Hyperprogression on Immunotherapy: When Outcomes Are Much Worse

Sharon Worcester

April 28, 2021

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types.

But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed "hyperprogressive disease" (HPD).

It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a "provocative phenomenon," comment the authors of a recent commentary entitled "Hyperprogresssion and Immunotherapy: Fact, Fiction, or Alternative Fact?"

"This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease," says the author of another commentary.

Dr Kartik Sehgal

But the tide is now turning toward acceptance of HPD, says Kartik Sehgal, MD, oncologist at Dana-Farber Cancer Institute and Harvard University, Boston, Massachusetts.

"With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease," says Sehgal.

He authored an invited commentary in JAMA Network Open about one of the latest meta-analyses to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. He emphasizes the need to study hyperprogression in well-designed prospective studies.

Existing Data on HPD

HPD was described as "a new pattern of progression" seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited "anecdotal occurrences" of HPD among patients in phase 1 trials of anti–programmed cell death protein–1/programmed cell death–ligand-1 (PD-1/PD-L1) agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti-PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and were reported at the time by Medscape Medical News, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population ― worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

Dr Vivek Subbiah

However, there is little so far to show for those effort, Vivek Subbiah, MD, of MD Anderson Cancer Center, Houston, Texas, said in an interview.

"Many questions remain to be answered," said Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the Division of Cancer Medicine at MD Anderson. He was the senior author of the "Fact, Fiction or Alternative Fact?" commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, note Subbiah and colleagues.

Other "[p]roposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways," notes Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Subbiah said.

The main challenge is defining HPD, he added.

Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3100 patients ranged from 5.9% to 43.1%.

"Hyperprogressive disease could be overestimated or underestimated based on current assessment," Park and colleagues concluded. They highlighted the importance of "establishing uniform and clinically relevant criteria based on currently available evidence."

Steps for Solving the HPD Mystery

"I think we need to come up with consensus criteria for an HPD definition. We need a unified definition," Subbiah agreed. "We also need to design prospective studies to prove or disprove the immunotherapy-HPD association."

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

"We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk," he said. "We also need to know what to do if they are at risk."

Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes "colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful," he said.

Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, "sufficiently quantitative" criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Sehgal said.

"Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this...so that interventions can be brought on earlier," he said in an interview.

"If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD," he said.

Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimates the true incidence of immunotherapy-related HPD will be in the 9% to 10% range.

"This is a substantial number of patients, so it's important that we try to understand this phenomenon, using, again, uniform criteria," he said.

Current Treatment Decision Making

Until more is known, Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

"Is that the only factor that is going to make me choose one thing or another? No...," but it would make him more "proactive in making sure the patient is doing clinically okay" and in determining when to obtain on-treatment imaging studies.

Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

"Immunotherapy has been a game changer, it has been transformative in the lives of these patients," Subbiah said. "So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD."

Trends Cancer. 2020 Mar;6:181-191. Full text

JAMA Netw Open. Published online March 24, 2021. Full text; Commentary

Sharon Worcester is a reporter for MDedge News, part of the Medscape Professional Network.

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