Pharma watchers have always suspected that AstraZeneca and Daiichi Sankyo’s Enhertu is a better HER2 therapy than Roche’s Kadcyla. But guessing is all they could do without a head-to-head trial to show just how different the two antibody-drug conjugates are.
Enhertu slashed the risk of disease progression or death by a massive 71.6% over Kadcyla in second-line HER2-positive metastatic breast cancer patients previously treated with Roche’s Herceptin and chemo, AstraZeneca and Daiichi reported at the European Society for Medical Oncology 2021 virtual meeting.
The showing is so impressive that the study authors concluded that the study, dubbed Destiny-Breast03, will lead to a paradigm shift in the treatment of HER2-positive breast cancer. Jefferies analysts recently pegged Enhertu’s peak sales in the second-line setting at $500 million.
Enhertu showed superior benefits on several fronts in the trial. The median time to disease progression or death was not reached for Enhertu and 6.8 months for Kadcyla, according to a blinded independent review, which led to the above 71.6% progression-free survival edge. By investigator’s analysis, the median time to progression or death was 25.1 months for Enhertu versus 7.2 months for Kadcyla, and there was a risk reduction of 73.5%.
Kadcyla appeared to show an inferior efficacy profile compared with its historical clinical results. In its own phase 3 Emilia trial among second-line patients, Kadcyla recorded a progression-free survival of 9.6 months.
Kadcyla did seem to have underperformed in some patients, Dave Fredrickson, AstraZeneca’s head of oncology business unit, acknowledged in an interview, but he pointed out that the Emilia trial was run at a time when Roche’s Perjeta wasn’t approved for the postsurgery treatment of patients with early breast cancer. So those patients didn’t have the big upfront impact from early treatment with Perjeta. In the post-Perjeta as adjuvant era, Kadcyla’s performance is largely in line with real-world experience, he said.
In Destiny-Breast03, Enhertu also more than doubled the number of patients who responded to treatment, as the AZ-Daiichi med shrunk tumors in about 8 of 10 its patients, while the rate for Kadcyla was just a little over one third.
“The investigators that we talked to start talking about maybe we’re opening up the possibility for some women that a cure could be possible in advance disease,” Fredrickson said.
The life extension data remain immature; Enhertu cut the risk of death by 44.5% at the interim analysis, though it hasn’t met the statistical significance bar. The estimated 12-month survival rate was 94.1% for Enhertu versus 85.9% for Kadcyla.
Decreasing interstitial lung disease rate 'very encouraging'
Beyond the unquestionable efficacy win, industry watchers have been keeping a close eye on the potentially dangerous side effect of interstitial lung disease (ILD), which has appeared at higher rates in drugs developed with Daiichi’s antibody-drug conjugate technology. Doctors often cite the safety signal as a key reason why they aren’t already prescribing Enhertu in the FDA-approved third-line breast cancer setting.
Here, Fredrickson described Enhertu’s safety profile as “very encouraging.” ILD turned up in 10.5% of Enhertu patients, none in the severe grade 4 or 5 groups. For Kadcyla, the problem occurred in 1.9% of patients, all belonging to grade 1 or 2. Previously, the Destiny-Breast01 trial in late-line disease linked Enhertu to a 13.6% ILD rate, including 2.2% of deaths.
Lower overall ILD rate and no patient deaths are improvements for Enhertu, but two breast cancer experts had previously told SVB Leerink that Enhertu’s ILD rate needs to come in along the lines of 5% to significantly penetrate the front- or second-line breast cancer settings.
Fredrickson argued that physicians are mainly focused on grade 4 or 5 ILD event, because “there is an acceptance that grade 1/ 2 ILD is something that is manageable.” AZ has invested in awareness, monitoring and management of ILD, he added, and the rates in the real-world appear to be “much lower” as a result of those efforts.
AZ and Daiichi have recently moved Enhertu into a front-line HER2-positive breast cancer trial and are exploring the ADC in a range of disease areas. These include the Destiny-Breast 04 trial in second-line HER2-low breast cancer, which expects to read out in the first half of 2022.
Adding new stomach cancer, lung cancer data
Also at ESMO 2021, the pair unveiled data from the single-arm Destiny-Gastric02 trial of Enhertu in Western patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Among patients who received one or two prior lines of therapy, Enhertu triggered a response in 38% of patients, lasting a median 8.1 months.
The numbers were slightly weaker than in the pivotal Destiny-Gastric01 trial in Japan and South Korea that earned Enhertu its FDA go-ahead in previously treated stomach cancer in January. There, the drug spurred a response in 43% of patients, with a median duration of 11.3 months among a group of patients who had received a median two previous therapies for advanced disease.
The prevalence of stomach cancer and how it’s treated are different between Asian populations and in the West, Fredrickson explained. AstraZeneca said the two trials complement each other and “will support ongoing discussions with global health authorities.”
In addition, Enhertu also reported at ESMO 2021 more data from the phase 2 Destiny-Lung01 trial. After a median follow-up of 13.1 months, Enhertu shrunk tumors in 54.9% of patients with HER2-mutant non-small cell lung cancer who had received a median two prior cancer therapies.
Probably because these patients already suffered from lung disease, the rate of ILD was high at 26.4% in the trial, including 6.6% at grade 3 or above.
Combined with the latest data with the positive readout reported earlier from the HER2-overexpressing cohort of the study, AZ and Daiichi are talking to regulators about a path forward for Enhertu in NSCLC, Fredrickson said.