Malignant pleural mesothelioma (MPM) is an aggressive cancer which originates from the pleura in the lung.2 This type of cancer is most frequently associated with previous asbestos exposure.2 Due to the long latency period of MPM, screening is challenging and patients often present with advanced disease, leading to poor prognosis.2 The median survival in patients with unresectable malignant pleural mesothelioma is around 12 months, with cisplatin in combination with pemetrexed being the current standard of care.3 A multimodality treatment approach which includes surgery, chemotherapy and RT is adopted to maximize survival in patients with MPM, and chemotherapy remains current standard of care in patients who are ineligible for curative surgery.2
An in vitro study investigating the antiproliferative effect of TTFields on mesothelioma cell lines suggests that the optimal frequency is 150 kHz, and the combination of TTFields and chemotherapy (cisplatin and pemetrexed) resulted in an additive effect of treatment benefits.4 Based on these pre-clinical findings, a phase II STELLA study was conducted to investigate the efficacy and safety of adding TTFields into standard chemotherapy in patients with unresectable, treatment-naïve MPM.5
References:
- U.S. Food and Drug Administration approval. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=431319. Accessed 6 April 2022.
- Bianco A, et al. J Thorac Dis. 2018;10:S253–S261.
- Vogelzang NJ, et al. J Clin Oncol. 2003;21:2636–2644.
- Munster M, et al. The combined treatment of 150 kHz tumor treating fields (TTFields) and cisplatin or pemetrexed inhibits mesothelioma cells in vitro. Abstract 307. Presented at the American Association for Cancer Research Annual Meeting 2019;2019;30:ii72–ii73.
- Ceresoli GL, et al. Lancet Oncol. 2019; 29 March–3 April, 2019; GA, USA.
STELLAR in unresectable, treatment-naïve MPM
STELLAR study was a prospective, multicentre, single-arm, phase II study designed to identify the efficacy and safety of TTFields at a frequency of 150 kHz, in combination with pemetrexed and cisplatin or carboplatin, in patients with unresectable, treatment-naïve malignant pleural mesothelioma.2
Study design2
Adapted from Ceresoli GL, et al. from the 2019 American Association for Cancer Research Annual Meeting.
The STELLAR trial recruited 80 patients from 12 sites in Europe, including Italy, Poland, France, Belgium, Spain and the Netherlands.2 Patients received continuous TTFields applied at a frequency of 150 kHz to the thorax for at least 18 hours per day and intravenous pemetrexed treatment (500 mg/m2), together with either cisplatin (75 mg/m2 ) or carboplatin (AUC 5) on day 1 of a 21-day cycle for up to six cycles.2 TTFields were offered as maintenance for those who did not progress after receiving chemotherapy.2
- Primary endpoint: OS
- Secondary endpoints: PFS, objective response and safety
Efficacy
The survival analysis results are summarized below2:
| TTFields + Pemetrexed + Carboplatin / Cisplatin (n=80) | |
|---|---|
| Median OS | 18.2 months |
| (95% CI, 12.1–25.8) | |
| Median PFS | 7.6 months |
| (95% CI, 6.7–8.6) | |
The median follow-up period was 12.5 months. CI, confidence interval; OS, overall survival; PFS, progression-free survival
The 1-year OS rate was 62.2% (95% CI; 50.2–72.0) and the 2-year OS rate was 41.9% (95% CI, 28.0–55.2).2 Post hoc analysis showed that patients with epithelioid histology had longer median OS (21.2 months vs 12.1 months) and median PFS (8.3 months vs 6.5 months) than those with non-epithelioid histology.2 With the addition of TTFields to pemetrexed and carboplatin or cisplatin, 40% of patients had a partial response and 57% had stable disease, with 3% progressed at first follow-up scan.2 The median duration of response was 5.7 months (IQR 3.0–9.3).2
Safety
From the STELLAR study, the addition of TTFields to the standard first-line chemotherapy was not associated with increased systemic toxicity.2 Skin reaction, specifically localise dermatitis, manifested underneath the transducer arrays was the most common mild to moderate (grade 1–2) adverse event, accounting for 66% of the study population.2 During the study period, 36% had severe (grade 3–4) adverse events, and the most common severe adverse event was anaemia, neutropenia, thrombocytopenia and treatment-related medical device site reactions (skin reactions). However, none of the severe adverse events which led to hospital admission were considered TTFields-related.2
The safety results are summarised below2:
| Grade 1–2 | Grade 3 | Grade 4 | Grade 5 | |
|---|---|---|---|---|
| Patients with ≥1 adverse event | 43 (54%) | 24 (30%) | 5 (6%) | 3 (4%) |
| Blood and lymphatic system disorders | 27 (34%) | 16 (20%) | 2 (3%) | 0 |
| Anaemia | 25 (31%) | 8 (10%) | 1 (1%) | 0 |
| Febrile neutropenia | 0 | 1 (1%) | 0 | 0 |
| Leukopenia | 0 | 2 (3%) | 1 (1%) | 0 |
| Neutropenia | 0 | 6 (8%) | 1 (1%) | 0 |
| Thrombocytopenia | 0 | 4 (5%) | 0 | 0 |
| Cardiac disorders | 0 | 2 (3%) | 1 (1%) | 0 |
| Atrial fibrillation | 0 | 1 (1%) | 0 | 0 |
| Cardiac tamponade | 0 | 0 | 1 (1%) | 0 |
| Pericardial effusion | 0 | 2 (3%) | 0 | 0 |
| Gastrointestinal disorders | 30 (38%) | 3 (4%) | 0 | 0 |
| Constipation | 8 (10%) | 0 | 0 | 0 |
| Gastric ulcer haemorrhage | 0 | 1 (1%) | 0 | 0 |
| Nausea | 17 (21%) | ·· | 0 | 0 |
| Vomiting | 0 | 2 (3%) | 0 | 0 |
| General disorders and administration site conditions | 34 (43%) | 6 (8%) | 0 | 0 |
| Asthenia | 11 (14%) | 1 (1%) | 0 | 0 |
| Chest pain | 10 (13%) | 1 (1%) | 0 | 0 |
| Fatigue | 10 (13%) | 3 (4%) | 0 | 0 |
| Pain | 0 | 1 (1%) | 0 | 0 |
| Hepatobiliary disorders | 0 | 1 (1%) | 0 | 0 |
| Cholelithiasis | 0 | 1 (1%) | 0 | 0 |
| Infections and infestations | 17 (21%) | 0 | 1 (1%) | 2 (3%) |
| Bronchopneumonia | 0 | 0 | 1 (1%) | ·· |
| Candida sepsis | 0 | 0 | 0 | 1 (1%) |
| Oral candidiasis | 0 | 1 (1%) | 0 | ·· |
| Pneumonia | 0 | 0 | 0 | 1 (1%) |
| Investigations | 15 (19%) | 2 (3%) | 0 | 0 |
| Neutrophil count decreased | 0 | 1 (1%) | 0 | 0 |
| Platelet count decreased | 0 | 1 (1%) | 0 | 0 |
| White blood cell count decreased | 0 | 1 (1%) | 0 | 0 |
| Metabolism and nutrition disorders | 8 (10%) | 0 | 0 | 0 |
| Musculoskeletal and connective tissue disorders | 0 | 1 (1%) | 0 | 0 |
| Neck pain | 0 | 1 (1%) | 0 | 0 |
| Nervous system disorders | 12 (15%) | 0 | 0 | 1 (1%) |
| Epilepsy | 0 | 0 | 0 | 1 (1%) |
| Renal and urinary disorders | 0 | 1 (1%) | 0 | 0 |
| Oliguria | 0 | 1 (1%) | 0 | 0 |
| Respiratory, thoracic, and mediastinal disorders | 17 (21%) | 3 (4%) | 1 (1%) | 0 |
| Cough | 8 (10%) | 0 | 0 | 0 |
| Dyspnoea | 0 | 2 (3%) | 0 | 0 |
| Pulmonary embolism | 0 | 1 (1%) | 0 | 0 |
| Respiratory failure | 0 | ·· | 1 (1%) | 0 |
| Skin and subcutaneous tissue disorders | 54 (68%) | 4 (5%) | 0 | 0 |
| Medical device site reaction | 53 (66%) | 4 (5%) | 0 | 0 |
| Pruritus | 11 (14%) | 0 | 0 | 0 |
| Vascular disorders | 8 (10%) | 0 | 0 | 0 |
Data are n (%). Patients shown for each grade represent patients who had that grade as the highest for that specific adverse event. Grade 1 or 2 adverse events occurring in at least 10% of patients and all grade 3–5 adverse events are reported.
References:
- U.S. Food and Drug Administration approval. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=431319. Accessed 6 April 2022.
- Ceresoli GL, et al. Lancet Oncol. 2019; 29 March–3 April, 2019; GA, USA.
- Ceresoli GL, et al. Final results of phase II STELLAR trial: TTFields with chemotherapy in unresectable malignant pleural mesothelioma. Abstract CT201. Presented at the American Association for Cancer Research Annual Meeting 2019; 29 March–3 April, 2019; GA, USA.