Tumor treating fields (TTF) therapy in combination with immune checkpoint inhibition improved overall survival in the pretreated, primarily immunotherapy-naive setting in metastatic non–small cell lung cancer (NSCLC), according to findings from the phase III LUNAR study. These results were discussed by Christine M. Bestvina, MD, Assistant Professor and Director of Clinical Operations for the Thoracic Oncology Program at the University of Chicago, at the 2023 Best of ASCO Seattle.¹ However, she warned, treatment sequencing from this trial does not reflect the current standard of care, so this modality for metastatic NSCLC is “not yet ready for prime time.”

Christine M. Bestvina, MD

Metastatic NSCLC presents a significant challenge in clinical oncology, particularly since most of these patients will eventually stop responding to immunotherapy. This reality has prompted research into novel mechanisms to improve outcomes. The LUNAR study investigated the potential of TTF therapy in combination with standard-of-care treatments (either immune checkpoint inhibitors or docetaxel) after disease progression on platinum chemotherapy.

What Is TTF Therapy?

TTF therapy is a noninvasive anticancer treatment modality delivered locoregionally to the chest by a wearable medical device and two pairs of arrays (adhesive bandages with biocompatible insulated ceramic disks covered by hydrogel). Tumor treating fields are electric fields that exert physical forces on electrically charged components in dividing cancer cells, leading to an antimitotic effect. The downstream effects of tumor treating fields include cell stress–induced immunogenic cell death, triggering a systemic antitumor immune response.

This modality is approved by the U.S. Food and Drug Administration (FDA) for the treatment of glioblastoma and malignant pleural mesothelioma. A pilot study previously demonstrated the safety and feasibility of TTF therapy with pemetrexed in advanced NSCLC.

LUNAR Trial Details

Key eligibility criteria for enrollment in the LUNAR study included disease progression on or after platinum-based therapy. “Of note, prior immunotherapy was not required [for enrollment in the trial],” said Dr. Bestvina. “This is due to the fact that, when this clinical trial was designed, immunotherapy was not yet standard in the front-line setting for patients who had wild-type disease.”

Patients were randomly assigned to either TTF therapy with the standard of care (investigator’s choice of immune checkpoint inhibitor monotherapy or docetaxel) or the standard of care alone. The study’s primary endpoint was overall survival. PD-L1 status was unknown in almost 50% of patients; 90% had one prior line of therapy, and 10% had two or more lines of therapy.

“A total of 30% of patients had prior immune checkpoint inhibitor exposure, and almost all of them were in the docetaxel arm. This means that almost all patients who received immunotherapy plus TTF were immunotherapy-naive,” she pointed out.

Primary Endpoint Met

Median overall survival was 13.2 months with TTF therapy vs 9.9 months with the standard of care, with a statistically significant hazard ratio of 0.74. The survival benefit was highest in patients treated with TTF therapy and immunotherapy. Here, median overall survival was 18.5 months vs 10.8 months in patients treated with immune checkpoint inhibitor therapy alone, with a hazard ratio of 0.63.

“Again, the majority of these patients were naive to immune checkpoint inhibitors,” Dr. Bestvina emphasized.

Patients treated with TTF therapy and docetaxel did not see as great a magnitude of benefit. Median overall survival was 11.1 months vs 8.7 months in the docetaxel-alone group, with a hazard ratio that did not meet statistical significance (0.8).

“Of note, progression-free survival and response rate were not improved with the addition of tumor treating fields,” reported Dr. Bestvina. “This is another trial that confirms immunotherapy-based clinical trials should be using overall survival as the primary endpoint, so we don’t miss some of these signals.”

Safety and Tolerability

The primary side effect associated with TTF therapy was dermatitis, which was reported in 43% of those given TTF therapy plus the standard of care. However, 2% had grade ≥ 3 dermatitis, and it resolved with removal of the device.

Overall, patients found the TTF device to be tolerable, noted Dr. Bestvina. Median device usage was 15 weeks when combined with immunotherapy and 13 weeks with docetaxel.

What Next?

Although the LUNAR study met its primary endpoint of overall survival, its limitations should also be considered, commented Dr. Bestvina. The trial did not reflect the current standard of care, as many patients without actionable alterations now receive immune checkpoint inhibitors as first-line treatment. “These study patients were in the second line, and the majority were immunotherapy-naive in the immunotherapy arm,” she noted.

To better integrate TTF therapy into the current standard of care, future trials should explore front-line immune checkpoint inhibition plus TTF therapy or second-line immune checkpoint inhibition plus TTF therapy in an immunotherapy-exposed population.

According to Dr. Bestvina, despite the potential of this novel therapy, further research is needed to refine treatment sequencing and fully establish its role in the evolving landscape of metastatic NSCLC treatment. 

DISCLOSURE: Dr. Bestvina has served as a consultant for AstraZeneca, BMS, CVS, Daiichi Sankyo, Genetech, Jazz, JNJ, Novartis, Novocure, Pfizer, Regeron, Sanofi, Seattle Genetics, Takeda, and Tempus; has received research funding from AstraZeneca and BMS; and has served on the speakers bureau for Merck.

REFERENCE

1. Bestvina CM: Tumor treating fields therapy with standard of care in metastatic non–small cell lung cancer following platinum failure: Randomized, phase 3 LUNAR study. 2023 Best of ASCO Seattle. Abstract LBA9005. Presented July 21, 2023.