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Enhertu Shows Promise as Tumor-Agnostic HER2-Targeted Therapy

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This story has been updated to add that Daiichi Sankyo is also Enhertu's sponsor, and to correctly state the objective response rate in bladder cancer patients was 39 percent and HER2 IHC 1+ cervical cancer patients were eligible for the trial.

CHICAGO – Interim results from the tumor-agnostic Phase II DESTINY-PanTumor02 trial presented at the American Society of Clinical Oncology (ASCO) annual meeting on Monday suggest broad activity for its HER2-targeted antibody-drug conjugate Enhertu (trastuzumab deruxtecan) across HER2-expressing solid tumors.

Enhertu, which AstraZeneca is jointly developing with Daiichi Sankyo, is currently approved for treating HER2-positive and HER2-low metastatic breast, HER2-positive gastric, and HER2-mutant non-small cell lung cancer (NSCLC). Although HER2 expression is associated with an aggressive phenotype in a range of solid tumors, testing for HER2 expression is not routine, and approved HER2-targeted treatments are not currently available outside of tumor-specific indications.

In preclinical studies, Enhertu has shown activity against other tumor types including salivary gland, biliary tract, and endometrial tumors. The drugmakers are advancing Enhertu in the tumor-agnostic setting to fill an unmet need for therapies for patients with HER2-expressing tumors, particularly those who have failed standard therapies.

In DESTINY-PanTumor02, researchers enrolled patients with HER2-positive biliary tract, bladder, cervical, endometrial, epithelial ovarian, and pancreatic cancers, as well as other rare tumors. The trial excluded patients with certain tumor types including NSCLC, gastric cancer, and colorectal cancer who had progressed on prior treatment or are out of options. To be eligible for the trial, patients had to have HER2 expression immunohistochemistry scores of 2+ or 3+, except in the cervical cohort which included patients with a core of 1+.

Participants received Enhertu at a dose of 5.4 mg/kg every three weeks. The primary endpoint in DESTINY-PanTumor02 was objective response rate, and secondary endpoints included duration of response and disease control rate. As of a Nov. 20, 2022, cutoff date, 44 patients out of the original 267 remained in the study. Most patients who dropped out did so due to disease progression.

The overall response rate for all patients was 37.1 percent, and for those with IHC 3+ scores 61.3 percent; 46 percent of all patients had stable disease on Enhertu. The disease control rate at 12 weeks was 68.2 percent. The median duration of response was 11.8 months in all patients and 22.1 months in IHC 3+ patients. Response rates in gynecological cancers were higher with 50 percent of cervical cancer, 57.5 percent of endometrial cancer, and 45 percent of ovarian cancer patients responding to Enhertu. Patients with biliary cancer and bladder cancer had objective response rates of 22 percent and 39 percent, respectively.

The pancreatic cancer cohort was the smallest with just 25 patients. The trial investigators identified one pancreatic cancer patient who had an objective response on Enhertu, while by independent central review there were three responders. In this subset, the stable disease rate was 68 percent. Funda Meric-Bernstam, lead investigator of the trial and chair of the department of investigational cancer therapeutics at MD Anderson Cancer Center, said in her presentation at the meeting that overall survival and progression-free survival endpoints will be determined with additional follow-up.

"[Enhertu] demonstrated clinically meaningful activity across a broad range of HER2-expressing solid tumors including those that are hard to treat," Meric-Bernstam said. "This is also the first study to show tumor activity across tumor types for an [antibody-drug conjugate]. DESTINY-PanTumor02 shows [Enhertu] is a potential treatment option for patients with HER2-expressing solid tumors."

Reflecting on the DESTINY-PanTumor02 results, Kohei Shitara, an oncologist at National Cancer Center Hospital East, Japan, highlighted the use of IHC testing to select patients for the trial.

He said each of the three methods of testing for HER2 — tissue-based IHC, tissue-based next-generation sequencing, and liquid biopsy-based NGS — has pros and cons associated with it. Tissue-based IHC testing, which was used in DESTINY-PanTumor02, has the benefit of being a low-cost test that is already widely used in breast and gastric cancer.

However, Shitara pointed out that IHC testing is affected by tumor heterogeneity, and interpretations can be inconsistent between pathologists reading the test. It is also subject to having discordant results when carried out by central laboratories versus local laboratories with the results differing significantly between cancers. Shitara cited previous studies showing HER2 expression IHC concordance rates between central and local labs have improved from 48 percent to 92 percent over 12 years in breast cancer, whereas in gastric cancer, the concordance rate is around 70 percent to 80 percent. For a tumor-agnostic test, he said quality assurance of IHC testing will be critical.

"In our study, we'll be formally looking at the discordance question," Meric-Bernstam said, acknowledging the variability in IHC scoring and the fact that IHC is not routinely ordered for cancers other than breast, gastric, and lung. "We're looking at a multi-tumor scoring strategy that could be harmonized for patient selection," she noted. Her team also plans to use fluorescence in situ hybridization (FISH) tests in the future to study responses between HER2-amplified and non-amplified tumors.

Shitara agreed with Meric-Bernstam that Enhertu has the potential to garner tumor-agnostic approval in HER2-positive cancers. He said compared with other agents that have already been approved in a tumor-agnostic setting, such as Merck's checkpoint inhibitor Keytruda (pembrolizumab), GlaxoSmithKline's checkpoint inhibitor Jemperli (dostarlimab), and Loxo Oncology's NTRK inhibitor Vitrakvi (larotrectinib), Enhertu showed a similar response rate and duration of response across tumor types.

"Conducting randomized control trials in each cancer type might not be feasible and too time-consuming," said Shitara. "Results from the current study warrant further discussion with regulatory authorities."