Summary

What Is the Indication Under Review?

The indication under review is for the treatment of adults with ndGBM following maximal debulking surgery and completion of RT together with and after standard of care maintenance chemotherapy with temozolomide. GBM is the development of cancer among glial cells in the central nervous system and is the most common form of brain cancer in Canada. There are approximately 1,850 patients with GBM in Canada (data from 2010 to 2017).¹

What Is Optune?

Optune is a portable medical device that produces alternating electrical fields called TTFields to target the growth of cancerous cells in addition to chemotherapy. Current treatment for GBM consists of a combination of surgery, RT, and chemotherapy.

How Did CADTH Evaluate Optune?

To examine the value of Optune for the treatment of ndGBM, CADTH:

• reviewed and critically appraised the evidence submitted by the sponsor, including clinical evidence on Optune’s efficacy and safety and economic evidence on its cost-effectiveness and budget impact
• reviewed the literature to assess the validity of the sponsor’s modelling approaches, assumptions, and estimates regarding Optune, and to identify and describe ethical considerations relevant to the use of Optune for the treatment of ndGBM in Canada
• solicited and sought input from patient and clinician groups through an open call, and established and consulted an expert panel to identify unmet needs, and place in therapy and implementation considerations for Optune.

CADTH’s Health Technology Expert Review Panel

HTERP is an advisory body to CADTH that develops guidance and/or recommendations on nondrug health technologies to inform a range of decision-makers within the Canadian health care system.

HTERP comprises 7 core members to serve for all topics under consideration during their term of office: chair, ethicist, health economist, patient member, 2 health care practitioners, and a health technology assessment specialist. In addition to the core members, HTERP comprises up to 5 expert members appointed to provide their expertise on a specific topic. For this reimbursement review, 1 member with expertise in neuro-oncology, 1 member with expertise in medical oncology, 1 member with expertise in radiation oncology, and 1 member with lived experience of GBM as a caregiver were appointed.

To make its recommendation, HTERP considered the following information:

• CADTH’s review of:
  • 1 multicentre, randomized, open-label trial in adults with ndGBM following maximal debulking surgery and completion of RT together with and after standard of care maintenance chemotherapy
  • the pharmacoeconomic model and report submitted by the sponsor
  • ethical issues related to Optune from published literature and patient and clinician group and expert panel input
• input received from an open call that included:
  • patients’ perspectives gathered by a patient group, the Brain Tumour Foundation of Canada
  • clinician input from a group of 20 oncologists in Canada who treat patients with ndGBM.

Rationale for the Recommendation

HTERP recognized the unmet needs of patients with GBM, for which there have been no new treatment options that improve survival since 2005.

One multicentre, open-label, randomized controlled trial (EF-14) that compared the efficacy and safety of Optune with temozolomide in adults with ndGBM following maximal debulking surgery and completion of RT together with and after standard of care maintenance chemotherapy resulted in the following benefits.

• Optune with temozolomide resulted in likely increases of PFS rates at 6 months of treatment (absolute difference = 19.1%; 95% confidence interval [CI], 10.6% to 27.4%). Delaying disease progression is another important goal of treatment for ndGBM that is important to patients and clinicians. HTERP concluded that Optune with temozolomide meets the need to delay disease progression at 6 months as the findings indicated a clinically meaningful benefit for PFS at this time point.
• Optune with temozolomide may increase OS rates at 24 months of treatment (absolute difference = 12.5%; 95% CI, 4.7% to 20.2%) compared to temozolomide alone. The main goal of treatment of ndGBM is prolonging life and HTERP concluded that Optune meets this need at this time point.
• In addition to extending life and delaying disease progression, patients identified the need for treatments that can maintain their quality of life and reduce side effects. Optune with temozolomide may result in little to no difference in HRQoL when compared to temozolomide alone, and the evidence suggests there is little to no difference in serious adverse events between Optune plus temozolomide and temozolomide alone. Optune treatment did not clearly add safety concerns to temozolomide alone.

However, HTERP acknowledged the limitations of the EF-14 study with concerns regarding possible selection bias that may affect the internal validity of the results with potential overestimation of the efficacy findings and low generalizability to real-world settings.

HTERP noted that, based on the economic evidence at the submitted monthly fee for Optune and public list price for temozolomide, the incremental cost-effectiveness ratio (ICER) for Optune plus temozolomide versus temozolomide alone was $899,470 per quality-adjusted life-year (QALY) gained (incremental costs = $336,902; incremental QALYs = 0.37). At this ICER, Optune plus temozolomide was not considered cost-effective relative to temozolomide alone at conventional willingness-to-pay thresholds (e.g., $50,000 per QALY gained or $100,000 per QALY gained). The budget impact of reimbursing Optune through the federal, provincial, and territorial public drug plans (excluding Quebec) is estimated to be $75,795,323 over 3 years.

Table 1

Reimbursement Conditions and Reasons.

Considerations

• Need:
  • None of the available treatments (including Optune) are curative and the disease has a poor prognosis.
  • There have been no new treatment options that demonstrate improved survival of people with GBM since the early 2000s.
  • The current standard of care for adults with ndGBM in Canada is maximal surgical resection, followed by RT plus the chemotherapeutic drug temozolomide. However, temozolomide is considerably less effective in patients with MGMT unmethylated tumours, which constitutes up to 60% of people with ndGBM.
• Quality of clinical evidence: HTERP noted the potential sources of bias impacting the interpretation of findings, including possible selection bias from enrolling patients with a better prognosis and deviation from the intended intervention (crossover). Additionally, only those patients who survived (without progression) from diagnosis to randomization were included in the study, which further affects the internal validity of the results. Because of these issues, the selection bias may result in higher survival outcomes in both treatment groups. HTERP acknowledged that in comparison to the average person with ndGBM presenting in real-world settings, the study participants were slightly younger, with better health status and degree of independent functioning. A higher proportion of patients in the trial underwent complete resection than what might be typically seen in Canadian practice. These factors lowered the generalizability of the trial results.
• HRQoL:
  • The efficacy analyses suggest that the benefit of Optune + temozolomide increases with the number of hours wearing the device, with perhaps at least 18 hours as an important threshold. How this will affect HRQoL and how the level of adherence and suggested stable HRQoL during the progression-free period will translate to real-world clinical settings is unknown based on the existing evidence.
  • An earlier version of the device (NovoTTF-100A) was used in the EF-14 trial. While it had the same functionality, the NovoTTF-100A was heavier (around 2.7 kg). The newer generation Optune (NovoTTF-200A) includes a redesigned electric field generator and smaller battery, which makes the device lighter (around 1.2 kg) and more user friendly, according to the manufacturer.² The lighter weight and reduced noise of the NovoTTF-200A could impact HRQoL; though, the degree of the impact is unknown.
• Patients’ experiences: Patients using Optune need to manage lifestyle adjustments, such as wearing it for 18 hours daily, maintaining regular head shaving, and applying the arrays to the head, which may require caregiver assistance.
• Economic impact:
  • HTERP discussed the ICER for Optune plus temozolomide, and noted that Optune plus temozolomide was not cost-effective relative to temozolomide alone at conventional willingness-to-pay thresholds.
  • HTERP noted that a price reduction of between 91% and 97% is required for Optune plus temozolomide to be considered cost-effective at a willingness-to-pay threshold between $50,000 and $100,000 per QALY gained.
  • HTERP discussed the key areas of uncertainty that impacted the economic evaluation and noted that there are wide ranges in time on treatment for patients using Optune in the EF-14 trial and differences in median and mean time on treatment. It is unclear whether time on treatment data from the EF-14 trial will align with time on treatment if Optune were funded in Canadian clinical practice.
  • HTERP discussed that, at the submitted monthly fee of $27,000, Optune is estimated to cost the payer $75,795,323 over 3 years. HTERP discussed the sponsor’s approach of considering the federal, provincial, and territorial public drug plans (excluding Quebec) to be appropriate, and noted that there was uncertainty as to who the appropriate payer would be for Optune.
• Implementation considerations:
  • HTERP noted there was uncertainty whether the subscription model and full set of included services indicated by the sponsor will be implementable by the health care system.
  • The effectiveness of Optune appears to be dependent on treatment adherence (i.e., time wearing the device); thus, patient motivation may be important in determining device uptake. Family and/or caregiver support may be important in increasing the ability to adhere to treatment.
  • The lifespan of Optune and its components is uncertain. The sponsor assumed that the device’s monthly rental fee would cover the repairs, replacement, maintenance, technical support, and clinical support associated with the device; however, the responsiveness of the sponsor to deliver the suggested services within the monthly fee is unknown. Furthermore, it is unclear if new versions of Optune will be covered under the submitted agreement or associated with changes to the sponsor’s fee structure.
  • To ensure the privacy, confidentiality, and security of the patient data collected by the device and sponsor, sound measures need to be considered and implemented to adhere to all applicable provincial and national privacy laws. Patient-provider consent conversations should cover privacy considerations before initiating treatment with Optune as use of the device requires transmitting patient data to the sponsor.
• Ethical considerations:
  • The acceptability of Optune, and the extent to which it meets people’s needs for effective, accessible, and easily usable treatment, will likely depend on an individual patient’s values (e.g., whether they see Optune as offering hope and an opportunity to regain a sense of control over the disease or as burdensome or a visible reminder of the condition), motivation, and caregiver support network.
  • As patients with ndGBM can be described as “vulnerable,” owing to their incurable and progressive condition and reliance on clinician recommendations and referrals as well as caregiver support, careful attention must be paid to the quality of consent conversations and shared decision-making. This includes ascertaining what is important for an individual patient, with consideration of their poor prognosis. and which treatment(s) and care are most likely to support achieving their goals of care and vision of a good life. Eliciting a patient’s values with respect to treatment is also important as disease progression may impair capacity to consent and require the involvement of a substitute decision-maker.
  • For implementation, it is important to consider and mitigate potential barriers to equitable access and effective use of Optune (e.g., due to geography, socioeconomic status, provincial funding of temozolomide, lack of caregiver support, language barriers).
  • Implementation of Optune raises ethical considerations for publicly funded health care systems related to fair allocation of scarce resources. This includes determining how to weigh providing access to a therapy with potential benefit for a small population that has a high unmet need with the opportunity costs of reimbursing a highly expensive treatment in the context of limited health care budgets and other significant needs.
• Future research: HTERP is aware of ongoing research assessing the efficacy of Optune among people with ndGBM.³ Once available, the findings of this study should be considered along with the EF-14 trial findings to further assess the clinical efficacy and safety of Optune.

Patients’, Caregivers’, and Clinicians’ Perspectives

A call for patient, caregiver, and clinician input opened on July 13, 2023, and closed on September 1, 2023. A total of 2 responses were received.

Patient input was received from the Brain Tumour Foundation of Canada, which gathered information via online surveys and videoconference interviews conducted in 2023. In total, 339 respondents were received for the online surveys (259 caregivers and 80 patients) and 10 interviews were conducted (6 patients and 4 caregivers, all of whom had experience with Optune). The majority of the survey respondents were from Canada (> 94%). Patients with GBM reported experiencing a wide range of symptoms, including headaches, cognitive changes, changes in behaviour, weakness or problems with arms and legs, seizures, nausea, and problem seeing; all of which have significant impact on their emotional and psychological well-being. In total, 88% and 93% of respondents indicated that they or their loved ones had undergone surgery or RT for GBT, respectively. It was noted in the submission that while these interventions have helped decrease tumour size or slow progression, the effects were often short-term and associated with side effects. Input from the 10 individuals who had experience with Optune (plus temozolomide) indicated that Optune resulted in clear MRI results and increased survival, and helped them resume several daily activities. Scalp irritation and dermatitis were the primarily reported negative side effects associated with Optune treatment, with a few mentions of low blood platelet count, nausea, constipation, and tiredness. Overall, most individuals with Optune experience noted that they would recommend the treatment be made accessible to people living with GBM.

Clinician input was received from a group of 20 oncologists who treat patients with ndGBM in Canada. The input noted that current treatment of GBM requires a multidisciplinary approach where surgery is generally followed by postoperative RT with concurrent temozolomide, after which maintenance temozolomide is given for a minimum of 6 months. The primary goal of therapy is to prolong life and PFS with minimal adverse events while maximizing the patient’s quality of life. Clinician input further stated that no new treatment options for ndGBM have been introduced since 2005 and currently available treatments continue to be associated with poor prognosis. Based on the EF-14 trial, clinicians indicated that outcomes used to assess treatment response would align with those in the EF-14 trial (e.g., PFS and OS). Factors including HRQoL, neurocognitive functioning, and treatment-related cytotoxicity should be used to determine treatment discontinuation. Finally, clinician input indicated that TTFields treatment requires no additional outpatient services, such as infusion sites.

The call for input was open to drug plan input; however, none was received for this review.

What Did CADTH Find?

A summary of key findings and uncertainties from the CADTH review of clinician, economic, and ethics considerations can be found in Table 2.

Key Findings and Uncertainties

Table 2

Summary of Key Findings and Uncertainties.

HTERP Core Members

Leslie Anne Campbell — Chair, Nova Scotia

Louise Bird — Patient member, Saskatchewan

Sandor Demeter — Health care practitioner, Manitoba

Lawrence Mbuagbaw — Health technology assessment specialist, Ontario

Brian Chan — Health economist, Ontario

Duncan Steele — Ethicist, Alberta

Note: As of January 2024, there is currently a committee seat vacancy for 1 health care practitioner.

Meeting date: January 12, 2024

Regrets: None

Conflicts of interest: None

References

1.

Walker EV, Zhou Y, Wu Y, et al. The Incidence and Prevalence of Primary Central Nervous System (CNS) Tumours in Canada (2010-2017), and the Survival of Patients Diagnosed with CNS Tumours (2008-2017). Curr Oncol. 2023;30(4):4311-4328. [PMC free article: PMC10137065] [PubMed: 37185442]

2.

Kinzel A, Ambrogi M, Varshaver M, Kirson ED. Tumor Treating Fields for Glioblastoma Treatment: Patient Satisfaction and Compliance With the Second-Generation Optune((R)) System. Clin Med Insights Oncol. 2019;13:1179554918825449. [PMC free article: PMC6351720] [PubMed: 30728735]

3.

Novocure Canada Inc. TRIDENT – Glioblastoma Clinical Trial. [2024]; https:​//novocuretrials​.com/cancer-clinical-trials​/glioblastoma-clinical-trial-trident/. Accessed 2024 Jan 23.

4.

Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. [PubMed: 15758010]

5.

Iorgulescu JB, Sun C, Neff C, et al. Molecular biomarker-defined brain tumors: Epidemiology, validity, and completeness in the United States. Neuro Oncol. 2022;24(11):1989-2000. [PMC free article: PMC9629432] [PubMed: 35460555]

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About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.

Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.

Sponsor: Novocure Canada, Inc.

Therapeutic area: Supratentorial glioblastoma multiforme

Recommendation: Reimburse with conditions