Esmo 2021 – Enhertu sets a very high bar

A move into the larger second-line breast cancer setting is surely on the way for the Astrazeneca and Daiichi drug.

Conferences

Enhertu has always looked like the biggest threat to Roche's dominance of the crowded anti-Her2 space, and data due to be presented at Esmo this weekend will confirm this view. The Destiny-Breast03 trial was toplined positive last month and then awarded a spot at the medical conference’s presidential symposium – and the results show why.

A highly significant 72% reduction in risk of progression versus Roche’s rival antibody-drug conjugate Kadcyla is a huge win for Daiichi Sankyo and Astrazeneca, partners on the product. The result will surely open up valuable earlier settings for Enhertu, and help persuade physicians that the drug's known toxicities are worth grappling with.

Enhertu’s problem is interstitial lung disease, and related pneumonia. This was seen in 10.5% of the 261 patients that received Enhertu in Destiny-Breast03, versus 1.9% with Kadcyla, according to the newly released late-breaking Esmo abstract. Most of the Enhertu cases were grade 1 or 2, with no cases judged to be the severest 4 or 5 grades and no drug-related deaths.

This is an improvement on rates seen in earlier trials, when interstitial lung disease did lead to deaths. Astrazeneca and Daiichi have said that efforts to educate physicians on how to manage Enhertu’s toxicities have been working, and these data seem to support this.

The medical community’s response to the full presentation is still needed; Destiny-Breast03 will be presented virtually on Saturday at 2pm CET, but the glimpse provided by the abstract points to an enthusiastic reception.

A clear winner? Enhertu vs Kadcyla in Destiny-Breast03
  Enhertu (n=261) Kadcyla (n=263) Stats
mPFS (by BICR) not reached  6.8 months  HR=0.28 (p0.0001)
mPFS (by investigator) 25.1 months 7.2 months HR=0.26 (p0.0001)
Confirmed ORR 79.1% 34.2% p<0.0001
Estimated 12mth OS rate 94.1% 85.9% HR=0.55 (p=0.007172)*
HR=hazard ratio. Note: *not significant. Source: Esmo and Dr Javier Cortes. 

The impressive hazard ratios for PFS make Enhertu’s benefits over Kadcyla seem pretty incontrovertible. And the almost 18-month advantage suggested by the investigator’s assessments puts this into real terms.

Numerically Enhertu also bestowed an overall survival advantage, although the data are not yet mature and investigators noted that the p value for the hazard ratio did not cross a prespecified boundary for significance. Given the May data cut-off in the abstract, a more recent update on this number at the weekend presentation is possible.

A stronger signal on overall survival would certainly help Astra and Daiichi make the case that Enhertu’s benefits are worth the risks.

Bigger potential?

The ADC’s safety has also been one of the biggest concerns for financial analysts. If interstitial lung disease had proved unmanageable it would have been unthinkable to move Enhertu into earlier – and much more valuable – treatment settings.

Not that consensus sales are exactly modest; Evaluate Pharma’s sellside consensus sits at forecast sales of $4.1bn by 2026. But this number masks a wide range, with the most conservative banks sitting 50% below this figure.

The Esmo data could help firm up expectations in even earlier settings. The neoadjuvant Destiny-Breast05 trial started late last year, while the first-line Destiny-Breast09, pitting Enhertu against Herceptin plus Perjeta, got under way a couple of months ago.

Many marvelled at the $1.4bn that Astra paid Daiichi for rights to Enhertu back in 2019. The emerging data suggest that  optimism was well placed.

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