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HER2 Antibody-Drug Conjugates Show Promise in Pan-Tumor Trials


NEW YORK – Results presented at the European Society for Medical Oncology Congress from two pan-tumor trials of AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) suggest the HER2-targeted drug could become the first antibody-drug conjugate approved in a tumor-agnostic indication.

In addition, early clinical results from two other tumor-agnostic trials further illustrate the potential of HER2-targeted antibody-drug conjugates beyond breast cancer.

HER2 mutations are believed to drive cancer through constitutive HER2 activation, leading to downstream signaling that, in turn, affects cell proliferation, survival, differentiation, and other processes. The mechanism is similar to, but distinct, from HER2 gene amplification and in most cases, HER2-mutated tumors are not associated with HER2 gene amplification. As a result, they can be missed by immunohistochemistry (IHC) or fluorescence in situ hybridization screening.

HER2 mutations have been found in a wide range of solid tumor types including lung, bladder, ovarian, pancreatic, salivary gland, and gynecological cancers. In addition to its breast cancer indications, Enhertu has been approved in the US and Europe as a second-line treatment for patients with advanced non-small cell lung cancer harboring HER2 mutations. It is also approved in the US for HER-positive gastric and gastroesophageal junction cancer and has been recommended in that setting by the European Medicines Agency's Committee for Medicinal Products for Human Use. Researchers are now expanding studies of Enhertu and other HER2-targeted ADCs to additional solid tumor types in the hope that these drugs can eventually be prescribed for patients based on HER2 positivity alone.

Previously, a Phase I trial of Enhertu in patients with HER2-expressing or mutated cancers yielded promising results for a potential pan-tumor indication for the drug. That trial reported an objective response rate of 36.7 percent and a disease control rate of 80 percent. In a subgroup of 19 patients with HER2-mutated cancer, the rate of confirmed partial response was 47.4 percent, "providing some preliminary clinical evidence to support further study," Bob Li, a thoracic oncologist at Memorial Sloan Kettering Cancer Center, said at ESMO.

Now in the DESTINY-PanTumor01 trial, researchers are aiming to replicate these results on a larger scale among patients with advanced HER2-mutated solid tumors. In a second trial, DESTINY-PanTumor02, they are looking at Enhertu in HER2-expressing tumors.

At ESMO, Li presented primary results from DESTINY-PanTumor01, an open-label Phase II trial of Enhertu in patients with solid tumors harboring HER2-activating mutations. To be eligible for the trial, patients had to test positive for at least one of a list of pre-specified HER2 mutations. Patients with HER2-overexpressing (IHC3+ or IHC2+/ISH+) breast, gastric, and gastroesophageal junction cancer and HER2-mutant lung cancers, however, were excluded because they already have a US Food and Drug Administration-approved HER2-targeted therapy available. Patients had received between three and 13 prior lines of therapy.

In the trial, the overall response rate was 29.4 percent. The median duration of response was not reached, and 54.2 percent of patients who initially responded were still responding after 18 months. Median progression-free survival was 5.4 months, median overall survival was 10.9 months, and the researchers saw responses across HER2 expression levels including in HER2 IHC0 tumors.

"Responses occurred across the board," in various tumor types, Li said, including in those with a range of HER2 mutations. Those mutations were predominantly in the HER2 kinase domain, but there were also responses in patients with mutations in the transmembrane domain. "Most of the responses actually happened in non-HER2 amplified tumors," he noted.

Li concluded that further research is warranted to better define which patients with HER2 mutations may derive the greatest benefit from Enhertu.

In a discussion of the results, Alex Adjei, chief of Cleveland Clinic's cancer institute, highlighted the 51 percent rate of grade three or higher adverse events and 9.8 percent rate of discontinued treatment due to adverse events. "Remember, this is very toxic chemo, even though it's directed," Adjei said, explaining that because Enhertu has an unstable linker, the ADC can be cleaved, releasing the payload into circulation.

Although this is in part a desirable mechanism, known as the bystander effect, that increases potency of the anti-tumor effect; it can also lead to toxicity by exposing healthy cells to the topoisomerase I inhibitor payload. This can cause interstitial lung disease via HER2 expression on lung parenchymal tissue and neutropenia through binding of the linker to CD33. In spite of these cautions around toxicity, Adjei said, "Dr. Li's study suggests actually that there's a possibility we are going to get the first ADC that has a tumor-agnostic approval just based on the HER2 mutation."

Meanwhile, Funda Meric-Bernstam, chair of the department of investigational cancer therapeutics at MD Anderson Cancer Center, presented updated results from the Phase II DESTINY-PanTumor02 trial at ESMO. In this trial, researchers enrolled patients with HER2-expressing biliary tract, bladder, cervical, endometrial, epithelial ovarian, and pancreatic cancers, as well as other rare tumors. To be eligible for the trial, patients had to have HER2 expression IHC scores of 2+ or 3+, except in the cervical cancer cohort, which included patients with a score of 1+.

In previously reported interim results, the objective response rate for all patients was 37.1 percent, patients with IHC 3+ scores had a 61.3 percent response rate, and 46 percent of all patients had stable disease. At 12 weeks, the disease control rate was 68.2 percent. The duration of response was 11.8 months in all patients and 22.1 months in IHC 3+ patients. Following those results, AstraZeneca initiated discussions with health authorities about regulatory filings for Enhertu in HER2-expressing cancers.

In the updated results — which included data for progression-free and overall survival — the objective response rate in all patients remained 37.1 percent, the median duration of response was 11.3 months, median progression-free survival was 6.9 months, and median overall survival was 13.4 months. Patients with IHC3+ scores had an overall response rate of 61.3 percent and a median duration of response of 22.1 months. In that group, median progression-free survival was 11.9 months, while the median overall survival was 21.1 months. Investigators saw treatment-related adverse events in 40.8 percent of patients, and 8.6 percent discontinued therapy due to an adverse event.

"We had responses in every tumor type but had especially high response rates in gynecological tumors and patients that were [IHC] 3+," Meric-Bernstam said, emphasizing that for IHC3+ patients with endometrial and cervical cancer, median progression-free survival had not been reached after more than two years of follow-up. Patients with pancreatic cancer had the lowest response rates, at 4 percent for all patients.

"The DESTINY-PanTumor02 trial very convincingly shows high efficacy in tissues beyond breast cancer," said Pamela Munster, a medical oncologist at the University of California, San Francisco, in a discussion of the results. "Also, despite the bystander effect and the promising efficacy we see in HER2-low, HER2 expression does matter. The more expression, the higher the response."

Additionally, Munster noted that tissue context remains relevant, as evidenced by the poor results in pancreatic cancer and lesser responses in biliary tract cancers compared to gynecological tumors.

"Not only does HER2 expression correlate with response, it also correlates with survival," Munster added, pointing out that progression-free survival in HER2 3+ patients was 11.9 months compared to 5.4 months in patients with IHC 2+ expression. She called the overall survival difference — 12.2 months in IHC2+ patients and 21 months in IHC3+ patients — "striking."

Two earlier-stage trials presented at ESMO appear to further shore up the hypothesis that HER2 can be successfully targeted in a tumor-agnostic manner. In a Phase I trial of Luzsana Biotechnology's anti-HER2 antibody SHR-A1811, patients with advanced gastric, gastroesophageal, and colorectal cancer who had failed or had no available standard treatment were treated with escalating doses of SHR-A1811 in the first part of the study and treated with selected tolerable doses in the second part. SHR-A1811 comprises a biosimilar of the anti-HER2 antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload.

The primary endpoints of the study were dose-limiting toxicities, safety, and a recommended phase II dose. Researchers also collected preliminary efficacy data, comparing HER2-positive and HER2-negative cohorts.

The objective response rate in gastric cancer and gastroesophageal adenocarcinoma was 38.2 percent compared to 43.8 percent in HER2-positive gastric and gastroesophageal adenocarcinoma. In colorectal cancer, HER2-positive patients had an objective response rate of 46.9 percent, compared to 44.2 percent for the HER2-negative group. The six-month progression-free survival rates in gastric and gastroesophageal cancer were 73.9 percent and 71 percent for HER2-positive and HER2-negative patients, respectively. In colorectal cancer, HER2-positive patients had a six-month progression-free survival rate of 85.5 percent versus 75.6 percent for the HER2-negative group.

Yiming Zhao, a director of RNA therapeutics and drug delivery, who presented the results, concluded that SHR-A1811 had promising anti-tumor activity in heavily pre-treated HER2-expressing or mutated advanced non-breast solid tumors with an acceptable safety profile.

In another Phase I study also presented by MSKCC's Li, researchers explored safety and preliminary activity of Bolt Biotherapeutics' HER2-targeted ADC BDC-1001. The drug consists of a biosimilar trastuzumab, a non-cleavable linker, and a TLR7/8 immune-stimulating payload. Unlike an ADC with a cytotoxic payload that is designed to kill tumor cells directly, BDC-1001 is designed to activate the immune system against tumor cells.

Patients with 16 different HER2-positive or HER2-low solid tumors representing 16 different tumor types were included in the trial, and the researchers saw clinical activity in multiple tumor types. Six patients had a partial response, 11 patients had stable disease, and among the 15 patients with HER2-positive tumors who received the recommended Phase II dose, the rate of clinical benefit was 47 percent with 27 percent having confirmed partial responses and 20 percent with stable disease.

The treatment, according to Li, was tolerable and safe with no treatment-related deaths and no grade three or higher adverse events.

Li said now that the trial has shown a favorable safety profile and preliminary clinical activity, it will be expanded to include monotherapy cohorts and combinations with Bristol Myers Squibb's Opdivo (nivolumab) in HER2-expressing colorectal, gastroesophageal, and endometrial cancers and with Genentech's Perjeta (pembrolizumab) in breast cancers.