SABCS: After Enhertu's modest showing in neoadjuvant breast cancer, Daiichi Sankyo's clinical oncology chief wants to see more

While Enhertu’s latest performance in a small, early-stage breast cancer trial is unlikely to win another standing ovation, Daiichi Sankyo’s head of global oncology clinical development is emphatic that he wants to see more.

This past summer, the antibody-drug conjugate (ADC) made history with an FDA nod as the first therapy targeted to treat unresectable or metastatic breast cancer expressing low levels of HER2, unlocking a new category previously consigned to the HER2-negative group.

Now, in an investigator-initiated phase 2 study of Enhertu as a presurgery neoadjuvant therapy in HER-2-low early breast cancer, based on the evaluation of 33 patients in the study, just one patient hit the trial’s primary endpoint of pathologic complete response, which is a “tried and true” endpoint in the presurgical arena, Daiichi’s clinical oncology chief Mark Rutstein, M.D., said in an interview ahead of the 2022 San Antonio Breast Cancer Symposium (SABCS).

In the trial, dubbed TRIO-US B-12 Talent, investigators defined pathologic complete response as total tumor regression and no lymph node involvement at the time of surgery.

When asked whether Daiichi and AstraZeneca still see a future in developing Enhertu for neoadjuvant HER-2-low breast cancer, Rutstein said that “based on the data set, the answer is yes.”

“We need more data,” he added, highlighting the need for larger sample sizes and additional data both at eight and six cycles. “I definitely want to see more.”

Investigators in TRIO-US B-12 set a 5% complete response rate as the primary goal of their study. 

For context, patients with localized, high-risk breast cancer often get chemotherapy before undergoing surgery. However, when those tumors express the estrogen receptor and/or the progesterone receptor, “the pathological complete response rate to neoadjuvant therapy is less than 5%,” which stresses the need for more treatment options, Aditya Bardia, the study’s presenting author, said in a press release.

Before drawing any bold conclusions, it must be noted that the trial data are "not mature," according to the authors, given that not all patients had scans or underwent surgery by the time of the trial's data cutoff. 

Enhertu could meet the researchers' goal if the ADC can keep up at its current pace. That said, 5% isn't the most encouraging target, being only slightly better than chemotherapy in this population.

Still, Daiichi Sankyo isn't discouraged. 

“Based on pathologic data and based on the overall response rate, there’s certainly preliminary evidence of activity here that needs to be further assessed,” Rutstein said of Enhertu’s showing. But the evidence is just that: preliminary. “This is not a conclusive result,” he stated, stressing the need for “more data.”

Taking a closer look at the design of the 58-subject study, half received Enhertu solo, while another 29 were given Enhertu plus the hormone treatment anastrozole. Patients were further broken down into subsets that received either six or eight treatment cycles of Enhertu. At the time of the analysis, 17 patients in the solo arm and 16 in the combo cohort were evaluated.

The patient who hit pathologic complete response was from the monotherapy arm and part of the eight-cycle cohort, Rutstein said. 

Overall, the study’s “modest sample sizes” make it difficult to draw too many conclusions, Rutstein added.

Another caveat Rutstein flagged was the concordance rate of tumor testing for HER2 expression—done locally and then repeated centrally to compare—which was “modest” at 55%. “That’s important to point out when we think about the difference between the population that we intend to enroll and the population that we do enroll,” he said.

Despite those limitations, Rutstein called the trial’s focus a “window of opportunity setting,” noting that despite the small efficacy signals seen, the investigator-launched study is still “analytically rich.”

For one, neoadjuvant testing provides researchers with tissue after surgery for translation analysis and investigations, the Daiichi executive explained. In turn, researchers get to explore that tissue for biomarkers.

The drug fared better on overall response, with around 75% responding to therapy in the Enhertu solo arm versus 63% in the group that got the anastrozole-paired regimen.

Rutstein also pointed to safety, which is important when introducing an ADC nto the neoadjuvant setting, which inherently alters the risk-benefit calculus versus later-stage disease. “Fortunately, the dataset demonstrated that the tolerability was quite adequate,” he said.

Also at SABCS 2022, Daiichi and AZ shared updated data on Enhertu from a head-to-head trial against Roche's Kadcyla, plus a later-line breast cancer confirmatory trial. 

In its clinical sparring match with Kadcyla in metastatic breast cancer, Enhertu charted "significantly longer" overall survival in HER2-positive patients after one prior therapy. Second-line patients who received Enhertu had a 36% lower risk of death than those treated with Roche's med, which was statistically significant, the study's authors pointed out.

Enhertu previously snared second-line approval based on progression-free survival data versus Kadcyla. Now, the drug has also hit on overall survival, which is a gold standard endpoint for oncology trials.

In the confirmatory trial, meanwhile, Enhertu trumped capecitabine-based chemotherapy at helping patients achieve higher response rates and live longer in the third-line, HER2-positive setting after receiving treatment with Kadcyla.