Hyperprogression

Hyperprogression (HPD) during or after therapy with immune checkpoint inhibitors (ICI) is a tumor growth phenomenon that can occur in 8-10% of patients with malignant tumor entities treated in this way. Hyperprogression mainly affects tumor patients treated with PD-1/PD-L1 antibodies. Instead of inhibiting tumor growth, treatment with immune checkpoint inhibitors leads to tumor progression.

Hyperprogression is associated with older age (P < 0.05) and shorter progression-free survival (overall survival [OS]) (Abbas W et al. 2019). The use of PD-1 or PD-L1 blockers could pose a risk in the older population. Other risk factors include pre-existing conditions or an already advanced tumor.

A comparison of current HPD definitions reveals a wide variety of classifications. Most definitions are based on a RECIST (Response Evaluation Criteria in Solid Tumors) defined progressive disease (PD) and a tumor growth rate (TGR) at least two times higher than the previous assessment (Kato S et al. 2017). Hyperprogressive disease is often also caused by the appearance of multiple new metastases. The prognosis is then similarly poor as for patients with pre-existing distant metastasis.

The phenomenon of accelerated disease progression is not specific to anti-PD-1/PD-L1 agents and has sometimes been observed with other therapeutics, such as in melanoma using adjuvant IFNα, where patients in the treatment group who died during the study period had a significantly shortened time from relapse to death compared to control subjects(Strannegård Ö et al. 2016). Rapid progression has also been reported with treatment discontinuation after long-term response to VEGFR or EGFR tyrosine kinase inhibitors (TKIs) (Iacovelli R et al. 2015). Remarkably, the type of prior treatment has no impact on the risk of progression (Champiat S et al. 2017).

Accelerated tumor growth: The tumor enlarges faster under this therapy regime than before the therapy.

Worsening of symptoms: Patients often show rapidly increasing tumor-induced symptoms.

Radiological evidence of tumor progression: Imaging procedures (e.g. CT or MRI) show a significant increase in tumor size or the appearance of new metastases.

Time course: Hyperprogression occurs within a few weeks after the start of immunotherapy.

Treatment of hyperprogression

Discontinuation of immunotherapy: As a rule, immunotherapy is stopped immediately.

Alternative therapies: Chemotherapy, targeted therapies or palliative measures may be considered.

Symptomatic treatment: To control pain or other symptoms.

Antibodies that block immune checkpoints are fundamentally changing the treatment of cancer patients. Immune checkpoint inhibitors (ICI) are now approved for various tumor types, including melanoma, squamous cell carcinoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), head and neck squamous cell carcinoma (HNSCC), bladder cancer and Hodgkin's lymphoma. Interestingly, therapies with immune checkpoint inhibitors also lead to new tumor response patterns such as delayed tumor response or pseudoprogression, but also to completely undesired accelerated tumor growth (Champiat S et al. 2017).

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