Antibody-drug conjugates advance into early therapy

Astrazeneca/Daiichi’s Enhertu and Roche’s Polivy both score in pivotal trials that could see them threaten early-line incumbents.

Much of the potential of Astrazeneca’s Enhertu and Roche’s Polivy lies in advancing these antibody-drug conjugates into therapy lines earlier than those cited on their current labels. This morning both appeared to score important victories in pivotal studies designed to achieve this.

Although Enhertu and Polivy target different diseases – breast cancer and lymphoma respectively – they have led parallel existences, winning accelerated US approvals in 2019 but posting modest sales so far. No data are available yet from the Destiny-Breast 03 and Polarix trials toplined today, but they will determine whether the sellside’s respective 2026 revenue expectations of $4.1bn and $1.4bn are achievable.

Two weeks ago Astra reported $89m of first-half sales from Enhertu, a Her2-directed ADC, in its first indication of third-line or later Her2-positive breast cancer. Accelerated approval was won in this setting based on the uncontrolled Destiny-Breast 01 study.

This morning’s success related to Destiny-Breast 03, a second-line breast cancer trial that is the first to compare Enhertu against active control – Roche’s rival ADC Kadcyla. Astra said a data-monitoring committee had recommended an interim halt owing to “significant and clinically meaningful” improvement in median PFS; OS was said to be immature but trending positively.

Full data are needed to quantify the meaningfulness of the survival benefit and the rates of interstitial lung disease, a black-boxed adverse event that could hinder earlier-line use. Possible venues for full results presentation include the Esmo and the San Antonio Breast Cancer meetings.

Still, Astra is wasting no time, and is running numerous breast cancer trials for Enhertu, including the front-line study Destiny-Breast 09, which got under way in the past three months. This is likely spurred by the large bet it made on Enhertu, licensed from Daiichi Sankyo for $1.35bn, and by mounting competition in Her2-positive breast cancer.

A tale of two antibody-drug conjugates
Study Setting Data Regulatory
Enhertu, Astrazeneca/Daiichi Sankyo (Her2+ve breast cancer)
Destiny-Breast 01 Median 6 prior lines, incl Kadcyla 60.9% ORR; 16.4mth mPFS; 13.6% interstitial lung disease Accelerated approval for ≥3L, Dec 2019
Destiny-Breast 03 2L (post Herceptin + taxane), vs Kadcyla Positive for mPFS; OS immature but numerically positive Filing H2 2021
Destiny-Breast 04 ≥2L, Her2-low, vs investigator's choice chemo Primary endpoint: PFS by independent review Filing H1 2022
Destiny-Breast 02 3L, post-Kadcyla, vs Herceptin/Tyverb + chemo Primary endpoint: PFS by independent review Filing H2 2022
Destiny-Breast 05 Adjuvant, vs Kadcyla Primary endpoint: iDFS Filing 2022+
Destiny-Breast 06 1L, Her2-low, vs investigator's choice chemo Primary endpoint: PFS by independent review Filing 2022+
Destiny-Breast 09 1L, +/-Perjeta, vs Herceptin + Perjeta + taxane Primary endpoint: PFS by independent review
Polivy, Roche (diffuse large B-cell lymphoma)
GO29365 ≥3L, benda+Rituxan combo, vs benda+Rituxan ORR 40% vs 18% Accelerated approval Jun 2019
Polarix 1L, Rituxan-CHP combo vs Rituxan-CHOP Positive for investigator-assessed mPFS Data being shared with regulators
Source: & company information.

Indeed, only today Seagen shelled out $200m for rights to a little-known anti-Her2 ADC, disitamab vedotin/RC48-ADC, originated by the Chinese company Remegen. However, breast cancer is not its primary focus; rather, disitamab has US breakthrough therapy designation for Her2-positive urothelial cancer, where data were presented two years ago.

Investors might well ask what the deal says about the faith Seagen has in its own Tukysa, a small molecule approved for second-line Her2-positive breast cancer in combination with Herceptin.

Lymphoma first?

For its part Roche is trying to position Polivy, an anti-CD79B ADC, as the first therapy in two decades to improve PFS in front-line diffuse large B-cell lymphoma, a claim it says is backed by the outcome of the Polarix trial toplined today.

Polivy is approved in combination with bendamustine and Rituxan for third-line or later DLBCL, a setting in which first-half 2021 sales came in at $103m. Polarix tested it front line on top of Rituxan plus CHP chemo, a regimen said to have beaten Rituxan plus CHOP chemo in terms of investigator-assessed mPFS.

DLBCL patients have not seen many treatment advances beyond the approvals of Car-T therapies in relapsed/refractory settings, and of Morphosys/Incyte’s anti-CD19 MAb Monjuvi for second-line use. Still, Jefferies analysts are sceptical that the benefit in Polarix will be enough to justify wholesale switching from Rituxan-CHOP; full Polarix data, possible at Ash in December, will reveal all.

Either way, it is clear that after years of misfires ADC-based drugs are making strides at last. And Seagen appears to have its finger in many pies in this small world: its technology lies behind Polivy, for instance, and the US company had a deal with Daiichi that is now the subject of a legal claim over Enhertu.

Why Seagen, an ADC expert, has had to go externally to Remegen to bring in an asset it might have been expected to develop itself is a question some investors might now be asking.

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