AstraZeneca and Daiichi Sankyo’s (trastuzumab deruxtecan) has been approved in the European Union (EU) as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) whose tumours have an activating HER2 (ERBB2) mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy.

Daiichi Sankyo...announced that ENHERTU® (trastuzumab deruxtecan) has been approved in Japan for the treatment of adult patients with unresectable advanced or recurrent non-small cell lung cancer (NSCLC) with HER2 (ERBB2) mutations that has progressed after chemotherapy.

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of:...adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.

For patients with advanced NSCLC and an activating HER2 (ERBB2) mutation, as detected by an US Food and Drug Administration–approved test, and who have received prior systemic therapy, clinicians may offer treatment (monotherapy) with trastuzumab deruxtecan...

...the NCCN NSCLC Panel recommends fam-trastuzumab deruxtecan-nxki as a preferred subsequent therapy option for patients with metastatic NSCLC and ERBB2 (HER2) mutations...

Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN) have received notification of acceptance of the supplemental Biologics License Application (sBLA) of ENHERTU® (fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients in the U.S. with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 (ERBB2) mutation and who have received a prior systemic therapy. The application has also been granted Priority Review.

AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo)’s Enhertu (trastuzumab deruxtecan) has been granted Breakthrough Therapy Designation (BTD) in the US for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumours have a HER2 mutation and with disease progression on or after platinum-based therapy

...- Documented HER2 exon 19 or 20 mutation from central FFPE tumour tissue testing....

...- For Cohort 2 only: Participant has any known documented activating HER2 mutation from an archival tumor tissue sample analyzed by CLIA laboratory or equivalent....

...Pathologically documented metastatic NSCLC with a known activating HER2 mutation (please refer to the list of HER2 mutations, Table 10.2). ...

...- Pathologically documented metastatic NSCLC with a known activating HER2 mutation....

...- Histologically documented non-squamous NSCLC with HER2 mutation in exons 19 or 20 by tissue NGS or ctDNA...

With T-DXd 5.4 and 6.4 mg/kg, cORR (95% CI) was 50.8% (37.9-63.6) and 73.3% (54.1-87.7), median DoR was 16.8 months (mo) (7.1-not estimable [NE]) and NE (6.8-NE), median PFS was 10.8 mo (7.4-NE) and 15.4 mo (9.5-NE), and median OS was 19.5 mo (14.9-NE) and NE (12.1-NE), respectively....In this descriptive subgroup analysis, both T-DXd doses showed strong and durable responses and manageable safety in Asian pts with previously treated HER2m mNSCLC.

T-DXd showed IC activity in pts with metastatic HER2m NSCLC, some with complete IC responses. The presence of BL BMs did not impact systemic response among pts treated with T-DXd.

ENHERTU® (trastuzumab deruxtecan) has been recommended for approval in the European Union (EU) as a monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) whose tumors have an activating HER2 (ERBB2) mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy....The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on the primary results from the DESTINY-Lung02 phase 2 trial...

DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population....T-DXd demonstrated clinically meaningful responses at both doses.

Both T-DXd 5.4 and 6.4 mg/kg continued to demonstrate strong and durable responses as well as an acceptable and generally manageable safety profile in patients with pretreated HER2m mNSCLC. The 5.4 mg/kg dose was associated with a more favorable safety profile and a reduced incidence of ILD/pneumonitis versus the 6.4 mg/kg dose.

In the PEC, cORR was 53.8% (95% CI, 39.5-67.8%) and 42.9% (95% CI, 24.5-62.8%) in pts receiving T-DXd 5.4 or 6.4 mg/kg, respectively….DESTINY-Lung02 demonstrated clinically meaningful activity with T-DXd 5.4 mg/kg and 6.4 mg/kg in pts with previously treated HER2m NSCLC in the PEC, with a more favorable safety profile with T-DXd 5.4 mg/kg.

Pts with HER2m NSCLC refractory to standard therapy received T-DXd 6.4 mg/kg IV Q3W….In the overall population, median PFS was 8.2 mo (95% CI, 6.0-11.9); median OS was 18.6 mo (95% CI, 13.8-25.8); median DOR was 10.6 mo (5.8-17.7); DCR was 92.3% (95% CI, 84.8-96.9).

Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1)....Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC.

Centrally confirmed ORR was 54.9% (95% CI, 44.2-65.4). Efficacy was consistent across subgroups, including pts previously treated with a HER2 TKI or with CNS metastasis....T-DXd demonstrated robust and durable activity in pts with previously treated HER2m NSCLC...

In a multicenter, 2-cohort phase 2 trial, pts with HER2m NSCLC refractory to standard treatment received T-DXd 6.4 mg/kg....Centrally confirmed ORR was 54.9% (95% CI, 44.2-65.4). Efficacy was consistent across subgroups, including pts previously treated with a HER2 TKI or with CNS metastasis....Additional biomarker analyses showed responses across different HER2m subtypes, as well as in pts with no detectable HER2 expression or HER2 gene amplification.

T-DXd demonstrated promising clinical activity with high ORR and durable responses in patients with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies.

HER2 mutations may clinically confer sensitivity to HER2-directed agents as recently shown in a phase II clinical trial with antibody-drug conjugate against HER2 trastuzumab deruxtecan in patients with non-squamous non-small cell lung carcinoma.

It also elicited high response rates in phase II trials of HER2-mutant non-small cell lung cancer and HER2-positive colorectal cancer.

T-DXd demonstrated promising clinical activity with high ORR and durable responses in pts with HER2-mutated NSCLC.

In HER2 -mutant non–small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1–14.3) months.

...Median treatment duration was 7.75 mo (range, 0.7-14.3 mo); 45.2% of pts remained on treatment. Confirmed ORR by ICR among the 42 pts was 61.9% (95% CI, 45.6%-76.4%); median DOR was not reached at data cutoff; 16 of 26 responders remained on treatment at data cutoff; DCR was 90.5% (95% CI, 77.4%-97.3%); estimated median PFS was 14.0 mo (95% CI, 6.4-14.0 mo)...T-DXd demonstrated promising clinical activity with high ORR and durable responses in pts with HER2-mutated NSCLC.