FDA starts swift review of tumour-agnostic use of Enhertu

AstraZeneca and Daiichi Sankyo’s Enhertu could become the first therapy approved by the FDA for use in any HER2-positive cancer, regardless of its location in the body.

The US regulator has started a priority review of the HER2-targeting antibody-drug conjugate (ADC) for the treatment of adults with unresectable or metastatic HER2-positive solid tumours who have been treated previously or have limited treatment options.

The tumour-agnostic indication for Enhertu (trastuzumab deruxtecan) is based mainly on the results of the DESTINY-PanTumor02 trial, which showed “clinically meaningful and durable” improvements in both progression-free survival (PFS) and overall survival (OS) with the drug.

The results of the trial were reported at last year’s ASCO cancer congress and revealed a median PFS of 6.9 months and median OS of 13.4 months in the overall trial population, which included patients with HER2-positive biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic cancers, amongst others.

It also showed an objective response rate (ORR) of 37% and a median duration of response (DoR) of 11.3 months in these patients. That is considered an encouraging result, as the subjects were generally heavily pre-treated, having previously undergone multiple lines of therapy, and were running out of options.

Enhertu is already approved as a treatment for a selection of HER2-positive and HER2-low solid tumours across breast, gastric, and lung cancers.

Individually the additional cancers represent relatively small patient populations, but collectively could represent a sizeable market opportunity for Enhertu – assuming the FDA opts to approve Enhertu with a broad tumour-agnostic label.

There were divergencies in efficacy seen with Enhertu across the different cancer types in DESTINY-PanTumor02, with a smaller benefit seen in pancreatic cancer where the ORR was 4%, for example, which could have a bearing on the FDA’s deliberations.

Susan Galbraith, AZ’s head of oncology R&D, said that the priority review “reflects the potential of this medicine to redefine the treatment of HER2-expressing cancers.”

She acknowledged that, while biomarkers for HER2 expression are already established in breast and gastric cancers, “we must now define them across tumour types,” recognising that HER2 testing would have to ramp up significantly to identify patients for treatment.

“We will continue working closely with the FDA to bring this potential first tumour-agnostic HER2-targeted medicine and biomarker to patients as quickly as possible,” she added. A decision on the application is due in the second quarter of this year.

The FDA has already approved several cancer drugs with tumour-agnostic indications based on biomarkers, including Eli Lilly’s Vitrakvi (larotrectinib) and Roche’s Rozlytrek (entrectinib) for NTRK-mutated tumours, Bayer/Eli Lilly’s RET inhibitor Retevmo (selpercatinib), Merck & Co’s Keytruda (pembrolizumab) for tumours with MSI-H or dMMR mutations, and GSK’s Jemperli (dostarlimab) for dMMR-positive cancers.

HER2 is more widespread than any of these, with low levels in some tumours like melanoma rising to 4% in lung cancer, 7% in colorectal cancer, and up to 12% in some forms of bladder cancer. Around 20% of breast cancers also express the biomarker.