The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a positive opinion recommending approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) as a monotherapy for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior treatment and have no satisfactory treatment options.¹ If converted to a full European Commission approval, T-DXd would become the first HER2-directed therapy and first antibody-drug conjugate to receive a tumor-agnostic indication in the European Union (EU), according to AstraZeneca.
The CHMP based its positive opinion on efficacy data from IHC 3+ patient subgroups spanning three phase 2 trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831).
In the pivotal IHC 3+ population across the three trials, confirmed objective response rates (ORRs) ranged from 46.9% to 52.9%, according to AstraZeneca. In DESTINY-PanTumor02, T-DXd induced a confirmed ORR of 51.4% and a median duration of response (DOR) of 14.2 months in 111 patients with IHC 3+ tumors spanning biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and other solid tumor types. In DESTINY-Lung01, the agent elicited a confirmed ORR of 52.9% and a median DOR of 6.9 months in 17 patients with centrally confirmed IHC 3+ non–small cell lung cancer (NSCLC). In DESTINY-CRC02, a confirmed ORR of 46.9% and a median DOR of 5.5 months were observed in 64 patients with centrally confirmed IHC 3+ colorectal cancer (CRC).
"HER2-directed therapies have already transformed care for certain HER2-expressing cancers, including breast and gastric cancers. However, many other cancers overexpress HER2, and targeted treatment options remain unavailable for most of these tumour types.”
-Susan Galbraith
Susan Galbraith is an executive vice president of Oncology Haematology R&D at AstraZeneca.
What were the key efficacy results from DESTINY-PanTumor02 supporting the CHMP opinion?
DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label phase 2 trial examining T-DXd at 5.4 mg/kg once every 3 weeks in previously treated patients with HER2-expressing solid tumors across seven tumor types.1,2 The trial enrolled 267 patients with HER2-positive (IHC 3+ [n = 111]; IHC 2+ [n = 156]; IHC 1+ [n = 5]) disease at sites across Asia, Europe, North America, South America, and Oceania.1 The primary end point was confirmed ORR by investigator assessment; secondary end points included DOR, disease control rate, progression-free survival (PFS), overall survival (OS), and safety.
Across the overall trial population at the primary analysis, T-DXd produced a confirmed ORR of 37.1% (95% CI, 31.3%-43.2%) and a median DOR of 11.3 months (95% CI, 9.6-17.8), with a median PFS of 6.9 months (95% CI, 5.6-8.0) and a median OS of 13.4 months (95% CI, 11.9-15.5), as published in the Journal of Clinical Oncology.2 The IHC 3+ subgroup (n = 75), which forms the basis for the CHMP opinion, showed substantially higher response depth: a confirmed ORR of 61.3% (95% CI, 49.4%-72.4%), a median DOR of 22.1 months (95% CI, 9.6-not reached [NR]), a median PFS of 11.9 months (95% CI, 8.2-13.0), and a median OS of 21.1 months (95% CI, 15.3-29.6). Among individual tumor cohorts in the IHC 3+ population, ORRs ranged from 56.3% in bladder and biliary tract cancers to 84.6% in endometrial cancer.
Funda Meric-Bernstam, MD, chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and principal investigator of DESTINY-PanTumor02, noted in a news release that the data confirm the potential of T-DXd to change the course of disease for patients with HER2-expressing advanced cancers who have limited treatment options and currently no approved HER2-directed therapies.1
Key findings across DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02
- In the IHC 3+ subgroup of DESTINY-PanTumor02 (n = 111), T-DXd elicited a confirmed ORR of 51.4% and a median DOR of 14.2 months across biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and other tumor types.
- In DESTINY-Lung01, T-DXd induced a confirmed ORR of 52.9% with a median DOR of 6.9 months in 17 patients with centrally confirmed IHC 3+ NSCLC.
- In DESTINY-CRC02, T-DXd produced a confirmed ORR of 46.9% in 64 patients with IHC 3+ CRC receiving the 5.4-mg/kg dose, irrespective of RAS mutation status.
- T-DXd has already received a tumor-agnostic approval in the United States and more than 15 countries/regions based on findings from these trials.
What did DESTINY-Lung01 and DESTINY-CRC02 contribute to the CHMP submission?
DESTINY-Lung01 is a global, open-label, two-cohort phase 2 trial assessing T-DXd at 5.4 mg/kg or 6.4 mg/kg in patients with HER2-mutant or HER2-overexpressing unresectable or metastatic NSCLC who had progressed on one or more prior systemic therapies. The CHMP submission drew on the HER2-overexpressing cohort (cohort 1a, 5.4 mg/kg), specifically the 17 patients with centrally confirmed IHC 3+ disease. In the broader HER2-overexpressing cohort, updated results from the 2022 ESMO Congress showed a confirmed ORR of 34.1% (95% CI, 20.1-50.6) with a median PFS of 6.7 months (95% CI, 4.2-8.4) and a median OS of 11.2 months (95% CI, 8.4-not evaluable) in patients receiving 5.4 mg/kg.3 Results from the HER2-overexpressing cohort were subsequently published in The Lancet Oncology.4
DESTINY-CRC02 is a global, randomized, two-arm phase 2 trial examining T-DXd at the 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated locally advanced, unresectable, or metastatic HER2-positive CRC. The trial enrolled 122 patients, including 64 with IHC 3+ tumors in the 5.4 mg/kg arm. In an OncLive News Network program,5 Tanios Bekaii-Saab, MD, FACP, of Mayo Clinic, provided an overview of DESTINY-CRC02.
In the overall 5.4-mg/kg arm (n = 82 evaluable), the confirmed ORR by blinded independent central review was 37.8% (95% CI, 27.3%-49.2%), with a median DOR of 5.5 months (95% CI, 4.2-8.1), a median PFS of 5.8 months (95% CI, 4.6-7.0), and a median OS of 13.4 months (95% CI, 12.5-16.8).6 Among patients with IHC 3+ tumors in the 5.4-mg/kg arm, the confirmed ORR reached 46.9% (95% CI, 34.3%-59.8%), compared with 5.6% (95% CI, 0.1%-27.3%) in patients with IHC 2+/ISH+ disease. Responses were observed regardless of RAS mutation status. Results from DESTINY-CRC02 were published in The Lancet Oncology.7
In a past interview with OncLive, Kanwal P. S. Raghav, MBBS, MD, of The University of Texas MD Anderson Cancer Center, discussed the primary findings from DESTINY-CRC02:8
