Hyperprogressive Disease in Patients Treated with PD-1/PD-L1 Inhibitors

Hyperprogressive disease (HPD) has recently been reported as a novel pattern of aggressive tumor growth following exposure to immune checkpoint blockade drugs such as anti-PD-1 and anti-PD-L1 antibodies. Hyperprogressive tumor growth has been identified in a wide variety of malignancies including melanoma, NSCLC, colorectal cancer, urothelial carcinoma, squamous cell carcinoma of the head and neck, ovarian malignancies, and lymphoma.

Determining the Incidence of HPD

The reported rate of HPD following exposure to immune checkpoint agents varies, ranging from 2.6 – 13.8% across three retrospective analyses.^1-3 The range of incidences can be attributed, in part, to the criteria used to define hyperprogression. For example, Champiat et al. used a 2-fold increase in tumor growth rate to define hyperprogression and produced a 9.0% incidence rate. Kato et al. added criteria such as time to treatment failure less than 2 months and a > 50% increase in tumor burden to produce a lower incidence of 2.6%. A third study used a much lower cutpoint of > 50% increase in tumor growth rate that resulted the highest incidence of HPD at 13.8%.³

It remains unclear whether the application of immune-related response criteria (irRC), which allow for more liberal radiographic interpretation of disease response to immunotherapy, would result in lower rates of HPD.⁴ Certainly aggressive disease patterns are well known to those who treat cancer patients even in the absence of immunotherapy. Ferrara et al. found that out of 59 immunotherapy-naïve NSCLC patients studied, 5.1% met criteria for HPD, indicating that the hyperprogressive state applies not only to those patients receiving immunotherapy but also to those receiving other forms of treatment.

Factors Associated with HPD

There are conflicting reports as to the role of baseline tumor burden and the likelihood of developing HPD; some studies report no association while others report two or more metastatic sites as being a risk factor.^2,3 Not enough data are available to formally evaluate the role of tumor PD-L1 antigen expression in the development of HPD although cases of HPD in PD-L1 negative tumors have been demonstrated.² The potential mechanisms underlying HPD remain elusive. Scattered pre-clinical data suggest complex immune mechanisms may allow for HPD through paradoxical immune suppression triggered by immune checkpoint drugs. Theories put forth include anti-PD-1 antibodies acting as agonists as opposed to antagonists on cytotoxic t-cells, inhibition of helper t-cells, or genetic alteration (polymorphisms) of PD-1 expression leading to paradoxical cytotoxic t-cell suppression by enhancing PD-L1/PD-1 ligation.⁵ One theory beyond the context of immune checkpoint drugs is that some patients suffer from biologically aggressive tumors that do not respond to available treatment modalities and would exhibit the same aggressive growth pattern irrespective of the type of treatment they receive.

Managing HPD

Regardless of the underlying mechanism, the illuminating studies of hyperprogression have identified a unique subset of patients that pose a significant challenge for providers. Prompt administration of cell cycle dependent cytotoxic chemotherapeutics such as taxanes, vinca alkaloids, and anthracyclines could be considered for those who develop rapid tumor growth following initiation of IO agents; however, outcomes for patients who experience HPD remain poor and further studies are needed to guide patient management.

Ryan Weight, DO, MS, is an assistant professor in the Department of Medical Oncology at the University of Colorado specializing in the treatment of cutaneous malignancies, including melanoma. He is a member of the Training & Education Working Group.

References

1. Kato S, Goodman A, et al. Hyperprogressors after immunotherapy: Analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242-4250.
2. Champiat S, Dercle L, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2016;23(8):1920-1928.
3. Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive disease in patients with advanced Non–Small Cell Lung Cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol. Published online September 06, 2018.
4. Hodi SF, Hwu W, et al. Evaluation of immune-related Response Criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol. 2016:34(13):1510-1517.
5. Xu-Monette ZY, Zhou J, Young KH. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood. 2018;131(1):68-83.