CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 18, 2023
Expiration: August 17, 2024
Introduction
In this module, Ditte Primdahl, MD, presents recent clinical data on tumor-treating fields (TTFields) technology for the treatment of multiple types of solid tumors. She discusses TTFields technology, including pivotal clinical studies that led to the approval of TTFields for glioblastoma multiforme (GBM) and malignant pleural mesothelioma (MPM). Dr. Primdahl also discusses ongoing trials looking at TTFields therapy in combination with chemotherapy, chemoradiation, or immunotherapy in other solid tumor types.
Please note that the key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slidesets, which can be found by clicking any of the slide thumbnails in the module alongside the expert commentary.
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TTFields: Mechanism of Action
TTFields devices work by applying alternating current electrical fields with low intensity (1-3 V/cm) and intermediate frequency, resulting in cellular stress that disrupts cancer cell growth with no systemic toxicity.1,2 The frequency of the electric field (100-300 Hz) used depends on the tumor type, and tumor cell division is disrupted through interaction of the electrical field with key molecules during multiple phases of mitosis.3,4
The electrical fields administered by TTFields exert a bidirectional force on intercellular elements such as tubulin and septin molecules. This force leads to atypical microtubule polymerization and cleavage furrow formation during cell division, and ultimately leads to disintegration of dividing cells.5,6
One study proposed a theoretical mechanism of action where TTFields leads to a change in cell membrane potential, causing an influx of calcium ions and subsequent abnormal spindle formation and apoptosis.7
Of importance, with TTField therapy only rapidly dividing cells are affected, leaving quiescent cells intact. Also, the intensity of the electrical fields is too low to have clinically relevant thermal or ionizing effects, so they do not cause DNA damage.2
Pilot Studies With TTFields in GBM
In preclinical tests, TTFields significantly reduced tumor size in mouse models1 and greatly increased the sensitivity of cultured human cancer cells to chemotherapy.8
A clinical pilot study looked at TTFields as salvage therapy in 10 patients with recurrent GBM.3 The median time to disease progression (TTP) was 26.1 weeks and the median OS was 62.2 weeks. The reported median TTP and OS from this pilot study were more than double the reported medians of historical controls.9
In another clinical pilot study, TTFields treatment was administered to 20 patients with GBM. Ten patients with recurrent GBM received TTFields as salvage therapy. Another 10 patients with newly diagnosed GBM received TTFields in combination with maintenance TMZ following surgery, RT, and adjuvant TMZ.8 For patients with newly diagnosed GBM, the addition of TTFields to maintenance TMZ did not increase treatment-related toxicity, but improved median PFS (155 vs 31 weeks) and median OS (>39 vs 14.7 months) compared with matched historical control patients receiving maintenance TMZ alone.
Patients in both of these pilot studies received an average of 1 year of continuous TTFields therapy, with no device-related serious adverse events (AEs), although 90% experienced mild to moderate contact dermatitis.3,8
Based on these promising results, larger clinical trials were initiated to explore the efficacy and safety of TTFields for the treatment of GBM.
EF-11: TTFields vs SoC in Recurrent GBM
In the open-label phase III EF‑11 trial, 237 patients with recurrent GBM were randomized 1:1 to receive TTFields monotherapy or physician’s choice of best SoC.10 The patient population in EF-11 was a heavily pretreated patient population, with a median of 2 prior therapies for enrolled patients (12% first recurrence, 47% second recurrence, 41% third recurrence or greater).
The primary endpoint for the study was OS, with secondary endpoints including 6-month PFS rate, median TTP, 1-year survival rate, radiologic response, safety, and quality of life (QoL).
EF-11: Efficacy and Safety
Most (93%) of the patients had died at a median follow-up of 39 months.10 The median OS (6.6 vs 6.0 months for the TTFields arm vs the SoC arm; HR: 0.86; 95% CI: 0.66-1.12; P = .27) and 6-month PFS (21.4% vs 15.1% for the TTFields arm vs the SoC arm; P = .13) were similar between the treatment arms. The objective response rate (ORR) was numerically higher (14.0% vs 9.6%; P = .19) with TTFields vs SoC.
Of importance, TTFields was better tolerated when compared with SoC chemotherapy. There were significantly more treatment-related AEs in patients treated with SoC chemotherapy, including gastrointestinal and hematological toxicities. Mild to moderate contact dermatitis occurred in 16% of patients treated with TTFields, and could be managed with topical corticosteroids. Dermatitis resolved completely after treatment cessation. At ≥3 months after treatment, a QoL analysis favored TTFields therapy in most domains including cognitive and emotional functioning.
Based on the results of the EF-11 trial, TTFields (NovoTTF-100A system) was approved for the treatment of recurrent GBM, following histologically or radiologically confirmed recurrence in the supratentorial region of the brain after receiving chemotherapy.11 The device is intended to be used as a monotherapy for adult patients (≥22 years of age) with histologically confirmed GBM as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.
EF-14: TTFields Plus Adjuvant TMZ vs Adjuvant TMZ Alone in Newly Diagnosed GBM
For patients younger than 70 years with good performing status, a first-line SoC for newly diagnosed GBM is 6 weeks of concurrent TMZ with RT, followed by adjuvant TMZ, based on a randomized phase III trial from 2005.12
The open-label phase III EF-14 trial evaluated the addition of TTFields to this regimen.13 In this trial, 695 patients with newly diagnosed GBM were randomized 2:1 to receive TTFields plus adjuvant TMZ or adjuvant TMZ alone. Participants received standard RT and concurrent TMZ before randomization.
The primary endpoint was PFS, with a secondary endpoint of OS.
Efficacy and Safety
At the final analysis (median follow-up: 40 months; minimum follow-up: 24 months), the addition of TTFields to adjuvant TMZ significantly improved both median PFS (6.7 vs 4.0 months; HR: 0.63; 95% CI: 0.52-0.76; P <.001) and median OS (20.9 vs 16.0 months; HR: 0.63; 95% CI: 0.53-0.76; P <.001) compared with adjuvant TMZ alone.13
The addition of TTFields to adjuvant TMZ did not significantly increase systemic AEs (48% vs 44%; P = .58). There was a higher incidence of localized skin toxicity (at site of the medical device) in patients treated with TTFields (mild to moderate skin irritation in 52% of patients; severe [grade 3] in 2%).
Based on the results of the EF-14 trial, TTFields (NovoTTF-100A system) with TMZ was approved for the treatment of adult patients with newly diagnosed, supratentorial GBM following maximal debulking surgery and completion of RT together with concomitant SoC chemotherapy.11
STELLAR: TTFields Plus Pemetrexed Plus Platinum Chemotherapy for Untreated, Unresectable Metastatic MPM
The multicenter, prospective, single-arm phase II STELLAR trial looked at TTFields plus pemetrexed and platinum-based chemotherapy in 80 patients with untreated, unresectable locally advanced or metastatic MPM.14 Patients received continuous TTFields and concurrent IV pemetrexed plus IV platinum chemotherapy (carboplatin or cisplatin) every 21 days for up to 6 cycles. TTFields was continued as a maintenance therapy until progression, unacceptable toxicity, or decision to halt treatment.
The primary endpoint was OS, with secondary endpoints including PFS, ORR, and safety.
STELLAR: Efficacy and Safety
The median OS was 18.2 months (95% CI: 12.1-25.8), which was longer than the matched historical controls treated with pemetrexed plus cisplatin (12.1 months).14,15 The median PFS in the STELLAR trial was 7.6 months (95% CI: 6.7-8.6).14 The most common grade ≥3 AEs included anemia (11% of patients), neutropenia (9%), and thrombocytopenia (5%). The only AE associated with TTFields treatment was skin reaction (any grade: 71%; grade 3: 5%), and there were no treatment-related deaths on this trial.
Based on these findings, TTFields (NovoTTF-100L system) was approved for the treatment of adult patients with unresectable, locally advanced or metastatic MPM to be used concurrently with pemetrexed and platinum-based chemotherapy.16
Rationale for Combination Therapy With TTFields
Since the earliest trials, researchers have continued to study how TTFields therapy works at the cellular level, and this research has informed the new approaches and combinations that are currently in clinical trials.
TTFields seem to have more mechanisms of action than first assumed. TTFields help downregulate the Fanconi-Anemia-BRCA DNA repair pathway, likely inducing increased sensitivity of tumor cells to RT and chemotherapy.17,18 In addition, TTFields may enhance antitumor immunity, inducing immunogenic cell death and enhancing the effect of immunotherapy.19 Finally, TTFields also weaken tight junctions between the endothelial cells that make up the blood–brain barrier, allowing anticancer drugs to pass through more easily and increasing local drug concentrations.20
Further translational data are suggestive of a synergistic effect for the combination of TTFields with other treatment modalities. The addition of TTFields enhanced the treatment efficacy of chemotherapy (pemetrexed, cisplatin, or paclitaxel), both in vitro and in animal models.21 The combination of TTFields with sorafenib (tyrosine kinase inhibitor) significantly inhibited xenograft tumor growth and led to a greater reduction of in vivo STAT3 expression compared with monotherapy by either agent.22 Synergistic effects have also been seen in vitro when TTFields was combined with cisplatin, or the combination of TTFields plus a PARP inhibitor, with or without subsequent RT.23
These data support the investigation of TTFields in combination with other therapies including chemotherapy with or without RT and immunotherapies for the management of solid tumors.
HEPANOVA: TTFields Plus Sorafenib in Unresectable Advanced HCC
We will begin by looking at data for the combination of TTFields with a tyrosine kinase inhibitor, sorafenib, in hepatocellular carcinoma (HCC). Preclinical data showed a synergistic effect with TTFields in combination with sorafenib, reducing colony formation and inducing apoptosis and autophagy in human HCC cell lines.24 In a rat model of HCC, treatment with TTFields plus sorafenib resulted in a significantly smaller increase in tumor volume (1.6-fold vs 5.9-fold; P <.0001) compared with the untreated controls.
Subsequently, the single-arm phase II HEPANOVA trial evaluated the safety and efficacy of TTFields delivered with the NovoTTF-100L(P) system plus sorafenib in 27 patients with unresectable advanced HCC.25 The primary endpoint was ORR, with key secondary endpoints including 1-year in-field control rate, distant metastases-free survival, OS, PFS, and safety.
HEPANOVA: Efficacy
The 21 evaluable patients treated with TTFields plus sorafenib had a numerically higher ORR (9.5% vs 4.5%; P = .24) compared with historical controls treated with sorafenib alone. Patients who received ≥12 weeks of TTFields plus sorafenib (n = 11) had an even better ORR (18%). The combination therapy was well tolerated, and 70% of all patients had grade 1/2 TTFields-related skin AEs.
LUNAR: TTFields Plus SoC in Metastatic NSCLC
Now we go over some exciting data on the use of TTFields in non-small-cell lung cancer (NSCLC).
A pilot phase I/II study demonstrated the safety and feasibility of TTFields in combination with pemetrexed for the treatment of advanced NSCLC.26
At the 2023 American Society of Clinical Oncology meeting, we saw the reports of a later-phase trial evaluating TTFields combination therapy in NSCLC. The randomized phase III LUNAR trial tested TTFields (NovoTTF-200T device) in combination with SoC therapy vs SoC alone in 276 adult patients with metastatic NSCLC who had progressed on previous platinum-based chemotherapy.27 SoC was defined as investigator’s choice of docetaxel or immune checkpoint inhibitor (ICI) (pembrolizumab, atezolizumab, or nivolumab). Patients who had received prior ICI therapy were permitted in the study. The primary endpoint was OS, with secondary endpoints including OS by SoC subgroup (ICI vs chemotherapy), PFS, ORR, QoL, safety, and PFS/OS by histology.
LUNAR: Overall Survival in ITT Population
The LUNAR trial met its primary endpoint, with a significant improvement in median OS (13.2 vs 9.9 months; HR: 0.74; 95% CI: 0.56-0.98; P = .035) for TTFields plus SoC vs SoC alone.27 In the TTFields arm, 1-year and 3‑year OS rates were 53% and 18%, respectively, compared with 42% and 7% in the SoC-alone group.
LUNAR: OS by SoC Subgroup
The type of SoC received greatly affected the outcome; patients who received ICI therapy as SoC along with TTFields had a significantly improved median OS (18.5 vs 10.8 months; HR: 0.63; 95% CI: 0.41-0.96; P = .03) compared with SoC alone. I think it's important to highlight that this is a 37% reduction in the risk of death in the ICI group. For patients who received TTFields plus docetaxel as SoC, there was a 19% reduction in the risk of death. However, the difference in median OS was not significant when comparing TTFields plus docetaxel vs docetaxel alone (11.1 vs 8.7 months, respectively; HR: 0.81; 95% CI: 0.55-1.19; P = .28).27 These results highlight the possible synergistic effect in immune response when TTFields are combined with an immunotherapy.
LUNAR: Safety
In the LUNAR trial, toxicity was minimal in the intervention group, with dermatitis being the most frequent TTFields-related AE (any grade: 43% of patients; grade ≥3: 2%); 87% of dermatitis cases were resolved, with a median duration of 3 weeks.27 The median device usage was similar among patients receiving ICI or docetaxel (15 vs 13 weeks). There were no grade 4 adverse device effects and no deaths because of TTFields.
2-THE-TOP: TTFields Plus Pembrolizumab and Maintenance TMZ in Newly Diagnosed GBM
The phase II 2‑THE‑TOP trial looked at the addition of TTFields and pembrolizumab (ICI) to TMZ maintenance following maximal debulking surgery and the completion of RT with concomitant TMZ in 26 patients with newly diagnosed GBM.28 TTFields was started at cycle 1 of adjuvant TMZ, with pembrolizumab added at cycle 2. The primary endpoint was improved PFS compared with case-matched historical controls, with secondary endpoints including OS, toxicity, and tolerability.
2-THE-TOP: Efficacy and Safety
At final analysis, the addition of TTFields and pembrolizumab to maintenance TMZ resulted in a significantly prolonged median PFS compared with case-matched controls (12.0 vs 5.8 months; HR: 0.377; 95% CI: 0.217-0.653; log rank P = .003). There was also a numerical improvement in 12-month PFS (50.0% vs 28.2%; P = .058) compared with controls. An OS benefit over controls was seen, with a median OS of 24.8 vs 14.6 months (HR: 0.522; 95% CI: 0.301-0.905; P = .048) and a 2-year OS (52.4% vs 12.0%; P = .004), compared with the historical controls.28
Furthermore, robust T-cell activation by TTFields was confirmed by molecular analyses before the start of pembrolizumab therapy.
As a follow-up, a double-blinded, placebo-controlled phase III clinical trial (EF-41/Keynote D58) that will look at TTFields plus TMZ with or without pembrolizumab in patients with newly diagnosed GBM has been announced. However, this trial has not begun enrolling.
TRIDENT: TTFields Plus RT Plus TMZ for Newly Diagnosed GBM
TTFields therapy is also being investigated as a first-line treatment for GBM, rather than in the adjuvant phase. The randomized phase III TRIDENT trial (NCT04471844) is evaluating the addition of TTFields therapy to frontline SoC in adult patients with newly diagnosed GBM.29 The planned enrollment is 950 patients, who will be randomized 1:1 to receive concomitant RT and TMZ with or without continuous TTFields therapy. After this initial therapy, both treatment arms will go on to receive TMZ maintenance with continuous TTFields therapy until the first disease progression. After first progression, TTFields therapy will be given in combination with second-line therapy, surgery, stereotactic radiosurgery, or a combination of these.
The primary endpoint is OS, with secondary endpoints including PFS, 1-year and 2-year OS, ORR, safety, QoL, and 6-month and 12-month PFS rates.
TTFields Plus Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma
TTFields are also being tested in pancreatic adenocarcinoma. The phase II PANOVA trial showed the safety and tolerability of TTFields in combination with chemotherapy (gemcitabine or gemcitabine plus nab-paclitaxel) in patients with newly diagnosed, locally advanced or metastatic pancreatic adenocarcinoma.30
The prospective, randomized phase III PANOVA-3 study (NCT03377491) is investigating the efficacy and safety of TTFields (NovoTTF-200T device) plus gemcitabine and nab-paclitaxel in patients with locally advanced pancreatic adenocarcinoma, with a planned enrollment of 556 patients.31 The primary endpoint is OS, with key secondary endpoints including PFS, ORR, 1-year survival rate, QoL, pain‑free survival, puncture‑free survival, resectability rate, and toxicity.
INNOVATE‑3: TTFields Plus Weekly Paclitaxel for Recurrent, Platinum-Resistant Ovarian Carcinoma
The single-arm phase II INNOVATE trial showed the safety of TTFields in combination with weekly paclitaxel in 31 patients with recurrent, platinum‑resistant ovarian carcinoma.32
Currently, the prospective, randomized phase III INNOVATE-3 trial (NCT03940196) is looking at TTFields (NovoTTF-100L[O] device) plus weekly paclitaxel in the same patient population.33 Eligible patients can have a maximum of 5 prior lines of systemic therapy, with no more than 2 lines following a diagnosis of platinum resistance. The primary endpoint for INNOVATE-3 is OS, with main secondary endpoints including PFS, ORR, safety, and QoL.
Practical Considerations for TTFields: Use of the Device
When used for GBM, the portable TTFields device weighs approximately 1.2 kg, and treatment involves using adhesive patches called transducer arrays on the shaved scalp.34 Thus, having a good home support system is important with TTFields because the patient will often need help with scalp shaving and array placements. Transducer arrays should be changed approximately 2 times per week (maximum every 4 days), and loose‑knit wigs, hats, and other head coverings can be worn over the arrays.35
In a post-hoc analysis of the EF-11 trial, a significantly higher median OS (7.7 vs 4.5 months; P = .0447) was seen in patients who wore the device for ≥75% of the time on average (≥18 hours/day) compared with those who wore it for less time.36 Similarly, in a subgroup analysis of the EF-14 trial, extended OS and PFS were noted with increased compliance beyond 50%.37 For this reason, we emphasize to patients and caregivers the importance of skin care and management of skin AEs to avoid treatment limitations.
There is no evidence that using TTFields for longer than 2 years will provide clinical benefit.
Practical Considerations for TTFields: QoL
As healthcare professionals, we desire not only to improve survival but also to maximize the QoL of our patients. This is a very important endpoint when we discuss potential treatment options with them.
QoL was included as a secondary endpoint in the phase III EF‑11 trial (TTFields vs best SoC in recurrent GBM); cognitive and emotional functioning and role functioning favored TTFields, whereas patients treated with chemotherapy reported increased pain and fatigue.10
In the phase III EF-14 trial (TTFields plus TMZ vs TMZ alone in newly diagnosed GBM), QoL was evaluated in EF‑14 as an exploratory endpoint and was not negatively influenced by the addition of TTFields therapy except for itchy skin, which was higher in the TTFields arm.38 Patients treated with TTFields had significantly improved deterioration‑free survival for global health (4.8 vs 3.3 months; P <.01), pain (5.6 vs 3.6 months; P <.01), leg weakness (5.6 vs 3.9 months; P <.01), and physical (5.1 vs 3.7 months; P <.01) and emotional functioning (5.3 vs 3.9 months; P <.01), likely related to the longer PFS observed. Time to 6-point decline in Mini-Mental State Exam score was significantly longer in patients receiving TTFields in addition to TMZ (16.7 vs 14.2 months; HR: 0.79; 95% CI: 0.66-0.95; P = .01) compared with those receiving TMZ alone.13 Similarly, the time to 10-point decline in Karnofsky performance score was significantly longer in patients receiving TTFields plus TMZ (5.5 vs 3.9 months; HR: 0.80; 95% CI: 0.67-0.95; P = .009) compared with those receiving TMZ alone.
Practical Considerations for TTFields: Toxicity
Toxicity is obviously another very important aspect to keep in mind and to discuss with our patients. The predominant AEs associated with TTFields are dermatologic, with a pooled prevalence of approximately 38.4%.39 Only 2 studies have reported severe (grade ≥3) dermatologic AEs, which include dermatitis, ulcers, and skin infection. In the phase III EF-14 trial, 2% of patients treated with TTFields had grade 3 skin AEs,13 and a global postmarketing safety surveillance reported severe device-related skin reactions in <1% of patients receiving TTFields.40 No overlapping toxicity has been found in combination with chemotherapy, and all the toxicity seen with TTFields is local, with no systemic-related toxicities observed to date.
Preventing Dermatologic AEs Associated With TTFields
The dermatologic toxicity associated with TTFields therapy can potentially limit the duration of treatment and thereby the prognosis. Thus, it is important to help guide patients and caregivers through the prevention of such dermatologic toxicity. Here is a treatment algorithm for the prevention and management of dermatologic AEs with TTFields that is very useful to share with patients and caregivers.
In brief, patients should be assessed for risk factors of determining dermatologic AEs including allergies to hydrogels, pre-existing skin conditions, previous exposure to radiation, and concomitant systemic therapies.35
Skin care is important for the prevention of skin toxicity. Changing arrays twice weekly and shifting the arrays by approximately 2 cm at each change can help.35
Managing Dermatologic AEs Associated With TTFields
Early discovery of any toxicity is important, and symptomatic skin management can help patients maximize their usage of TTFields, optimizing the therapeutic benefit while maintaining a good QoL. Management strategies include the use of topical aluminum chloride or corticosteroids for hyperhidrosis or pruritus, respectively.35 In the case of skin ulcers, antibiotics may also be useful. If symptoms persist despite appropriate management strategies, it may be necessary to interrupt TTFields therapy for 2-7 days or longer depending on symptoms and their severity.
The ongoing open-label phase II PROTECT study (NCT04469075) is looking at prophylactic skin toxicity therapy with clindamycin and triamcinolone in patients with GBM who are being treated with TTFields.
Contraindications for TTFields
We have discussed the general lack of significant toxicity for TTFields therapy, but there are some patients who should not wear the devices. Patients with implanted medical devices (eg, programmable shunts or pacemakers) should not use these systems as these patients were not included in the clinical trials11,16 For the Novo-TTF100A system, contraindications also include patients with skull defects, especially if there is missing bone and no replacement, or those with bullet fragments.11 There are currently no data on the use of TTFields in individuals with bullet fragments or skull defects. Patients with a known sensitivity to conductive hydrogels (eg, those used with ECGs) should not use TTFields devices because they may also be sensitive to the gel used with the transducer arrays.11,16 There is a potential for redness and itching, or a life‑threatening allergic reaction. TTFields should also be avoided in patients who are pregnant or planning to become pregnant because the safety and efficacy of TTFields have not been tested during pregnancy.
We should also note that TTFields devices pose no risk of exposure to caregivers and family members, and the manufacturer is not aware of any effects of cell phones or microwaves on the efficacy of the devices.
Cost of TTFields
There are some challenges facing the greater adoption of TTFields therapy. In the United States, the cost is different for each patient based on income, insurance, and other factors. As a result of its approval by the FDA, TTFields therapy is covered by many insurance companies, but the estimated price of treatment with the Novo-TTF100A without commercial insurance is approximately $21,000 a month per patient.41 The manufacturer has a 24/7 support team that works with the individual patient’s insurance companies and healthcare providers to arrive at a total cost for each patient. In most cases, patients are able to begin TTFields treatment while waiting for approval from their insurance company.
Barriers to Uptake of TTFields
The uptake of TTFields therapy is relatively low despite the fact that it has FDA approvals. TTFields is a different type of treatment than what most oncologists are used to, which may be a barrier to adopting it. However, once healthcare professionals have established a relationship with the manufacturer of TTFields, they may find that they are easy to work with for both providers and for patients and their caregivers. Some healthcare professionals may hesitate to recommend TTFields for eligible patients because of a lack of awareness and familiarity with the treatment. For newly diagnosed GBM, for example, the clinical benefit has been proven by available data, and there has even been a lot of research on how to prevent some of the toxicities. I hope that my discussion will help HCPs to better understand TTFields, including efficacy, limitations, and how to manage toxicities.
Key Takeaways
Here is a brief recap of what we have covered in this module:
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