Hyperprogressive Disease during Anti-PD-1 (PDCD1) / PD-L1 (CD274) Therapy: A Systematic Review and Meta-Analysis

Abstract

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-effects model and explored between-study heterogeneity and small-study effects. 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 effect 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.

Hyperprogression Under Immune Checkpoint-Based Immunotherapy—Current Understanding, The Role of PD-1/PD-L1 Tumour-Intrinsic Signalling, Future Directions and a Potential Large Animal Model

“…Associations were made with increased age [11], higher lactate dehydrogenase (LDH) concentration in the serum [31], female sex [35], previous irradiation of the tumour area [37], pre-existence of liver-located or more than two metastatic sites [46], MDM2/MDM4 and EGFR genetic alterations [32,47] and mutations in a variety of oncogenes [48]. Most results were not replicated by other studies [49].…”

“…The concept of hyperprogression (HP) or Hyperprogressive Disease (HPD) was introduced by Champiat et al in 2016, based on the observation that a subset of patients receiving ICB experiences extremely rapid disease progression that leads to fast patient deterioration [11]. Importantly, in these patients, the survival time is often shorter than 2 months [31]. Attempts by multiple groups to capture the cases of HPD led to several definitions of the phenomenon (summarised in Table 2) and were comprehensively described by Kim et al [31].…”

“…Importantly, in these patients, the survival time is often shorter than 2 months [31]. Attempts by multiple groups to capture the cases of HPD led to several definitions of the phenomenon (summarised in Table 2) and were comprehensively described by Kim et al [31]. A lack of a unified definition adds to the controversy around HP and makes it difficult to compare studies or to combine their results for higher statistical power.…”

“…HP was associated with elevated serum LDH concentration, presence of more than two metastatic sites, liver metastases and Royal Marsden Hospital (RMH) prognostic score equal 2 or more. Strong expression of PD-L1 was inversely associated with HP [31]. The authors called for efforts to formulate a standardised definition since the lack thereof made comparisons of the available studies difficult.…”

“…High LDH indicates intratumoral hypoxia as well as extracellular environment acidification. The authors concluded that the link to HP is unknown [31]. It is known, however, that the solvent can influence the antibody functionality and the conformation of protein antigens [89].…”