Investigators Test Tumor-Treating Fields in Lung Cancer

William Reece, MD

Investigators are attempting to advance the late-stage non—small cell lung cancer (NSCLC) treatment paradigm by combining an emerging antimitotic modality with standard-of-care (SOC) therapies in the phase III LUNAR trial (NCT02973789).

“Surgery, radiation, and chemotherapy have been the mainstays of NSCLC cancer treatment. LUNAR is looking at a novel approach in lung cancer: electrical field therapy,” said William Reece, MD, principal investigator of LUNAR at Overlake Medical Center & Clinics in Bellevue, Washington, where he also serves as associate medical director.

LUNAR will test the safety and efficacy of tumor-treating fields (TTFields) produced by the noninvasive NovoTTF-100L System, developed by Novocure. The wearable, portable, battery operated device delivers low-intensity alternating electric fields to the site of the tumor by means of transducer arrays attached to the skin.^1,2

TTFields therapy inhibits tumor cell division and induces apoptosis in dividing cells, while having no effect on non-dividing cells.³ TTFields’ ability to interrupt mitosis and subsequently stymie tumor cell cytokinesis is critical, because “cancer cells divide more rapidly than normal cells,” Reece said.

Investigators hypothesize that TTFields’ mechanism of action, coupled with the anticancer activity of SOC immune checkpoint inhibitors (ICIs) or docetaxel, may confer greater survival benefit to patients.

Combination therapies offer the potential for synergistic destruction of cancer cells. “We don’t know precisely why that is, but oftentimes one of the therapies will damage a cancer cell, but not fully kill it. The second type of treatment will finish off the cancer cell that’s in the process of dying,” Reece said.

This coaction is what LUNAR investigators hope to see as they push for a new treatment for late-stage NSCLC. Advanced NSCLC is highly lethal and the available agents have limited efficacy; therefore, expanding treatment options is vital to improving patient outcomes in NSCLC.

“Standard therapies for patients with advanced NSCLC have historically resulted in average survivals of about 10 to 12 months,” Reece said. “Although ICIs have added value to the lung cancer armamentarium and have extended survivals close to 2 years, there’s a great need [for effective therapies] because this is one of the most common cancer types,” he added.

Notably, NSCLC accounts for 80% to 85% of all lung cancers. Most patients present with advanced stage III or IV disease.⁴

LUNAR will enroll an estimated 534 patients with inoperable stage IV NSCLC who experienced disease progression before or after completing platinum-based treatment (Figure). Patients will be randomized to receive either continuous TTFields treatment at 150 kilohertz (kHz) with the NovoTTF-100L System along with ICIs or docetaxel, or best SOC with either ICIs or docetaxel.

Figure. TTFields With SOC Therapies in Late-Stage NSCLC: Phase III Lunar Trial

The primary end point will be overall survival (OS) of patients treated with TTFields and either ICIs or docetaxel versus docetaxel or ICIs alone, measured by superiority analysis. Secondary end points include various other OS measures, progression-free survival (PFS), and overall radiological response rate.

Early Studies Show Additive Efficacy

The rationale for LUNAR is largely based on early positive findings from preclinical studies in NSCLC, Reece said. The first clinical trial to test TTFields in NSCLC was a single-arm prospective phase I/II study (NCT00749346) that enrolled 42 patients with inoperable stage IIIb and stage IV disease who progressed after ≥1 prior line of chemotherapy.⁵

More than half of the patients (n = 35) had nonsquamous histology and 7 had squamous histology. Patients received continuous TTFields therapy at 150 kHz for 12 hours a day using the NovoTTF-100L system with concurrent pemetrexed (Alimta).

Treatment with TTFields and pemetrexed demonstrated efficacy without an increase in toxicity and was “well tolerated by all patients,” regardless of histology, investigators said.5 Apart from dermatitis caused by contact with NovoTTF-100L’s transducer arrays, no TTFields-related adverse events were noted.

Although there were no complete remissions, 6 patients (14.6%) had a radiological partial remission and 20 had stable disease (48.8%). The median systemic PFS was 22.2 weeks and the median time to in-field progression was 28 weeks.³

Median PFS and median OS were 22.7 weeks and 12.4 months, respectively, for patients with nonsquamous disease, and 10.3 weeks and 13.8 months for patients with squamous histology.⁵ The 1-year survival rate was 53% and the 2-year survival rate was 27%.

The Broad Applicability of TTFields

The success of TTFields in disease settings other than NSCLC gave LUNAR investigators reason to hypothesize that this method might also improve treatment of NSCLC, according to Reece. “In other cancers, TTFields therapy has been an efficacious new avenue of treatment,” Reece said.

Alternating electric field therapy has been recognized as a survival-extending approach in glioblastoma multiforme (GBM) and is currently a category 1 recommendation for the treatment of patients <70 years of age with newly diagnosed GBM who have a good performance status (PS) in the National Comprehensive Cancer Network guidelines for Central Nervous System Cancers.⁶

In 2011, the FDA approved NovoTTF-100A for the treatment of adult patients with GBM brain tumors following tumor recurrence after chemotherapy.⁷

Electric field therapy has also conferred benefit in malignant pleural mesothelioma. In May 2019, the FDA approved the NovoTTF-100L System in combination with pemetrexed and platinum-based chemotherapy for the frontline treatment of adult patients with unresectable, locally advanced or metastatic malignant pleural mesothelioma; this is the first therapy backed by the FDA for this patient population in more than 15 years.⁸

Clinical investigation of TTFields therapy is robust and extends beyond LUNAR. For example, TTFields are being explored in the ongoing phase III METIS (NCT02831959) study, which is evaluating NovoTTF-100M in 270 patients with advanced NSCLC who have 1 to 10 brain metastases associated with their disease. The modality is also being assessed in other solid tumors.⁹

Earlier this year, the American Association for Cancer Research (AACR) and Novocure collaboratively established new funding initiatives to support further investigation with TTFields.10 The AACR and Novocure plan to extend grants to another set of investigators in 2020.

Findings from the LUNAR trial may add to the growing body of evidence supporting TTFields therapy in oncology.

“We’re excited about this whole new approach to treating patients with cancer,” Reece said. LUNAR is currently enrolling patients in multiple sites across Europe and is also open in the United States and Canada.

References

1. Novo-TTF-100L System—H180002. FDA website. www.fda. gov/medical-devices/recently-approved-devices/novottftm-100l-system-h180002. Published May 2018, 2019. Accessed November 11, 2019.
2. Science of TTFields. Novocuretrial website. novocuretrial.com/ lunar/science-of-TTFields-2/. Accessed November 12, 2019.
3. Pless M, Droege C, von Moos R, et al. A phase I/II trial of Tumor Treating Fields (TTF) therapy in combination with pemetrexed for advanced non—small cell lung cancer. Lung Cancer. 2013;81(3):445-450. doi: 10.1016/j.lungcan.2013.06.025.
4. Giladi M, Weinberg U, Schneiderman RS, et al. Alternating electric f ields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non—small cell lung cancer. Semin Oncol. 2014;41(suppl 6):S35-S41. doi: 10.1053/j.seminoncol2014.09.006.
5. Pless M, Betticher DC, Droege CM, et al. A phase II clinical trial of tumor-treating field (TTF) therapy concomitant to pemetrexed for advanced non—small cell lung cancer (NSCLC). J Clin Oncol. 2017;30(suppl 15; abstr e18012). doi: 10.1200/jco.2012.30.15_ suppl.e18012.
6. NCCN Clinical Practice Guidelines in Oncology. Central Nervous System Cancers, version 3.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/cns. pdf. Published October 18, 2019. Accessed November 13, 2019.
7. FDA approves the NovoTTF-100A system for the treatment of patients with recurrent glioblastoma multiforme (GBM) brain tumors [news release]. Washington, DC: Novocure; April 15, 2011. s21. q4cdn.com/825405078/files/doc_news/2011/novocure-approval-v04-1511.pdf. Accessed November 13, 2019.
8. FDA approves the NovoTTF-100L system in combination with chemotherapy for the treatment of malignant pleural mesothelioma [news release]. St Helier, NJ: Novocure; May 23, 2019. novocure. com/fda-approves-the-novottf-100ltm-system-in-combination-with-chemotherapy-for-the-treatment-of-malignant-pleural-mesothelioma/. Accessed November 11, 2019.
9. Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD. Tumor-treating fields: a fourth modality in cancer treatment. Clin Cancer Res. 2018;24(2):266-275. doi: 10.1158/1078-0432.CCR-17-1117.
10. McLaughlin E. New AACR-Novocure funding initiatives support tumor treating fields research. The American Association for Cancer Research website. blog.aacr.org/new-aacr-novocurefunding-initiatives-support-tumor-treating-fields-research/. Published November 11, 2019. Accessed November 13, 2019.