR = 3.33, 2.07 5.34, p < 0.001), Royal Marsden Hospital prognostic score of 2 or above (OR = 3.33, 1.96–5.66, p < 0.001), and positive PD-L1 expression status that was inversely correlated with HPD (OR = 0.60, 0.36–0.99, p = 0.044). Between-study heterogeneity was low. Evidence of small-study e_ect was found in one association (PD-L1 expression). Subset analyses of patients with non-small cell lung cancer showed similar results. Future studies are warranted to identify underlying molecular mechanisms and to test their roles as predictive biomarkers of HPD.

Original languageEnglish
Article number1699
Issue number11
Publication statusPublished - 2019 Nov

Bibliographical note

Funding Information:
Conflicts of Interest: For effort support, S.O. received USA National Institutes of Health [grant numbers R35 CA197735]. The other authors declare no conflict of interest.

Funding Information:
We thank Hye Ryun Kim (Yonsei University College of Medicine) for providing us with valuable insights throughout the study.

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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