Enhertu succeeds where Kadcyla and others failed

In gastric cancer the Astra/Daiichi drug could tie a second string to its bow, but toxicities might put a dampener on forecasts.

Trial Results

Having secured US approval for breast cancer four months early Enhertu is already showing promise elsewhere. Today’s topline data from a registrational study suggest that the Astrazeneca/Daiichi Sankyo anti-Her2 antibody-drug conjugate could be used in late-line gastric cancer, too.

Other Her2-targeting agents, including Roche’s Kadcyla, have failed here, so Enhertu could give analysts a pleasant surprise, especially if inroads can be made into earlier lines of therapy. However, the sting in the tail is Enhertu’s toxicities, especially interstitial lung disease.

This emerged as the side effect to watch in Enhertu’s Destiny-Breast01 study, which secured its approval last month. 14% of subjects suffered this side effect, leading to four treatment-related deaths (SABCS 2019 – Astrazeneca and Daiichi join the Her2 resistance, December 11, 2019).

At least no interstitial lung disease-related deaths were seen among the 189 Her2-positive subjects in Destiny-Gastric01, the trial that read out today, though this toxicity, and the related pneumonitis, were seen: most cases were mild, but there was one grade 4 and two grade 3 events.

Optimism

That said, there seems to be plenty of room for optimism, especially as in Destiny-Gastric01 Enhertu improved overall survival as well as overall remission, its primary endpoint, versus physician’s choice. To enter the study subjects had to be Her2-positive and to have failed at least two treatments.

Her2-positive gastric cancer patients have Herceptin plus chemo as a first-line standard of care, but options are limited after they relapse. Lilly’s Cyramza, for instance, has a second-line label in all comers; if a first-line patient got chemo only then Herceptin logically remains a second-line option.

However, Enhertu’s real triumph is in having shown activity after the failure of Herceptin. One assumption is that once a patient fails the Roche MAb they would no longer respond to another Her2-directed drug, but like in Destiny-Breast01 Enhertu has disproved such a theory.

Astra and Daiichi argue that Enhertu’s high-intensity payload and cell membrane permeability might enable it to target tumours that express Her2 at relatively low levels, and so far this theory is playing out. Moreover, Enhertu looks especially promising in light of the failures of other anti-Her2 therapies.

Most recently Roche’s Kadcyla failed in the Gatsby trial in second-line, Her2-positive gastric cancer. And earlier Novartis’s Tykerb flunked the Tytan trial in a similar population of Asian subjects. Roche’s Perjeta is being studied in front-line and neoadjuvant Her2-positive gastro-oesophageal adenocarcinoma.

Astra and Daiichi investors will now want to know how big an opportunity this could become: for now EvaluatePharma sellside consensus sees just $58m of Enhertu’s 2024 sales of $2.2bn coming from gastric cancer.

Enhertu’s next gastric cancer test will be a second-line study ending in October. Astra told Vantage that it was planning other gastric cancer trials, and stressed that it was educating doctors and patients about early identification, intervention and management of interstitial lung disease and pneumonitis.

If a front-line label represents a best-case scenario this will surely require a head-to-head beat of Herceptin, not to mention the allaying of fears over lung disease.

Enhertu in Her2-positive gastric cancer
Trial Setting Data
Muti-tumour basket trial Various post-Herceptin 4 pneumonitis cases (three grade 2 and one grade 3)
Destiny-Gastric01 ≥3rd line Stat sig ORR & OS improvements vs physicians' choice; ILD & pneumonitis at grades 1, 2, 3 (two cases) & 4 (one)
U205 2nd line Completion Oct 2020

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