With its latest approval in April 2024, ENHERTU now has five approved indications, marking a significant expansion since its initial approval in 2019. This collaboration between AstraZeneca and Daiichi Sankyo has substantially broadened the reach of the antibody-drug conjugate (ADC) in the United States. The FDA granted accelerated approval for ENHERTU to address unresectable or metastatic HER2-positive solid tumors in adults. Given that this approval utilized the FDA's accelerated pathway, it's likely that a confirmatory trial will be required to validate the drug's efficacy and maintain its approval status.

The accelerated approval was based on findings from a mid-stage study, primarily focusing on objective response rate (ORR) and duration of response (DoR). Furthermore, ENHERTU's tumor-agnostic approval by the FDA was supported by results from the Phase II DESTINY-PanTumor02 trial. This trial encompassed patients with HER2-positive tumors, including those in the biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, or other locations. AstraZeneca and Daiichi also investigated ENHERTU's impact on patients with confirmed HER2-positive non-small cell lung cancer (NSCLC) and centrally confirmed HER2-positive colorectal cancer in the respective DESTINY-Lung01 and DESTINY-CRC02 trials.

As of June 2023, 41 patients with BTC and 25 patients with pancreatic cancer were treated with ENHERTU. In the BTC group, 9 out of 41 patients showed a reduction in tumor size, with 9 out of 16 patients with a specific type of tumor (IHC 3+) responding to the treatment. In the pancreatic cancer group, only 1 out of 25 patients responded to ENHERTU.

The side effects observed with ENHERTU were expected. In more than 5% of BTC patients, severe side effects included a drop in neutrophils leading to neutropenia (9.8%), nausea (7.3%), and fatigue (7.3%). In the pancreatic cancer group, severe side effects in more than 5% of patients included anemia (a drop in red blood cells) and neutropenia, both occurring in 8% of patients.

The findings endorse ENHERTU as a viable treatment option for patients with HER2-positive (IHC 3+) biliary tract cancers that are metastatic or unresectable, following prior systemic treatments when no other satisfactory alternatives exist. However, further investigation is necessary to determine its effectiveness in treating pancreatic cancers.

KOL insights

“We are fully in the era of ADCs. We've gone from the era of targeted agents to the IO era, and now we're in the era of ADCs. Question number one is: Can we give this [trastuzumab deruxtecan] to patients with lower HER2 expression? We saw data in [HER2-low] breast cancer. Can we see efficacy in other [HER2-low] tumors? That will be something that would need to be evaluated further. Then there are combination strategies, both with targeted agents and IO agents, in particular the PD-1 inhibitors. Those studies are also ongoing.” –Expert Opinion.

“ENHERTU showed antitumor activity and durable responses in heavily pretreated patients across multiple tumor types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody–drug conjugates and our findings support further investigation of ENHERTU in the pan-tumor setting.” –Expert Opinion.

Conclusion

ENHERTU has shown significant clinical benefits for patients with biliary tract cancer, regardless of the primary tumor location. Although the pancreatic cancer cohort had limited patient numbers, the data indicate the need for further investigation of ENHERTU in this group. Safety findings align with established profiles, affirming ENHERTU as a promising treatment option for HER2-expressing BTC. With AstraZeneca and Daiichi Sankyo securing ENHERTU's latest FDA approval via the accelerated pathway, the companies will likely conduct a confirmatory trial to validate its efficacy and uphold its newfound approval.