Enhertu hits with pan approach
Strong data prompt talk of a tumour-agnostic approval, but regulators could prove reluctant in the broad Her2 setting.
Amy Brown
5 June, 2023
Enhertu is already known to be a highly effective Her2-targeting agent in breast, lung and gastric cancers, and new data unveiled at Asco suggest that the Daiichi Sankyo/Astrazeneca antibody-drug conjugate can hit tumours regardless of their location. Whether regulators are prepared to green light a Her2 tumour agnostic label is the big question here.
When the partners toplined the Destiny-Pantumor02 study in March they said the data would be “shared with regulators”. Their regulatory strategy is unclear, but the results look strong enough to make a case for accelerated approval: overall response rate hit 37% in all comers, rising to 61% in those with very high Her2 expression; patients were very treatment refractory and/or had run out of options.
The FDA has permitted a couple of tumour-agnostic labels in the last few years, but these have encompassed tiny patient populations characterised by molecular or gene expression. NTRK positivity, in which Lilly's Vitrakvi is approved, is thought to affect up to 5,000 newly diagnosed patients a year. Tumours that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), for which Merck & Co's Keytruda is approved, also make up a tiny niche.
That might not be the case with Her2, which is a biological target. Destiny-Pantumor02 cohorts included endometrial, ovarian and biliary tract tumours, and Her2 positivity might not be fully appreciated in some tumour types.
Biliary tract is an interesting example. This tumour type is being targeted by competitors including Jazz Pharmaceuticals, which has paid more than $300m to license Zymeworks’ zanidatamab, a bispecific that hits two Her2 epitopes. Jazz has said that up to 19% of the 210,000 people diagnosed with biliary tract cancer globally each year could be Her2 positive – a small but not insignificant number.
At Asco this year Jazz presented biliary tract data from the Herizon-BTC-01 trial, results that helped secure that large up-front payment. That phase 2b trial, in relapsed metastatic patients, generated a 41% objective response rate, although this was driven by patients with high Her2 expression, the full data published in the Lancet Oncology reveal (for a fuller report on the Herizon-BTC-01 data, see coverage from our sister publication Scrip).
Her2 expression is measured by immunohistochemistry testing (IHC), which gives a score of 0 to 3+. A score of 2+ is borderline and 3+ represents Her2-positive disease.
In Herizon-BTC-01, ORR in IHC 3+ patients was 52%, dropping to 6% for the IHC 2+ group. In comparison, Enhertu generated an ORR of 56% in the biliary tract cohort in IHC 3+ patients in Destiny-Pantumor02, with no responses seen in the IHC 2+ cohort.
Cross-trial comparisons are always imperfect, but any broadening of Enhertu's label could have big ramifications for competitor projects.
Case by case?
The breadth of the Her2 space means that regulators might prefer to look at the Destiny-Pantumor02 data on a tumour-by-tumour basis. Dr Kohei Shitara of Japan’s National Cancer Center Hospital East, who discussed the results for Asco, seemed to agree, telling the conference that Enhertu’s exact clinical value may be better discussed in each tumour type.
Not that he was unimpressed with the data. “Considering the survival benefit of Enhertu in breast and gastric cancer, and the consistently high response rates across tumour types [in Destiny-Pantumor02]. I believe conducting randomised control trials in each cancer type may not feasible and too time consuming to provide this to our patients,” he said, adding the results warrant discussion with regulators.
The breadth of the Her2 space means that regulators might prefer to look at the Destiny-Pantumor02 data on a tumour-by-tumour basis.
A look at the trial's results by Her2 expression levels – patients were split into IHC 2+ and 3+ cohorts – shows that those in the latter group clearly did better. And, aside from pancreatic, response rates were impressive and consistent.
Pancreatic is always a tough target, and MD Anderson’s Dr Funda Meric-Bernstam, who presented the new Enhertu data to journalists at a press conference at Asco, pointed out that only two pancreatic patients had high Her2 expression.
Asked by Evaluate Vantage whether the small patient numbers in certain subgroups was a concern, Dr Meric-Bernstam, the study’s lead author, maintained that Destiny-Pantumor02 was quite large for a tumour-agnostic trial.
“We saw activity across all tumour types with high ORR,” she told journalists at a Sunday press briefing. “The ‘other’ tumour bucket response rate is also quite compelling. This really suggests this is a compelling treatment option for Her2-expressing tumours.”
Median duration of 11.8 months in all comers, extending to 22.1 months in IHC3+ patients, is persuasive, she said.
The trial recruited 267 patients in total, and was open label. One patient died of interstitial lung disease, a known Enhertu toxicity, and this is an issue regulators will struggle to ignore should they consider an agnostic label.
While stating that the results were early, Dana Farber’s Dr Bradley McGregor was sufficiently impressed to say the trial could “represent a shift in how to think about cancer care”. Speaking at the press conference to review the trial, he said that, because testing for Her2 status was easily accessible, this should perhaps be done more routinely.
This would be music to Astrazeneca and Daiichi’s ears, of course, although a more circumspect approach from regulators cannot be ruled out. The trial is ongoing, with survival data expected later this year, information that agencies will also be very keen to see when considering broadening Enhertu's label.
Whatever that label ends up looking like, this antibody-drug conjugate looks likely to arrive in smaller Her2 settings sooner or later. And, as breast cancer rivals have found, Enhertu is a very fierce competitor.
Scrip and Evaluate Vantage are part of the same parent company, Norstella.
