Do We Need Biomarkers to Predict Tumor Hyper-Progression Following Immunotherapy?

A new study published in Clinical Cancer Research provides evidence that researchers can use biomarkers to identify patients whose tumors will grow at a faster rate following immunotherapy treatment.

The study evaluated tumor biopsies of 155 stage IV cancer patients who had received immunotherapy treatments—inhibitors of CTLA-4, programmed death 1 (PD-1), programmed death ligand-1 (PD-L1), or other immunotherapy agents. Hyper-progression was defined as:

• Time-to-treatment failure less than 2 months
• At least a 50% increase in tumor burden compared with pre-immunotherapy imaging
• More than a 2-fold increase in progression pace

Based on next-generation sequencing results, the authors latched-in on alterations in MDM2/MDM4 and EGFR as indicators of hyper-progression. Of the 6 patients who had carried alterations in MDM2/MDM4, 4 showed a dramatic increase in tumor growth (55% to 258%) following PD-1/PD-L1 treatment, in addition to new large masses and an increase in the pace of disease progression (2.3-, 7.1-, 7.2- and 42.3-fold compared with 2 months before immunotherapy). Two patients out of 10 who carried EGFR mutations saw a 53.6% and 125% increase in the size of their tumors.

One of the 4 hyper-progressors had a high mutational rate, which is typically a marker of tumor response. Age was not a determinant of hyper-progression in this study, the authors write.

“There’s some phenomenon here that seems to be true, and I think we cannot just give this therapy randomly to the patient,” said study author, Shumei Kato, MD, an oncologist at UC San Diego. “We need to select who’s going to be on it.”

In their discussion, the authors recommend additional studies on this phenomenon, including combination studies using MDM2 inhibitors that could help reduce hyper-progression following immunotherapy. They also specify the need to conduct further investigation to confirm the role of said genes in promoting hyper-progression.

Similar results were published by researchers from Gustave Roussy, a cancer research institute in Paris, France, just over a year back, where hyper-progression was defined as a more than 2-fold increase in the tumor growth rate following treatment with a PD-1/PD-L1 agent. Those authors found an association with higher age and worse outcome. Interestingly, the study found patients with hyper-progression had fewer new lesions compared with patients whose disease progressed, but who were not classified as hyper-progressive.

There are skeptics who do not believe in this phenomenon. “Tumor growth is not a precise measurement, and if you measure lots of people, some will have faster growth just because of the error in the test,” according to Vinay K. Prasad, MD, MPH, assistant professor of Medicine at the Oregon Health and Sciences University. Antoni Ribas, MD, PhD, a physician scientist who is involved in clinical studies with immunotherapies, warns against letting “anecdotal evidence” overshadow the potential benefit of immunotherapy.

These reports can raise doubts in the minds of patients and their treating oncologist—what is needed is clear communication to ensure clinical decisions are made in an informed manner.