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News|Articles|May 25, 2026

T-DXd Approaches EU Approval for Previously Treated HER2-Positive Metastatic Solid Tumors

Author(s)Kristi Rosa

Key Takeaways

  • CHMP’s recommendation targets heavily pretreated IHC 3+ solid tumors in a tumor-agnostic framework, potentially establishing the first EU-wide HER2-directed ADC approval beyond histology.
  • DESTINY-PanTumor02 demonstrated enriched activity in IHC 3+ disease, including ORR 61.3%, median DOR 22.1 months, median PFS 11.9 months, and median OS 21.1 months.
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CHMP recommended trastuzumab deruxtecan for HER2-positive (IHC 3+) metastatic solid tumors, marking the first tumor-agnostic ADC opinion in the EU.

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

What is the safety profile of T-DXd across the three supporting trials?

The toxicity profile of T-DXd was consistent across DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02, with no new safety concerns identified in any trial, according to AstraZeneca. In DESTINY-PanTumor02, grade 3 or higher treatment-related adverse effects (TRAEs) included neutropenia (19.1%), anemia (10.9%), fatigue (7.1%), and thrombocytopenia (5.6%).9 Treatment-related interstitial lung disease (ILD) or pneumonitis occurred in 10.5% of patients, with the majority grade 1 or 2 (9.0%); one grade 3 event (0.4%) and three grade 5 events (1.1%) were observed as adjudicated by an independent committee.

In DESTINY-Lung02, which supported the broader NSCLC HER2-mutant approval program and informed the dose selection of 5.4 mg/kg, grade 3 or higher TRAEs occurred in 31.7% of patients at the 5.4 mg/kg dose and 58.0% at 6.4 mg/kg.4 ILD or pneumonitis was observed in 5.9% of patients at 5.4 mg/kg and 14.0% at 6.4 mg/kg, with no grade 4 or 5 ILD events at either dose. In DESTINY-CRC02, grade 3 or higher TRAEs at the 5.4 mg/kg dose included neutropenia (16.9%), anemia (9.6%), and thrombocytopenia (6.0%); ILD or pneumonitis occurred in 8.4% of patients receiving 5.4 mg/kg, with no grade 3, 4, or 5 ILD events in that arm.6

T-DXd has received tumor-agnostic approval in the US and more than 15 countries/regions worldwide based on data from these trials; the CHMP positive opinion now positions the EU as the next regulatory milestone for this indication.

References

  1. Enhertu recommended for approval in the EU by CHMP for patients with previously treated HER2-positive metastatic solid tumours. News release. AstraZeneca. May 22, 2026. Accessed May 22, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/enhertu-recommended-in-eu-for-her2-solid-tumours.html
  2. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005
  3. Enhertu continues to demonstrate clinically meaningful tumour response in patients with HER2-mutant metastatic non-small cell lung cancer. AstraZeneca. September 11, 2022. Accessed May 22, 2026. https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-continues-to-demonstrate-clinically-meaningful-tumour-response-in-patients-with-her2-mutant-metastatic-non-small-cell-lung-cancer.html#!
  4. Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol. 2024;25(4):439-454. doi:10.1016/S1470-2045(24)00064-0
  5. Bekaii-Saab T. DESTINY-CRC02: trastuzumab deruxtecan in HER2+ metastatic colorectal cancer. OncLive.com. July 21, 2023. Accessed May 22, 2026. https://www.onclive.com/view/destiny-crc02-trastuzumab-deruxtecan-in-her2-metastatic-colorectal-cancer
  6. Enhertu demonstrated clinically meaningful and durable responses in patients across multiple HER2-expressing advanced solid tumours. News release. AstraZeneca. June 5, 2023. Accessed May 22, 2026. https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-demonstrated-clinically-meaningful-and-durable-responses-in-patients-across-multiple-her2-expressing.html#!
  7. Raghav K, Siena S, Takashima A, et al. Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial. Lancet Oncol. 2024;25(9):1147-1162. doi:10.1016/S1470-2045(24)00380-2
  8. Raghav KPS. Dr Raghav on trastuzumab deruxtecan in HER2+ mCRC. OncLive.com.June 4, 2023. Accessed May 22, 2026. https://www.onclive.com/view/dr-raghav-on-trastuzumab-deruxtecan-in-her2-mcrc
  9. Enhertu demonstrated clinically meaningful survival across multiple HER2-expressing advanced solid tumours in DESTINY-PanTumor02 phase II trial. News release. AstraZeneca. October 23, 2023. Accessed May 22, 2026. https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-demonstrated-clinically-meaningful-survival-across-multiple-her2-expressing-advanced-solid-tumours-in-destiny-pantumor02-phase-ii-trial.html#!

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