Synergy of Combination Therapy for NSCLC Brain Metastases?

When treating brain metastases in patients with non–small cell lung cancer (NSCLC), brain radiotherapy has been the standard option. However, a growing body of evidence indicates that immunotherapy can improve outcomes in this patient population and, more notably, that combining radiotherapy and immunotherapy may have a synergistic effect.

Still, questions remain about the appropriate sequence of immunotherapy and radiotherapy, as well as the toxicities associated with using both.

How should oncologists integrate immunotherapy and radiation to treat this patient population?

Here’s what the evidence indicates so far.

Immunotherapy and the Brain

Although the evidence to date is limited, research suggests that some patients with NSCLC and brain metastases respond to immune checkpoint inhibitors.

A 2020 open-label, phase 2 study, for instance, found that pembrolizumab demonstrated activity in brain metastases in about 30% of patients (11 of 37) with untreated or previously treated stable brain metastases who had PD-L1 expression.

A pooled analysis of KEYNOTE-021, -189 and -407 data, published in 2021, showed that pembrolizumab combined with chemotherapy led to a significant overall survival benefit compared with chemotherapy alone — 18.8 months vs 7.6 months — in patients with advanced NSCLC and stable brain metastases.

“We know [immunotherapy] can work in untreated or previously treated but stable brain metastases,” said Anil Tibdewal, MD, of Tata Memorial Hospital in Mumbai, India, in a review of the topic at the recent World Conference on Lung Cancer.

But how does a large molecule, like pembrolizumab, reach the brain?

The blood-brain barrier, which is composed of tightly connected endothelial and mural cells, astrocytes, and basement membranes, allows only small- and medium-sized molecules to cross, which means the ability of large-molecule immune checkpoint inhibitors to cross the blood-brain barrier is “very, very, very limited,” Tibdewal said.

But the brain is not an “immune-privileged” organ, Tibdewal explained. This means the brain is subject to immune responses, and immune checkpoint inhibitors can have an indirect role on the brain. These inhibitors work by prompting T-cell infiltration, which triggers peripheral T cells originating in lymph nodes to migrate into tissues and attack tumor cells in those tissues, including in the brain.

Is There a Synergistic Effect?

A growing body of evidence indicates that combining radiotherapy and immunotherapy has a synergistic effect against brain metastases in patients with NSCLC.

Most studies have explored upfront radiotherapy followed by immunotherapy. Part of the reasoning for providing radiation therapy first is that radiation therapy can disrupt the blood-brain barrier, as can brain metastases themselves, which increases permeability and potentially enhances the effectiveness of immunotherapy. Preclinical studies have also shown that radiotherapy can change the local tumor microenvironment in ways that can prime it for immunotherapy.

A Japanese study found that overall survival outcomes in the first-line setting in patients with NSCLC and brain metastases significantly improved with upfront radiotherapy followed by an immune checkpoint inhibitor vs the immune checkpoint inhibitor alone — a median of 24.7 months vs 7.9 months (hazard ratio [HR], 0.45).

A systematic review and meta-analysis of 19 studies comparing brain radiotherapy plus immune checkpoint inhibitors with brain radiotherapy alone in patients with NSCLC found an overall survival benefit in the combination arm (HR, 0.77) and similar rates of grade 3 or 4 neurologic adverse events (risk ratio, 0.91; 95% CI, 0.41-2.02; P = .809).

Can immunotherapy come before radiotherapy as well?

Multiple studies suggest that outcomes don’t differ much based on sequencing as long as both treatments are given, Tibdewal said.

However, Tibdewal noted that giving them concurrently appears to provide the best outcomes overall.

One study demonstrated improved survival when delivering immune checkpoint inhibitors and stereotactic radiosurgery-stereotactic radiation therapy concurrently vs before (HR, 3.82) or after (HR, 2.64) immune checkpoint inhibitors. The study also found a lower incidence of new brain metastases and no increased toxicity with concurrent therapy.

Another study demonstrated better response rates and durability, as well as improved overall survival, when both were given concurrently instead of delivering immunotherapy first.

Combining radiotherapy and immunotherapy did not appear to markedly affect patients’ risk for treatment-related toxicity. The lesion-specific 12-month cumulative incidence of radiographic radiation necrosis was 3.5% in the combination arm vs 3.2% in the immune checkpoint inhibitor–first arm.

Although combining the two approaches is generally safe, radiation necrosis can be a concern, Tibdewal said.

“We also know that steroid use for the management of brain metastases or for the management of radiation necrosis can negatively impact the overall survival, so we need to be very careful and watchful as far as radiation necrosis is concerned,” he said.

In terms of optimal radiotherapy approach and dose, stereotactic radiosurgery and radiotherapy both show improved outcomes but data are limited for whole brain radiotherapy, and evidence shows that any single dose above 4 Gy is acceptable for extracranial radiation “as far as the synergistic effect of radiation therapy and immune checkpoint inhibitors,” Tibdewal noted.

Overall, it appears that combining immunotherapy and radiotherapy in patients with NSCLC and brain metastases is the best approach, but randomized controlled trials in this space are still needed, Tibdewal said.

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape Medical News, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X: @SW_MedReporter.