TTFields With SOC Induces Clinically Meaningful Survival Results in mNSCLC

Ticiana Leal, MD

In the phase 3 LUNAR trial (NCT02973789), the use of tumor treating fields (TTFields) with standard-of-care (SOC) therapies led to a clinically meaningful 3-month improvement in median overall survival (OS) among patients with metastatic non–small cell lung cancer (NSCLC).^1-2

Data were presented at the 2023 American Society of Clinical Oncology Annual Meeting showed that the trial met its primary end point, reducing the risk for death by 26% (HR, 0.74; 95% CI, 0.56-0.98; P = .035).

“TTFields therapy should be considered part of standard of care for metastatic non–small cell lung cancer following progression after platinum-based chemotherapy,” Ticiana Leal, MD, a researcher and medical oncologist at Winship Cancer Institute of Emory University and associate professor and director of the Thoracic Medical Oncology Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, said during a presentation of the data. “TTFields therapy is a potentially paradigm-shifting new treatment modality.”

Median OS in the intent-to-treat (ITT) population was 13.2 months (95% CI, 10.3-15.5) with TTFields plus SOC, compared with 9.9 months (95% CI, 8.1-11.5) with SOC alone. With the addition of TTFields, 1- and 3-year OS rates were 53% (95% CI, 44%-61%) and 18% (95% CI, 11%-27%), respectively, compared with 42% (95% CI, 34%-60%) and 7% (95% CI, 2%-15%) in the SOC-alone group.

Among patients treated with an immune checkpoint inhibitor, median OS was 18.5 months (95% CI, 10.6-30.3) with the addition of TTFields, compared with 10.6 months (95% CI, 8.2-17.6) with SOC alone, reducing the risk for death by 37% (HR, 0.63; 95% CI, 0.41-0.96; P = .03). Among patients treated with docetaxel, median OS was 11.1 months (95% CI, 8.2-14.1) and 8.9 months (95% CI, 6.5-12.2), respectively, reducing the risk for death by 19% (HR, 0.81; 95% CI, 0.55-1.19; P = .28).

When stratifying patients by histology, those with non-squamous histology demonstrated a median OS of 12.6 months (95% CI, 8.8-19.8) with TTFields, compared with 9.9 months (95% CI, 6.9-16.4) with SOC alone (HR, 0.90; 95% CI, 0.54-1.16; P = .28), while those with squamous histology demonstrated medians of 13.9 months (95% CI, 9.7-17.1) and 10.1 months (95% CI, 8.3-14.3), respectively (HR, 0.67; 95% CI, 0.44-1.01; P = .05).

Median progression-free survival (PFS) with the addition of TTFields was 4.8 months (95% CI, 4.1-5.7), compared with 4.1 months (95% CI, 3.0-4.7) with SOC alone (HR, 0.87; 95% CI, 0.67-1.14).

In the TTFields arm, the overall response rate (ORR) was 20% (95% CI, 14%-28%)–including 3% of patients with a complete response (CR), 18% with a partial response (PR), 49% with stable disease (SD), 18% with progressive disease (PD), and 2% who were not evaluable (NE)–compared with 17% (11%-25%) with SOC alone–which included 1% of patients with a CR, 17% with a PR, 47% with SD, 26% with PD, and 1% who were NE.

Of note, all 5 complete responses occurred in patients receiving an immune checkpoint inhibitor, 4 of which were in the TTFields arm.

Adverse events (AEs) occurred in 97% of the TTFields arm and 91% of the SOC-alone arm. The incidence of TTFields-related AEs was 71%; however, the majority were grade 1 and 2 local skin irritation. Eight patients (6%) reported a grade 3 AE, and there were no grade 4 toxicities and no deaths attributable to TTFields.

The most common any grade AEs in the TTFields arm were dermatitis (43%), musculoskeletal pain (36%), fatigue (28%), anemia (23%), dyspnea (20%), diarrhea (19%), nausea (19%), cough (18%), leukopenia (17%), pneumonia (15%), respiratory tract infection (15%), localized edema (15%), and alopecia (10%).

Most device-related AEs were grade 1-2 dermatitis, which resolved in 87% of cases after a median duration of 3 weeks.

“The results of the LUNAR study are highly encouraging,” Leal said in a press release.2 “The LUNAR trial is the first study in more than 7 years to show a significant improvement in overall survival in metastatic non-small cell lung cancer post-platinum chemotherapy. I am heartened by this progress and the potential of this innovative therapy to help many metastatic lung cancer patients in need of new treatment choices following platinum therapy, without added systemic toxicity.”

Use of TTFields

TTFields are electric fields that exert physical forces on electrically charged intracellular components in dividing cancer cells, which affect and disrupt mitosis. In turn, this leads to aneuploidy and induction of endoplasmic reticulum stress, which includes downstream effects such as immunogenic cell death, triggering a systemic anti-tumor immune response, Leal explained.

“TTFields therapy is a noninvasive anti-cancer treatment modality,” she added, explaining that the electric fields are generated by a portable, at-home medical device and delivered to the tumors through 2 pairs of arrays applied to the chest with local regional delivery.”

Preclinical evidence has supported activity from treatment with TTFields in combination with checkpoint inhibitors and taxanes. In addition, a pilot study demonstrated the safety and feasibility of TTFields therapy with pemetrexed in advanced NSCLC.

Currently, TTField therapy is approved for glioblastoma and malignant pleural mesothelioma.

Unmet Need

Leal highlighted the fact that metastatic NSCLC remains incurable for the most part, and unfortunately, most patients will develop disease progression with a 5-year survival of only 9%.

“There remains a high unmet need for new, effective and well tolerated therapies in the second line and beyond,” she said.

Therefore, Leal and colleagues evaluated the safety and efficacy of TTFields therapy with SOC, compared with SOC alone, in metastatic NSCLC that progressed on or after platinum-based therapy.

In the pivotal, global, randomized phase 3 LUNAR study, 276 patients were randomized 1:1 to receive either TTFields plus SOC–which included investigator’s choice of an immune checkpoint inhibitor or docetaxel–or SOC alone. Patients were followed every 6 weeks and continued on therapy until progression or intolerable toxicities.

To be eligible for the trial, patients had to be 22 years or older, have metastatic NSCLC, progression on or after a platinum-based therapy, and an ECOG performance status of 0-2.

OS served as the primary end point. Secondary end points included OS in the immune checkpoint inhibitor subgroup and OS in the docetaxel-treated subgroup, as well as PFS, ORR, PFS and OS by histology, quality of life, and safety.

Baseline demographics were similar across both study arms. Overall, median age was 64 years (range, 22-86), the majority of patients were male (65%), and had an ECOG performance status of 0-1 (96%).

Data cutoff was November 26, 2022.

“The LUNAR trial results represent tremendous progress for the treatment of metastatic non-small cell lung cancer, and the LUNAR trial demonstrates the broad and versatile potential of TTFields therapy in improving the survival of cancer patients with high unmet needs,” William Doyle, executive chairman of Novocure, said in the release.2 “We are energized by the LUNAR results and are moving forward quickly to make TTFields therapy available to patients with metastatic non-small cell lung cancer.”

References:

1. Leal T, Kotecha R, Ramlau R, et al. Tumor Treating Field (TTFields) therapy with standard of care (SOC) in metastatic non-small cell lung cancer (mNSCLC) following platinum failure: Randomized, phase 3 LUNAR study. J Clin Oncol. 2023;41(17):LBA9005.

2. Novocure News Release. LUNAR Phase 3 Clinical Trial Demonstrates Statistically Significant and Clinically Meaningful Extension in Overall Survival for Patients with Metastatic Non-Small Cell Lung Cancer After Platinum-Based Therapies. Published: June 6, 2023. https://rb.gy/xx0kf. Accessed: June 6, 2023.