'Contrary' to Wide Belief, Abscopal Effect Is Rare in Cancer

RT Plus Immunotherapy Still Has Potential

Nick Mulcahy

October 07, 2020

There was no evidence of an 'abscopal effect' with the addition of limited radiation therapy to nivolumab (Opdivo) in patients with metastatic head and neck squamous cell carcinoma, according to new results from a randomized trial. 

The phase 2, single-center study was conducted in 62 patients with head and neck cancer and at least two metastatic lesions. They were randomly assigned to receive nivolumab with or without additional radiation, delivered as stereotactic body radiation therapy (SBRT), but directed at only one of the metastatic lesions.

The results showed a similar rate of tumor shrinkage and disappearance in both groups (34.5% for nivolumab vs 29.0% for the combination; P = .86) report Sean McBride, MD, MPH, Memorial Sloan Kettering Cancer Center, New York City, and colleagues in a paper published online in the Journal of Clinical Oncology.

The finding indicates that there was no abscopal effect, the team concludes.

The abscopal (from the Latin ab 'away from' and scopus 'target') effect, first described in the 1950s, is a hypothetical result of radiation, whereby tumors situated outside the radiation field are reduced or eliminated by an assumed reaction mediated by the immune system.

This study is only the second randomized controlled trial to look at this effect. A previous trial in lung cancer (JAMA Oncol. 2019;5:1276) also failed to show a significant difference in objective response rate, the primary outcome.

In both studies, there was also no improvement in progression-free survival (PFS) or overall survival (OS) with the addition of radiation.

It is clear from our data — there is no abscopal response. Dr Nancy Lee

"There are still die-heart proponents of the existence of an abscopal response, but it is clear from our data — there is no abscopal response," lead study author Nancy Lee, MD, told Medscape Medical News.

Lee, also from Memorial Sloan Kettering, was referring to this trial in head and neck cancer, specifically. But previous nonrandomized studies have also reported response rates for the combination of SBRT and immunotherapy that are similar to monotherapy, the authors point out. Overall, the collective data in oncology suggest that the abscopal response is "relatively rare," the team comments.

A more emphatic statement comes from a pair of oncologists writing an accompanying editorial published September 28.

The new study "provides the clearest evidence so far that the abscopal effect, contrary to widely held perception in the field, remains exceedingly rare…" write Tanguy Seiwert, MD, medical oncologist, and Ana Kiess, MD, PhD, radiation oncologist, both at Johns Hopkins University in Baltimore, Maryland.

This is a "well-executed study that has broader implications beyond head and neck cancer and speaks to larger issues of combination therapies in the era of cancer immunotherapy," they also write.

The practice of using limited SBRT on any tumor type — along with anti–PD-1/PD-L1 therapy — "should not be pursued for the sole purpose of induction of an abscopal effect until we have better data to support any benefit," the editorialists add.

It's time to put the abscopal effect to rest, suggested study investigator Lee.

"Instead of focusing on whether an abscopal response exists or not, as it clearly did not in our phase 2 study, our focus should shift to the broader picture. What is the optimal timing of PD-1 or PD-L1 therapy in relation to radiotherapy?" she said.

The answer appears to be sequentially — and not concurrently, which is how radiation has been used to induce the would-be abscopal effect, she explained. "I personally feel that immunotherapy should not be given concurrently with radiation therapy."

Damning data for the concurrent approach come from the phase 3 Javelin Head and Neck 100 trial, she said. In March, trial sponsors announced that the trial was terminated as it was unlikely to meet its primary endpoint. Specifically, adding an anti–PD-L1 therapy to chemoradiotherapy was not superior to chemoradiotherapy alone.

On the other hand, in the phase 3 lung cancer study known as PACIFIC, chemoradiotherapy followed by sequential anti–PD-L1 therapy showed "dramatic" improvements in PFS and OS, point out the editorialists.

Radiation and Immunotherapy Combinations

Despite the failure of this trial, radiation has "significant potential for combination with immunotherapy," observe the editorialists, Seiwert and Kiess.

There are at least three potential roles of radiation therapy in combination with anti–PD-1/PD-L1 therapy, they write.

They explain that the first is single-site palliative radiation therapy/SBRT, which can control local symptoms.

The second is "consolidation" of all tumor sites with radiation therapy/SBRT, which may decrease tumor burden and heterogeneity.

And the third potential role is definitive locoregional radiation therapy to achieve long-term locoregional tumor control.

Thus, the editorialists, like Lee, believe the question of concurrent vs sequential immunotherapy is "important." But the field of oncology has an abundance of treatments that can now be aimed at a cancer, in a variety of potential combinations, they observe.

The editorialists conclude their commentary with a long list of needed work: "We should take this study to guide us to explore promising approaches in rigorous clinical trials, with a focus on sequential approaches such as definitive RT followed by immunotherapy, consolidative SBRT of all tumor sites in combination with immunotherapy, and trials that incorporate surrogate immunotherapy-relevant biomarkers to assess earlier and more efficiently the impact of an intervention."

The study was partly supported by a grant from the National Cancer Institute. Bristol-Myers Squibb provided the study drug and funded tumor staining.

Multiple study authors have financial ties to industry, including two with ties to Bristol-Myers Squibb. The full list can be found with the original article. Both editorialists have ties to industry, including Seiwert's ties to Bristol-Myers Squibb.

J Clin Oncology.  
Study - published online August 21, 2020
Editorial - published online Sept 28, 2020

Nick Mulcahy is an award-winning senior journalist for Medscape. He previously freelanced for HealthDay and MedPageToday and has had bylines in WashingtonPost.com, MSNBC, and Yahoo. Email: nmulcahy@medscape.net and on Twitter: @MulcahyNick

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