The juggernaut that is Daiichi Sankyo Co. Ltd.’s Enhertu (fam-trastuzumab deruxtecan-nxki) continued to roll into this weekend’s American Society of Clinical Oncology (ASCO) virtual meeting, bringing momentum from its December FDA approval for HER2-positive breast cancer, along with fresh data from three new studies in other indications.

Data from the phase II DESTINY-Gastric01 trial show Enhertu is the first HER2-directed medicine to improve overall survival (OS) for previously treated metastatic gastric cancer, notching a 41% reduction in the risk of death vs. chemotherapy. The data were based on a hazard ratio of 0.59 (95% confidence interval 0.39-0.88; p=0.0097) at a prespecified interim analysis. The median OS was 12.5 months vs. 8.4 months with chemotherapy. The estimated OS rate at one year in the Enhertu arm was 52.1% and 28.9% for the chemotherapy arm.

The data from Daiichi and Astrazeneca plc also show a statistically significant improvement in objective response rate (ORR), the study’s primary endpoint. The ORR, an independent central review concluded, was 42.9% with Enhertu monotherapy (6.4 mg/kg) compared to 12.5% with investigator’s choice of chemotherapy (paclitaxel or irinotecan). Ten complete responses (CRs) and 41 partial responses (PRs) were seen in patients treated with Enhertu vs. no CRs and seven PRs seen in patients treated with chemotherapy.

The trial evaluated patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma that had progressed following two or more treatment regimens, including trastuzumab and chemotherapy.

In its April 29 conference call to investors, Astrazeneca’s management said it will commence regulatory submissions for Enhertu in gastric cancer in the second quarter of the year.

Cowen analysts held a key opinion leaders session preview of ASCO. Those consultants called Enhertu one of the most active anti-HER2 drugs. They said their main concern is the risk of interstitial lung disease (ILD) but said they remain hopeful better patient management will reduce its severity. In the DESTINY-Gastric01 trial, there were 12 cases (9.6%) of confirmed treatment-related ILD and pneumonitis, an independent review determined. Most were grade 1 or 2 with two grade 3s, one grade 4 and no grade 5 ILD-related deaths.

The Dec. 20 FDA approval for the antibody-drug conjugate (ADC) in breast cancer came nearly four months ahead of expectations and, after reviewing the new data in HER2-positive colorectal and lung cancers, some analysts predict early approvals may be in the cards for both.

Key opinion leaders rounded up by SVB Leerink declared accelerated approval is plausible for Enhertu in HER2-positive unresectable and/or metastatic colorectal cancer, based on data presented from the phase II DESTINY-CR01 trial. Enhertu showed clinically meaningful activity in those patients who received at least two prior lines of standard treatment. The confirmed objective response rate tallied 45.3% of patients treated with Enhertu as a monotherapy achieved a tumor response. The disease control rate was 83%, with a median progression-free survival (PFS) of 6.9 months.

The Leerink analysts also applauded an interim analysis showing Enhertu’s meaningful clinical activity in patients with HER2-mutant unresectable and/or metastatic non-squamous non-small-cell lung cancer in the phase II DESTINY-Lung01 trial. The study’s primary endpoint of confirmed ORR was 61.9% for those treated with Enhertu as a monotherapy. The patients achieved a 90.5% disease control rate with an estimated median PFS of 14 months. The control rate, the analysts noted, “could potentially enable an accelerated pathway,” adding that the safety profile across those trials appears consistent with prior reported data, including ILD/pneumonia risk.

The December approval for adults with HER2-positive breast cancer that has spread to other parts of the body or cannot not be removed by surgery has been a money maker since its January launch. A significant price tag came with the package, as Astrazeneca paid Daiichi $1.35 billion up front and pledged up to $5.55 billion in additional payments as part of the April 2019 deal. Astrazeneca also paid Daiichi $125 million in a milestone payment when the FDA gave its approval.

Since the January launch, Astrazeneca reported $14 million in collaboration revenue based on $30 million of sales that Daiichi booked in the first quarter of 2020. Enhertu now has about a 30% share in the third-line setting, according to Astrazeneca, with about 800 accounts opened in the first three months of 2020 and about 1,000 patients treated during that time.

ADCs for cancer treatment are a rarity. In the three years since an ADC gained approval, only five have reached the market. Finding the right balance between toxicity and efficacy has baffled developers. Of the three oncology drugs on the Cortellis Drugs to Watch blockbuster list, two are ADCs, including Enhertu. The other is Immunomedics Inc’s Trodelvy (sacituzumab govitecan-hziy), which received accelerated approval on April 22 for adults with metastatic triple-negative breast cancer who received at least two prior therapies for metastatic disease.

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