Asco 2023 – Novocure sinks as Lunar’s limitations become clear
A pivotal lung cancer hit in an outdated setting means the company might struggle with adoption.
Confidence in Novocure’s ability to break into lung cancer with its tumour-treating fields technology took a major knock yesterday, as doctors at Asco raised serious questions about the therapy’s value as a second-line treatment. Shares in the company plunged 43%.
The pivotal Lunar trial, presented at the medical conference yesterday, was technically a success, and thus Novocure’s tech might gain approval in this new indication. But the result was achieved in an outdated setting, with different subgroup responses raising further concerns about mechanism of action. The technology is starting to look like the very last of last-ditch treatments.
The phase 3 study assessed the use of Novocure’s tumour-treating fields, in which a device called NovoTTF-200T emits 150kHz electrical fields that are believed to disrupt cell division. It enrolled 276 patients with metastatic NSCLC who had progressed on or after platinum therapy, with prior checkpoint inhibitor use permitted. The tumour-treating fields were delivered continuously until progression or intolerable toxicity, and were compared against doctors’ choice of checkpoint inhibitors or docetaxel.
Lunar was toplined a hit in January, and now the extent of that hit has been revealed as 3.3 months of additional median overall survival. One-year survival rates were also significantly improved in the tumour-treating fields group, though PFS did not hit significance.
|Novocure's Lunar (NCT02973789) data - abstract LBA9005|
|NovoTTF-200T + SOC||SOC alone||Stats|
|Median overall survival||13.2mth||9.9mth||HR 0.74; p=0.035|
|One-year survival rates||53%||42%||p=0.040|
|Three-year survival rates||18%||7%|
|Median progression-free survival||4.8mth||4.1mth||HR 0.85, p=0.23|
|Adverse event rates||97%||91%|
|Grade 3 or above adverse event rates||59%||56%|
|NovoTTF-200T + CI||CI alone||Stats|
|Median overall survival||18.5mth||10.8mth||HR 0.63; p=0.03|
|NovoTTF-200T + docetaxel||Docetaxel alone||Stats|
|Median overall survival||11.1mth||8.7mth||HR 0.81, p=0.28|
|SOC=standard of care. CI=checkpoint inhibitor. Data at minimum follow up of 12mth. Source: Company communications, Asco.|
Massachusetts General Hospital’s Dr Rebecca Heist, who discussed the data for Asco after the study presentation, was unconvinced.
“The major caveat for me is that the study design does not reflect the current standard of care,” she told the meeting.
This is the central issue here. When Lunar was designed, metastatic NSCLC patients mostly received platinum doublet chemo first line, followed by checkpoint inhibitors and then docetaxel. Under current protocols, patients in the west generally get checkpoint inhibitors with or without chemo first, with docetaxel used second line.
The abstract disclosed that just 31% of Lunar’s subjects had received prior checkpoint inhibitors, a cohort that would reflect a relevant second-line population. Results in those patients were not broken out, however, and Novocure had not responded to EvaluateVantage’s request for further information at time of press.
The company has said it is planning further first and second-line studies, but clarity on whether TTFields works alongside current practice is unlikely to emerge for several years. Keynote B36, a small first-line Keytruda-combo phase 2 trial, might reveal hints later next year.
In the meantime, many oncologists will remain unconvinced.
“It’s a positive trial,” Dr Jyoti Patel of Chicago’s Northwestern Memorial Hospital told Evaluate Vantage on the sidelines of Asco. “However, its relevance to the majority of patients in 2023 is yet to be demonstrated, with [standard of care seeing] the incorporation of novel targeted therapies and better immunotherapies.”
Dr Lauren Byers of the University of Texas MD Anderson Cancer Center agreed, telling Vantage that she did not expect Novocure’s therapy to be routinely incorporated into practice with the current data.
|Novocure's NSCLC programme|
|Lunar||2L, + CI or docetaxel, post-platinum, hit Jan 2023 but relevance questionable|
|Keynote-B36||1L, + Keytruda, to report 2024|
|Lunar-2||1L, + CI and chemo - planned|
|Lunar-3||1L, + CI, post-chemoradiation - planned|
|Lunar-4||2L, + CI or docetaxel, post-CI + chemo - planned|
|CI = checkpoint inhibitor. Source: company presentation.|
The failure of the Lunar trial’s docetaxel subgroup, arguably its most relevant dataset, will make Novocure’s job even harder.
“This is surprising to me, because the proposed mechanism of action of tumour-treating fields should have an effect on docetaxel-treated patients as well,” said Heist. “The lack of clarity around the mechanism of action does give me pause and [TTFields’] place in the current treatment paradigm is unclear.”
It should be noted that Lunar enrolled patients in China as well as in Europe and North America. Perhaps the primary endpoint hit might be more applicable for the China market, where checkpoint inhibitors are not so established, and around half of NSCLC patients get platinum-based chemo alone first line, according to SVB analysts. The Shanghai-based biotech Zai Lab is Novocure’s partner for the China market.
The final drawback raised by doctors was the device’s inconvenience, with potential impacts on quality of life. The NovoTTF-200T machine must be worn as a backpack or shoulder bag, with large electrodes taped to the chest, for months on end. Patients in Lunar wore it for a median of a year.
“The burden of this treatment is significant to a patient who is trying to return to previous function. Some will want to do everything; however, others will hope for better therapies that are less intrusive,” Northwestern Memorial’s Patel said.
“Tumour-treating fields are non-invasive, but they are bulky and I’d be interested to see what the quality-of-life outcomes are,” Heist said.
In the Asco presentation the Lunar investigators said addition of tumour-treating fields to standard of care did not negatively affect health-related quality of life, adding that a detailed analysis was ongoing.
Speaking to Vantage in February, Novocure’s executive chairman, Bill Doyle, said the group believed that the Lunar data would secure a second-line label for the NovoTTF-200T device. This might well happen, but the extent of subsequent demand is an open question.