Tumor Treating Fields Concomitant with Sorafenib in Advanced Hepatocellular Cancer: Results of the HEPANOVA Phase II Study

Our plain-English summary of Tumor Treating Fields Concomitant with Sorafenib in Advanced Hepatocellular Cancer: Results of the HEPANOVA Phase II Study, by E. Gkika, A.L. Grosu, T. Macarulla Mercade, et al (Cancers, 2022).

The study

• Authors: E. Gkika, A.L. Grosu, T. Macarulla Mercade, A. Cubillo Gracián, T.B. Brunner, M. Schultheiß, M. Pazgan-Simon, T. Seufferlein, Y. Touchefeu
• Journal: Cancers
• Published: 2022;14(6)
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Advanced hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis. Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional treatment approved for glioblastoma and malignant pleural mesothelioma. HCC preclinical and abdominal simulation data, together with clinical results in other solid tumors, provide a rationale for investigating TTFields with sorafenib in this patient population. HEPANOVA was a phase II, single arm, historical control study in adults with advanced HCC (NCT03606590). Patients received TTFields (150 kHz) for ≥18 h/day concomitant with sorafenib (400 mg BID). Imaging assessments occurred every 12 weeks until disease progression. The primary endpoint was the overall response rate (ORR). Safety was also evaluated. Patients (n = 27 enrolled; n = 21 evaluable) had a poor prognosis; >50% were Child−Turcotte−Pugh class B and >20% had a baseline Eastern Clinical Oncology Group performance status (ECOG PS) of 2. The ORR was higher, but not statistically significant, for TTFields/sorafenib vs. historical controls: 9.5% vs. 4.5% (p = 0.24), respectively; all responses were partial. Among patients (n = 11) with ≥12 weeks of TTFields/sorafenib, ORR was 18%. Common adverse events (AEs) were diarrhea (n = 15/27, 56%) and asthenia (n = 11/27, 40%). Overall, 19/27 (70%) patients had TTFields-related skin AEs; none were serious. TTFields/sorafenib improved response rates vs. historical controls in patients with advanced HCC, with no new safety concerns or related systemic toxicity.

In plain English

HEPANOVA, a prospective, open-label, single-arm phase II trial, studied adults with advanced hepatocellular carcinoma, a liver cancer, not asbestos disease. At six European sites, 27 patients were to receive Tumor Treating Fields, which are electric fields delivered through abdominal arrays, for at least 18 hours a day. Mean usage was 64%, below the recommended 75%. All but one also received sorafenib 400 mg twice daily. Six patients died before the first 12-week scan. Among the 21 who could be assessed, the response rate was 9.5%, against 4.5% for earlier sorafenib-alone studies (p = 0.24), which was not statistically significant. All responses were partial. Among 11 patients treated at least 12 weeks, it was 18%. Estimated one-year survival for all 27 was 30% (95% confidence interval 11 to 52%). Diarrhea (15 of 27) and asthenia (11 of 27) were the most common reported adverse events. Nineteen patients had skin adverse events related to the fields, none serious. The authors concluded the combination was feasible and tolerable. They called for a randomized phase III study of the fields with current standard treatment and named the small, non-randomized design as a limitation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: prospective, open-label, phase II, single-arm clinical trial compared with historical controls
• Who was studied: 27 adults with advanced hepatocellular carcinoma (HCC) were enrolled at six sites in six European countries, out of 35 screened. 21 could be assessed for response because six patients (all Child–Turcotte–Pugh class B) died before the first 12-week scan. Median age was 65 years, and 26 of 27 were male.
• Exposure: No asbestos exposure was studied. The intervention was Tumor Treating Fields (150 kHz), prescribed for at least 18 hours a day through arrays placed on the abdomen, with sorafenib 400 mg twice daily. Mean usage of the fields was 64%, below the 75% the protocol recommended. One patient did not receive sorafenib.
• Main results:
  • In the 21 evaluable patients, the overall response rate was 9.5%. The rate for historical sorafenib-alone controls was 4.5% (p = 0.24, not statistically significant). All responses were partial.
  • In the subgroup of 11 patients who received at least 12 weeks of treatment, the overall response rate was 18.0%, against 4.5% for historical controls.
  • In the intent-to-treat population (n = 27), the 1-year overall survival rate was 30% (95% CI, 11–52). The 1-year progression-free survival rate was 23% (95% CI, 7–45).
  • In exploratory analyses, the disease control rate was 76% in the 21 evaluable patients. In the intent-to-treat population, median time to progression was 8.9 months (95% CI, 3.1 to not reached).
  • 26 of 27 patients (96%) had at least one adverse event. The most frequent were diarrhea (15, 56%), asthenia (11, 41%), decreased appetite (8, 30%) and ascites (6, 22%).
  • 16 of 27 patients (59%) had severe (grade 3 to 4) adverse events.
  • 19 of 27 patients (70%) had skin adverse events related to the fields. Of these, 18 had grade 1 to 2 events and one had a grade 3 skin erosion. No serious adverse events related to the fields were reported.
  • 18 deaths had been reported as of 20 April 2021, and none were judged related to the study treatment.
• The authors' conclusion: The authors concluded that Tumor Treating Fields with sorafenib appeared to be a feasible and tolerable treatment option in advanced HCC. They said the use of the fields with current standard-of-care treatment warrants further study in a larger randomized phase III trial.
• Limitations the authors state:
  • The study had a small patient population, a single-arm design and no randomization, which the authors said limits how far the findings can be generalized.
  • Many patients died early, before response could be assessed, which may have weakened the efficacy findings.
  • Mean usage of the treatment device was 64%, below the 75% the protocol recommended.
  • Some patients may have received other HCC treatments, such as immunotherapy, in earlier clinical studies.
  • Direct comparisons with the historical sorafenib studies cannot be made because trial designs and populations differ.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Treating Fields (TTFields), Sorafenib (Nexavar), Carcinoma, Prognosis, Pleural Mesothelioma, Disease Progression, Performance Status.

Related studies

• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)
• Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma — D. Chen, S.B. Le, et al. (2022)
• The Mechanisms of Action of Tumor Treating Fields — J.C. Moser, E. Salvador, et al. (2022)
• Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Acting Dynamics — T. Voloshin, R.S. Schneiderman, et al. (2020)
• Prevention and Management of Dermatologic Adverse Events Associated With Tumor Treating Fields in Patients With Glioblastoma — M.E. Lacouture, M.J. Anadkat, et al. (2020)
• The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy — G. Tanzhu, L. Chen, et al. (2022)

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