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Wednesday, 15 August 2018

Tumour-treating fields: moving beyond glioblastoma treatment

Tumour treating fields: more than just
fun with physics

Glioblastoma (GBM), that most aggressive of brain cancers, is notoriously resistant to treatment and a variety of leading edge approaches, including immunotherapy, virotherapy and gene therapy  are under investigation as means of extending survival by a meaningful amount.

One of the few treatments to have gained regulatory approval in the last decade is a medical device, Optune™, a custom-made, shower cap-like array of electrodes worn constantly on a shaven scalp, which is claimed to disrupt and slow tumour growth through the application of low intensity, alternating electrical current- so-called “tumour treating fields (TTFs).

I’m probably not alone in being reminded of 19th century quackery and the various galvanic treatments advocated by the beauty industry, but Optunes’s developer, NovoCure, a publicly traded US-based company, has managed to navigate the rocky path of clinical development to satisfy both American and European regulators, although approval was not without controversy.

Optune™ (then designated NovoTTF-100A) received FDA approval for the treatment of recurrent GBM in April 2011, on the back of clinical data that hinted at, rather than conclusively established, a degree of benefit comparable to chemotherapy, a comparison in itself made complex by differences in investigator choices of chemotherapy regimen. The FDA panel was accused of being overly influenced by pleas from GBM patients and their families during an open public hearing. Approval did come with the rider that NovoCure conduct a post-approval study to establish non-inferiority of TTF treatment to chemotherapy.

FDA approval for the treatment of newly-diagnosed GBM in conjunction with chemotherapy was granted in 2015 on the back of interim clinical data gathered from almost 700 GBM patients receiving radiotherapy and chemotherapy following surgery. The addition of TTF treatment increased the median time to progression, and overall survival, by almost three months over chemotherapy alone.

Neuro-oncologists remain divided on Optune™, being, with reason, critical of a pivotal clinical study that did not include sham treatment as a control, and the vagueness of the TTF mechanism of action, stated as involving “misalignment” of charged proteins critical to cell division. On the other hand, TTF in combination with chemotherapy is recommended in the authoritative National Comprehensive Cancer Center treatment guidelines. Despite the requirement of near constant wear (a minimum of 18 hours a day) and high treatment cost (around $20,000 per month with as yet limited reimbursement, Optune™ is currently in use by over 2,000 GBM patients in the US, Europe and Japan.

Recent data suggests that TTF may be of benefit in other forms of solid tumour. Two completed pilot studies of TTF in combination with standard chemotherapy in malignant mesothelioma and pancreatic cancer patients indicated improvements over historical progression-free survival and one year survival rates obtained with chemotherapy alone.

An apparent improvement in progression-free survival was observed in a small study conducted patients with recurrent ovarian cancer is more difficult to interpret due to difference in the treatment histories of individual patients and historical chemotherapy comparators.

Nonetheless, NovoCure is sponsoring three pivotal TTF studies in pancreatic cancer, non-small cell lung cancer (NSCLC) and in brain metastases arising from NSCLC, with final data from the latter study anticipated in 2020. TTF faces tougher competition in these indications from advances in precision chemotherapy and immuno-oncology, but should TTF even prove to be non-inferior to conventional therapies, it could find use in individuals intolerant of, or unresponsive to, other forms of cancer treatment.  Success may also serve to disarm TTF’s critics, as might elucidation of the putative mechanism(s) of action, along with the acid test of undertaking a  TTF study that includes a sham treatment control arm.

Image credit: Wikipedia(creative commons licence)

Updated 6th September 2018

According to a company press release, TTF in combination with chemotherapy for malignant pleural mesothelioma resulted in a increase median overall survival over the historical rate (18.2 months compared to 12.1 months), with improvement in median progression free survival (7.6 months,  compared to 5.7 months in the historical control). With the obvious caveat that this was a single-arm, open label study, the results do suggest that TTF might have application in an indication other than GBM.

Tumor Treating Fields Plus Standard of Care Chemotherapy Significantly Extends Median Overall Survival by 6.1 Months in STELLAR Phase 2 Registration Trial in Mesothelioma Compared to Historical Control. Company press release online 5th September, 2018

NovoCure company presentation, August 2018. http://tinyurl.com/ya2z95gf

Tumor treating fields: a new approach to glioblastoma therapy. Rick, JW et al. January 2018, Journal of Neuro-Oncology 137(3)DOI: 10.1007/s11060-018-2768-x, online 18th January 2018.

Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study. Vergote, I et al. Gynecologic Oncology July 2018 https://doi.org/10.1016/j.ygyno.2018.07.018, online 22nd July 2018.

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