Tumor-treating fields extend OS in metastatic NSCLC
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Key takeaways:
- Use of tumor-treating fields improved OS for patients with pretreated metastatic NSCLC.
- The magnitude of benefit appeared greater when combined with immune checkpoint inhibition than docetaxel.
CHICAGO — Tumor-treating fields prolonged survival for patients with metastatic non-small cell lung cancer whose disease progressed on or after platinum therapy, according to results presented at ASCO Annual Meeting.
Researchers observed no exacerbation in systemic toxicities and reported few high-grade device-related toxicities, results of the randomized phase 3 LUNAR study showed.
“The LUNAR study led to statistically significant and clinically meaningful improvement in overall survival, addressing a population of patients with advanced NSCLC in second line and beyond with high unmet need,” Ticiana Leal, MD, director of the thoracic medical oncology program in the department of hematology and medical oncology at Emory University, told Healio.
“Based on the results of LUNAR study, [tumor-treating fields] therapy should be considered as part of standard of care for metastatic NSCLC after progression on/after platinum-based chemotherapy,” Leal added. “This is a potentially paradigm-shifting new treatment modality that provides an effective and well-tolerated treatment strategy for patients in [the second-line setting] and beyond.”
Background and methods
Treatment options are limited for patients with advanced NSCLC and no actionable mutations if their disease progresses on first-line chemoimmunotherapy, Leal said.
Options include docetaxel with or without ramucirumab (Cyramza, Eli Lilly) or checkpoint inhibitors if patients did not receive them in the front-line setting.
“There is a pressing need for patients with advanced NSCLC for new, effective and well-tolerated treatment strategies,” Leal said.
Tumor-treating fields [TTFields (Novocure)] are electric fields that are utilized to exert physical forces to kill cancer cells.
They are delivered by a noninvasive, portable device approved in the United States for treatment of glioblastoma or mesothelioma.
Prior preclinical research in NSCLC showed TTFields improve antitumor immune response through disruption of mitosis and induction of immunogenic cell death, according to study background. They also are synergistic with immune checkpoint inhibitors and taxanes.
Leal and colleagues conducted the LUNAR study to evaluate TTFields in combination with investigator’s choice of docetaxel or immune checkpoint inhibition for patients with previously treated metastatic NSCLC.
The analysis included 276 patients (median age, 64 years; range, 22-86; 65% male) whose disease progressed on or after platinum therapy. The majority (89%) had received one prior line of systemic therapy, and about one-third (31%) received prior immune checkpoint inhibitor therapy.
More than half (56%) had nonsquamous histology, and all patients had ECOG performance status of 2 or less (0 or 1, 96%).
Researchers randomly assigned 137 patients to either immune checkpoint inhibition or docetaxel plus TTFields dosed at 150 kHz, delivered continuously. The other 139 patients received immune checkpoint inhibition or docetaxel alone.
Treatment continued until disease progression or intolerable toxicity.
OS served as the primary endpoint. Secondary endpoints included OS in the subgroups who received immune checkpoint inhibitor therapy or docetaxel, as well as PFS and adverse events.
Results
Minimum follow-up was 12 months.
The addition of TTFields did not significantly extend PFS (median, 4.8 months vs. 4.1 months; HR = 0.85; 95% CI, 0.67-1.11).
However, patients assigned TTFields exhibited a 26% improvement in OS (median, 13.2 months vs. 9.9 months; HR = 0.74; 95% CI, 0.56-0.98). A higher percentage of patients assigned TTFields remained alive at 1 year (53% vs. 42%; P = .04) and 3 years (18% vs. 7%).
“This is the first study that has shown a survival benefit [for] patients with advanced NSCLC in the second-line [setting] and beyond since the approval of docetaxel/ramucirumab back in 2014,” Leal told Healio.
The magnitude of the OS benefit with TTFields appeared greater among patients who received them with immune checkpoint inhibitor therapy than those who received them with docetaxel.
Researchers reported median OS of 18.5 months for those who received TTFields with immune checkpoint inhibitors vs. 10.8 months for those who received immune checkpoint inhibitors alone (HR = 0.63; 95% CI, 0.41-0.96). The addition of TTFields to immune checkpoint inhibitor therapy appeared linked to improved OS at 1 year (60% vs. 46%) and 3 years (27% vs. 9%).
“In the immune checkpoint inhibitor subgroup, there was a striking OS benefit with near-doubling of the median OS, and it is clinically meaningful,” Leal told Healio. “These clinical results are in line with the prior preclinical studies that demonstrated that TTFields with immune checkpoint inhibitors leads to immunogenic cell death and triggers a systemic antitumor immune response.”
Investigators reported median OS of 11.1 months for those who received TTFields with docetaxel vs. 8.7 months for those who received docetaxel alone (HR = 0.81; 95% CI, 0.55-1.19). Results showed numerically higher rates of OS at 1 year (46% vs. 38%) and 3 years (9% vs. 5%) with the addition of TTFields to docetaxel.
Analyses stratified by histology showed numerical improvements in OS with TTFields for patients with nonsquamous disease (median, 12.6 months vs. 9.9 months; HR = 0.8; 95% CI, 0.54-1.16) and squamous disease (median, 13.9 months vs. 10.1 months; HR = 0.67; 95% CI, 0.44-1.01).
Nearly all patients experienced adverse events (97% with TTFields vs. 91% without), and more than half experienced grade 3 or higher adverse events (59% with TTFields vs. 56% without).
Seventy-one percent of patients assigned TTFields experienced adverse events related to the modality. Forty-three percent developed dermatitis, with the majority of cases being grade 1 or grade 2. Dermatitis resolved in 87% of cases, with median duration of 3 weeks, Leal said.
Eight patients (6%) experienced grade 3 adverse events; no grade 4 toxicities and no deaths attributable to TTFields occurred.
Researchers observed no notable differences in health-related quality of life with the addition of TTFields, Leal said.
Additional studies are underway to assess TTFields with current standard-of-care therapy as first-line treatment for metastatic and locally advanced NSCLC, Leal said.
Perspective
Back to TopRebecca Heist, MD, MPH
The changing standard-of-care landscape really poses challenges for clinical trial design.
By 2016, at the time of study start, immune checkpoint inhibition was known to be superior to docetaxel in the second-line setting. By 2018, immune checkpoint inhibition had moved to the first-line treatment setting in lung cancer. We currently do not use immune checkpoint inhibition as was used in this study.
Within the limitations of this study design, LUNAR met its primary endpoint. There was an OS benefit seen, but no difference in response or PFS. We do see OS benefits without a corresponding response or PFS benefit — particularly in immune-oncology studies — but we always have to ask the question whether there was an imbalance and what were the rates of subsequent therapies?
There was an OS benefit with immune checkpoint inhibition but not for docetaxel-treated patients. This is surprising to me, as the proposed mechanism of action of tumor treating fields should have an effect among docetaxel-treated patients as well. There are mechanisms for immune checkpoint inhibition activity that are proposed but, again, immune checkpoint inhibition after platinum doublet is not currently a standard of care.
There is a suggestion of benefit in squamous but not nonsquamous histology, although that was a secondary outcome measure. There is not a clear mechanistic reason why that might be occurring, and it raises questions about whether there were differences in immune checkpoint inhibition or docetaxel treatments by histology. Also, were there differences in the extent of locoregional or distant disease, and might that have had an impact on activity?
So, should tumor treating fields be another modality in treatment? I personally as a clinician would always welcome new modalities to treat lung cancer. Tumor treating fields are noninvasive but they are bulky and I’d be interested to see what the quality-of-life outcomes are. The major caveat for me is the study design does not reflect the current standard of care. The lack of clarity of the mechanism of action does give me pause, and its place in the current treatment paradigm is unclear.
Perspective
Back to Top
The LUNAR study is intriguing because it used a different modality to try to move the needle, and there was good preclinical rationale that using TTF may make tumors more immunogenic.
We desperately need better post-IO treatment options. Given the ever-evolving landscape of standard of care, however, it's hard to design trials.
I applaud the investigators for tackling a huge unmet need in non-biomarker-driven metastatic NSCLC. However, the OS benefit is not practice changing.
The population of patients with metastatic NSCLC (without actionable biomarkers) who have been treated with immunotherapy in the first-line setting is quite high, especially in the United States and countries with a first-line immunotherapy approval. Therefore, it's hard to understand how the study will fit in the second-line treatment paradigm, given patients are no longer IO-naive.
I also am very much looking forward to seeing data on quality of life. I’m curious how patients will feel about wearing this device for a defined period of time. It may translate to clinical benefit but, given there are other regimens available, shared decision-making will be even more critical.
Collapse
Leal T, et al. Abstract LBA9005. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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