Combining Drugs, Radiation Is ‘Practice-Changing’ for Some Lung Cancer Subsets

Research is showing that combining radiation with targeted therapies and/or immunotherapies could be beneficial for patients with lung cancer, although ongoing studies are still determining what the best way to combine these treatment methods are, explained Dr. Percy Lee.

Lee is the medical director of Orange County Radiation Oncology, City of Hope National Medical Center. In the recent CURE® Educated Patient® Lung Cancer Summit, he discussed optimal strategies to combine targeted and immunotherapy with radiation in lung cancer.

As systemic (drug-based) treatments have become better and more personalized in recent decades, Lee said that localized therapy — meaning treatments like radiation administered directly to the site of the cancer — can play a role in ensuring better long-term outcomes.

“With increased efficacy of drug-based therapies in the past two decades, we realize that local therapy is even more important to prevent complications and reduce disease burden, and more importantly, to reduce the risk of developing clones of cells that may be resistant to future current or systemic therapy by getting rid of them with local therapy such as radiation or surgery,” Lee said in his presentation.

Radiation Plus TKI Therapies

Lee cited data from the SINDAS trial, which compared results of patients with oligometastatic (disease that has spread to distant parts of the body) non-small cell lung cancer who received either a tyrosine kinase inhibitor (TKI) drug alone or a TKI with radiotherapy. Of note, a TKI is a type of cancer drug that blocks specific enzymes, called tyrosine kinases, that are involved in the growth of cancer.

Findings showed that patients in the radiotherapy group tended to live longer without their disease worsening — a statistic known as progression-free survival (PFS) — compared with those who received a TKI alone. Specifically, the average PFS was 20.2 months in the TKI/radiotherapy group and 12.5 months in the TKI-only group.

Adding radiation therapy also seemed to improve overall survival (OS; time from treatment until death of any cause). Average OS was 25.5 months and 17.4 months in the radiotherapy and TKI-only groups.

More recently, findings from the phase 3 LAURA trial, which were presented at the 2024 ASCO Annual Meeting in early June 2024 showed that the TKI drug, Tagrisso (osimertinib), when given after standard chemoradiotherapy, reduced the risk of disease progression or death by 84% compared to post-chemoradiotherapy placebo in patients with locally advanced unresectable stage 3 EGFR-mutant non-small cell lung cancer (NSCLC).

“In this patient population, the goal is ideally cure, but many patients, unfortunately, are not cured from chemotherapy and radiation,” Lee said. “This [data from the LAURA trial] is certainly practice-changing.”

Radiation Plus Checkpoint Inhibitors

Researchers are also investigating the use of immune checkpoint inhibitors with radiotherapy. The ongoing phase 3 LONESTAR trial is investigating Opdivo (nivolumab) plus Yervoy (ipilimumab) in patients with stage 4 NSCLC.

All patients on the trial will be given 12 weeks of treatment with the immunotherapy duo. Then, those who do not experience progressive disease were randomly assigned to one of two groups. The first group continues Opdivo plus Yervoy for up to two years, while the second group undergoes radiotherapy followed by Opdivo and Yervoy for up to two years.

“We’ll know more as this study accrual is complete, whether there are subsets of these patients [who] would benefit from the treatment,” Lee said.

The phase 3 PACIFIC trial has already shown the benefit of a checkpoint inhibitor, Imfinzi (durvalumab) given after chemoradiotherapy in patients with unresectable stage 3 NSCLC. Findings showed that in the Imfinzi group, the median PFS was 16.9 months, compared with 5.6 months in the placebo group.

“This has become the standard of care, but not all patients would benefit from this regimen if they have a mutation-driven cancer,” Lee said.

Lee explained that ablative (tumor-destroying) therapies may enhance the efficacy of drugs that work by activating the patient’s immune system to find and fight cancer.

“We do know that ablative treatment like radiation or other types of ablation potentially can enhance the immune system by releasing antigens, therefore educating the immune system what the foreign cancer cells might look like” Lee explained. Of note, an antigen is something that the body sees as foreign, thereby stimulating an immune response.

Sequencing Systemic Therapies and Radiation

While radiation may boost the immune system, the treatment is a “double-edged sword,” highlighting the need to figure out what the best order of therapy is, according to Lee.

“We know that radiation can increase antigen presentation and potentially stimulate the immune system and can modulate the effectiveness of anti-PD—1 therapy,” he said. “But it also has intrinsic or immunosuppressive effects. T (immune) cells are very sensitive to radiation, so if you were to radiate large fields of radiation or give it with chemotherapy, that could potentially blunt the effect of immunotherapy.”

This is an ongoing field of research.

Lee cited the KEYNOTE-001 study, which evaluated Keytruda after radiotherapy in patients with stage 4 NSCLC. He said that it was not clear if the combination led to more side effects.

“We’re happy to report that it appears that when patients have prior Keytruda before starting Keytruda in this setting, they appear to have a longer [PFS] and [OS] in these cohorts,” Lee said.

As researchers continue to investigate the combination of systemic cancer therapy and radiation, it’s likely that there will not be one perfect method that will work for everyone, according to Lee.

“In some lung cancer patients — and other cancer types — we've realized over the last few decades that there is not one size fits all,” he said.

Editor's note: This program was made possible with support from Daiichi Sankyo Inc.

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