SAN ANTONIO – Next-generation HER2-targeting drugs are inching toward the market to further expand use of this treatment class in earlier lines of therapy and in patients with different clinical and genomic features, such as brain and liver metastases and low HER2 expression.
At the San Antonio Breast Cancer Symposium on Thursday, researchers presented data from later stage trials of HER2 therapies, in which HER2-positive breast cancer patients received them as earlier lines of treatment, including data on Jiangsu Hengrui Medicine's EGFR, HER2, and HER4 inhibitor pyrotinib and HER2-directed ADC SHR-A1811.
"The role of HER2 ADC monotherapy in early-stage HER2-positive breast cancer as an upfront treatment option remains challenging to define," Aleix Prat, head of the medical oncology department at the Hospital Clinic Barcelona, said in a discussion of Jiangsu Hengrui's drugs. "Enhancing outcomes in the first-line HER2-positive metastatic breast cancer setting might be challenging, given the high standard already set, but many pivotal trials are ongoing."
Also at the meeting, researchers presented data from early-stage trials of novel HER2-targeted treatments in previously treated HER2-positive breast cancer. The drugs highlighted included Jazz Pharmaceuticals' bispecific monoclonal antibody Ziihera (zanidatamab), SuZhou Teligene's HER2 inhibitor TL-938, Roche's HER2 inhibitor ZN-1041, and RemeGen and Seagen's antibody-drug conjugate disitamab vedotin.
Advances in frontline HER2 treatment
Jiangsu Hengrui's pyrotinib is already approved in China in combination with capecitabine for treating HER2-positive metastatic breast cancer patients who have received prior chemotherapy. In the PHILA trial, the company tested the agent's frontline activity in HER2-positive metastatic breast cancer.
The 590-patient trial compared pyrotinib plus Genentech's first-generation HER2-targeted drug Herceptin (trastuzumab) and chemo versus placebo plus Herceptin and chemo and showed that the pyrotinib-containing regimen improved progression-free and overall survival outcomes. At the symposium, Binghe Xu, a professor at the Chinese Academy of Medical Sciences, reported that the median progression-free survival was 22.1 months in the pyrotinib arm, more than double the 10.5 months median progression-free survival in the placebo arm. The four-year overall survival rate was 74.5 percent and 64.3, respectively.
Despite the encouraging readout, in a discussion of the data, Prat, who was not involved with the study, pointed out that the control arm in this study is not the standard of care regimen in most countries, which typically also includes Genentech's Perjeta (pertuzumab).
Researchers also presented results from the Phase II FASCINATE-N trial testing Jiangsu Hengrui's ADC SHR-A1811 as a monotherapy neoadjuvant treatment for HER2-positive breast cancer. The study included 265 patients who were randomized to receive either SHR-A1811; SHR-A1811 with pyrotinib; or standard neoadjuvant treatment with chemotherapy, Herceptin, and Perjeta. The pathologic complete response rates with SHR-A1811 monotherapy was 63.2 percent; 62.5 percent with SHR-A1811-pyrotinib; and 64.4 percent in the control arm in the whole study population, said Junjie Li, a researcher at Fudan University in Shanghai, during a presentation of the data.
SHR-A1811 demonstrated greater efficacy in patients who had hormone receptor (HR)-negative disease, with a 74.5 percent complete response rate, compared to a 50 percent complete response rate in those with HR-positive disease in the study.
There were fewer dose reductions and discontinuations with SHR-A1811 monotherapy than with SHR-A1811-pyrotinib and in the control arm. The SHR-A1811-pyrotinib arm had the highest rate of treatment-related adverse events.
"The standard four-drug combination [of taxane, carboplatin, Herceptin, and Perjeta] is quite effective, with a pathological complete response rate of up to 65 percent," Li said at the meeting. "It is quite challenging to identify a better regimen that can improve the pathological complete response rate. With comparable efficacy, SHR-A1811 might serve as a backbone and combination with targeted therapies."
Prat highlighted other ongoing trials of anti-HER2 therapies in the frontline setting, including the Phase III DESTINY-Breast09 study, evaluating AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) as a first-line treatment for HER2-positive advanced or metastatic breast cancer; and the Phase III HER2CLIMB-05 trial of Pfizer's Tukysa (tucatinib) with Herceptin and Perjeta as a maintenance therapy for HER2-positive breast cancer.
Novel therapies address gaps in early trials
In a Phase I trial, researchers explored Jazz's Ziihera, recently approved in the US for HER2-positive biliary tract cancer, in combination with ALX Oncology's anti-CD47 blocker evorpacept in HER2-positive and HER2-low metastatic breast cancer. The readout from this trial added to the growing data in the HER2-low breast cancer setting after Enhertu first reported activity in this population in 2022.
In the trial, researchers enrolled 44 breast cancer patients, 21 of whom were HER2-positive (IHC 3+ or IHC 2+ and in situ hybridization-positive) and 15 of whom were HER2-low (IHC 2+ and ISH-negative or IHC 1+). The study also included eight patients with other HER2-expressing cancers, such as gastroesophageal cancer, in a separate cohort.
In the HER2-positive breast cancer cohort, Ziihera demonstrated a 33.3 percent response rate and a median progression-free survival of 3.6 months. In the HER2-low group, three patients responded, yielding a 20 percent response rate. The disease control rate was 40 percent, including the three responders and another three patients with stable disease. The median progression-free survival was 1.9 months.
The researchers noted that "further development of this chemotherapy-free regimen is warranted" based on the results in both HER2-positive and HER2-low patients.
Mafalda Oliveira, senior consultant at the Vall d'Hebron University Hospital's Medical Oncology Department, who was not involved with the study, said in a discussion of the data that Ziihera's activity in the HER2-low population was interesting, but questioned whether the company was intending to use the Ziihera-evorpacept regimen in combination with other drugs like checkpoint inhibitors or chemo or pursue it as a chemo-free option.
In two other studies, researchers explored the activity of novel HER2 inhibitors in HER2-positive breast cancer patients with brain metastases.
"We know that approximately one-third to up to half of patients with HER2-positive breast cancer develop brain metastasis along the course of disease," Paolo Tarantino, a breast medical oncologist at Dana-Farber Cancer Institute, said in a discussion of the two brain metastases studies. "One issue we have with brain metastasis, there are treatments that do not penetrate the blood-brain barrier that well. There are novel [tyrosine kinase inhibitors] either trying to get even higher selectivity and particularly more brain retention."
In a Phase I trial of Roche's ZN-1041 with chemo, researchers enrolled 40 HER2-positive breast cancer patients with brain metastases who had no prior TKIs. Among 34 evaluable patients, the overall response to ZN-1041 was 79.4 percent and the intracranial response rate was 75 percent.
Among 32 patients with measurable brain lesions, the median progression-free survival on the drug was 17.4 months and the median duration of intracranial response was 14.7 months.
In another study, researchers evaluated SuZhou Teligene's TL-938 as a single-agent in patients with HER2-positive breast cancer that had spread to the brain. Among 18 patients, the overall response rate across all doses was 50 percent. The researchers noted that most responses were seen with the highest dose in the trial, which had a 70 percent response rate and a 100 percent disease control rate among 10 patients.
Tarantino, who was not involved in either trial, noted that these results for ZN-1041 with chemo and TL-938 monotherapy were "very encouraging." However, he noted that the patients in these studies did not receive standard treatment regimens prior to the study drug, such as Enhertu. "It's important to test these drugs in patients treated with these regimens," he added.
A Phase III trial of RemeGen's disitamab vedotin versus Novartis' HER2-targeted drug Tykerb (lapatinib) with chemo showed that disitamab vedotin could be an option for HER2-positive breast cancer patients with liver metastases. In 104 patients, the response rate was 58.5 percent for disitamab vedotin versus 54.9 percent for Tykerb and chemo. The median duration of response was 11.2 months in the disitamab vedotin arm compared to 6.97 months in the Tykerb arm.
Disitamab vedotin also improved progression-free survival outcomes, and researchers noted a trend toward improved overall survival compared to Tykerb and chemo. Patients on disitamab vedotin had a median progression-free survival of 9.9 months compared to 4.9 months on the Tykerb regimen. Overall survival data were immature for disitamab vedotin at the time of data cutoff with a median follow-up of 17.2 months.
While the data showed a clear benefit over Tykerb, Oliveira said, it was unclear where disitamab vedotin could fit into the current treatment algorithm.
"If we look at some data of [Enhertu] from DESTINY-Breast03 in patients with visceral metastases, [progression-free survival] is 22.2 months," Oliveira said. "Considering the current guidelines, it is unclear how disitamab vedotin could be integrated into the current algorithms that include [Enhertu]."