Enhertu

Pharmacotherapeutic group: cytostatics, HER2 inhibitors (human epidermal growth factor receptor 2), ATC code: L01FD04 Mechanism of action Enhertu, trastuzumab deruxtecan, is a HER2-targeted antibody-drug conjugate. The antibody is a humanised anti-HER2 IgG1 attached to deruxtecan, a topoisomerase I inhibitor (DXd), via a cleavable tetrapeptide-based linker. The antibody-drug conjugate is stable in plasma. Functionally, the antibody component binds to HER2, which is expressed on the surface of certain tumour cells. Following binding, the trastuzumab deruxtecan complex undergoes internalisation and intracellular linker cleavage by lysosomal enzymes that are upregulated in tumour cells. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death. DXd, an exatecan derivative, is approximately 10-fold more potent than SN-38, the active metabolite of irinotecan. In vitro studies suggest that the antibody portion of trastuzumab deruxtecan, which has the same amino acid sequence as trastuzumab, also binds to FcγRIIIa and complement C1q. The antibody mediates antibody-dependent cellular cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2. In addition, the antibody inhibits signalling through the phosphatidylinositol 3-kinase (PI3-K) pathway in human breast cancer cells that overexpress HER2. Clinical efficacy HER2-positive breast cancer DESTINY-Breast03 study (NCT03529110) The efficacy and safety of Enhertu were investigated in DESTINY-Breast03, a multicentre, open-label, active-controlled, randomised, two-arm phase 3 study that enrolled patients with HER2-positive unresectable and/or metastatic breast cancer who had received prior treatment with trastuzumab and a taxane for metastatic disease, or who had disease recurrence within 6 months of completing adjuvant therapy. Archival breast cancer specimens were required to confirm HER2 positivity, defined as HER2 IHC 3+ or ISH-positive. The study excluded patients with a history of ILD/pneumonitis requiring corticosteroid treatment or with ILD/pneumonitis at screening, patients with untreated and symptomatic brain metastases, patients with a history of clinically significant cardiac disease, and patients with prior treatment with an anti-HER2 antibody-drug conjugate in the metastatic setting. Patients were randomised 1:1 to receive either Enhertu at a dose of 5.4 mg/kg (n = 261) or trastuzumab emtansine 3.6 mg/kg (n = 263) administered by intravenous infusion once every three weeks. Randomisation was stratified by hormone receptor status, prior pertuzumab treatment and history of visceral disease. Treatment was administered until disease progression, death, withdrawal of consent or unacceptable toxicity. The primary efficacy endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1). Overall survival (OS) was a key secondary efficacy endpoint. Investigator-assessed PFS, confirmed objective response rate (ORR) and duration of response (DOR) were secondary endpoints. Patient demographics and baseline disease characteristics were balanced across the treatment arms. Among the 524 randomised patients, baseline demographics and disease characteristics were as follows: median age 54 years (range: 20 years to 83 years); 65 years or older (20.2%); women (99.6%); Asian (59.9%), White (27.3%), Black or African American (3.6%); Eastern Cooperative Oncology Group (ECOG) performance status 0 (62.8%) or 1 (36.8%); hormone receptor status (positive: 51.9%); presence of visceral disease (73.3%); presence of brain metastases at baseline (15.6%); and 48.3% of patients had received one line of prior systemic therapy in the metastatic setting. The proportion of patients who had received no prior treatment for metastatic disease was 9.5%. The proportion of patients previously treated with pertuzumab was 61.1%. At a prespecified interim analysis of PFS based on 245 events (73% of the total events planned for the final analysis), the study demonstrated a statistically significant improvement in BICR-assessed PFS in patients randomised to Enhertu compared with trastuzumab emtansine. BICR-assessed PFS data from the primary analysis (data cut-off 21 May 2021) and updated OS, ORR and DOR results from the data cut-off of 25 July 2022 are presented in Table 4. Table 4: Efficacy results in the DESTINY-Breast03 study Efficacy endpoint Enhertu n = 261 trastuzumab emtansine n = 263 Progression-free survival (PFS) by BICR a Number of events (%) 87 (33.3) 158 (60.1) Median, months (95% CI) NR (18.5; NE) 6.8 (5.6; 8.2) Hazard ratio (95% CI) 0.28 (0.22; 0.37) p-value p < 0.000001 † Overall survival (OS) b Number of events (%) 72 (27.6) 97 (36.9) Median, months (95% CI) NR (40.5; NE) NR (34.0; NE) Hazard ratio (95% CI) 0.64 (0.47; 0.87) p-value c p = 0.0037 PFS by BICR (updated) b Number of events (%) 117 (44.8) 171 (65.0) Median, months (95% CI) 28.8 (22.4; 37.9) 6.8 (5.6; 8.2) Hazard ratio (95% CI) 0.33 (0.26; 0.43) Confirmed objective response rate (ORR) by BICR b n (%) 205 (78.5) 92 (35.0) 95% CI (73.1; 83.4) (29.2; 41.1) Complete response n (%) 55 (21.1) 25 (9.5) Partial response n (%) 150 (57.5) 67 (25.5) Duration of response by BICR b Median, months (95% CI) 36.6 (22.4; NE) 23.8 (12.6; 34.7) CI = confidence interval; NE = not estimable; NR = not reached †Expressed to 6 decimal places a Data cut-off 21 May 2021 b Data cut-off 25 July 2022 for the prespecified interim analysis of OS c p-value by stratified log-rank test; crossed the efficacy boundary of 0.013. Figure 1: Kaplan-Meier plot of overall survival (data cut-off 25 July 2022) Figure 2: Kaplan-Meier plot of progression-free survival by BICR (data cut-off 25 July 2022) Similar PFS results were observed across prespecified subgroups, including prior pertuzumab therapy, hormone receptor status and presence of visceral disease. DESTINY-Breast02 study (NCT03523585) The efficacy and safety of Enhertu were investigated in DESTINY-Breast02, a multicentre, randomised, open-label, active-controlled phase 3 study that enrolled patients with HER2-positive unresectable or metastatic breast cancer that was resistant or refractory to prior T-DM1 treatment. Archival breast cancer specimens were required to confirm HER2 positivity, defined as HER2 IHC 3+ or ISH-positive. The study excluded patients with a history of steroid-treated ILD/pneumonitis or with ILD/pneumonitis at screening, patients with untreated and symptomatic brain metastases, and patients with a history of clinically significant cardiac disease. Patients were randomised 2:1 to treatment with Enhertu at a dose of 5.4 mg/kg (n = 406) administered by intravenous infusion every three weeks, or to treatment of physician's choice (n = 202; trastuzumab plus capecitabine or lapatinib plus capecitabine). Randomisation was stratified by hormone receptor status, prior pertuzumab treatment and history of visceral disease. Treatment was administered until disease progression, death, withdrawal of consent or unacceptable toxicity. The primary efficacy endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) according to RECIST v1.1. The key secondary efficacy endpoint was overall survival (OS). Secondary endpoints were investigator-assessed PFS, confirmed objective response rate (ORR) and duration of response (DOR). Demographics and baseline disease characteristics were similar across the two treatment arms. Among the 608 randomised patients, the median age was 54 years (range 22 to 88 years); women (99.2%); White (63.2%); Asian (29.3%); Black or African American (2.8%); Eastern Cooperative Oncology Group (ECOG) performance status 0 (57.4%) or 1 (42.4%); hormone receptor status (positive: 58.6%); presence of visceral disease (78.3%); presence of brain metastases at baseline (18.1%); and 4.9% of patients had received one prior line of systemic therapy targeting metastatic disease. The efficacy results are summarised in Table 5 and in Figures 3 and 4. Table 5: Efficacy results in the DESTINY-Breast02 study Efficacy endpoint Enhertu n = 406 Treatment of physician's choice n = 202 PFS by BICR Number of events (%) 200 (49.3) 125 (61.9) Median, months (95% CI) 17.8 (14.3; 20.8) 6.9 (5.5; 8.4) Hazard ratio (95% CI) 0.36 (0.28; 0.45) p-value p < 0.000001 † Overall survival (OS) Number of events (%) 143 (35.2) 86 (42.6) Median, months (95% CI) 39.2 (32.7; NE) 26.5 (21.0; NE) Hazard ratio (95% CI) 0.66 (0.50; 0.86) p-value p = 0.0021 Investigator-assessed PFS Number of events (%) 206 (50.7) 152 (75.2) Median, months (95% CI) 16.7 (14.3; 19.6) 5.5 (4.4; 7.0) Hazard ratio (95% CI) 0.28 (0.23; 0.35) Confirmed objective response rate (ORR) by BICR n (%) 283 (69.7) 59 (29.2) 95% CI (65.0; 74.1) (23.0; 36.0) Complete response n (%) 57 (14.0) 10 (5.0) Partial response n (%) 226 (55.7) 49 (24.3) Duration of response by BICR Median, months (95% CI) 19.6 (15.9; NE) 8.3 (5.8; 9.5) CI = confidence interval; NE = not estimable † Expressed to 6 decimal places a p-value by stratified log-rank test; crossed the efficacy boundary of 0.004. Figure 3: Kaplan-Meier plot of progression-free survival by BICR Figure 4: Kaplan-Meier plot of overall survival DESTINY-Breast01 study (NCT03248492) The efficacy and safety of Enhertu were investigated in DESTINY-Breast01, a multicentre, open-label, single-arm phase 2 study that enrolled patients with HER2-positive unresectable and/or metastatic breast cancer who had received two or more anti-HER2-based regimens, including trastuzumab emtansine (100%), trastuzumab (100%) and pertuzumab (65.8%). Archival breast cancer specimens were required to confirm HER2 positivity, defined as HER2 IHC 3+ or ISH-positive. The study excluded patients with a history of treated ILD or with ILD at screening, patients with untreated or symptomatic brain metastases, and patients with a history of clinically significant cardiac disease. Enrolled patients had at least 1 measurable lesion per RECIST v1.1. Enhertu was administered by intravenous infusion at a dose of 5.4 mg/kg once every three weeks until disease progression, death, withdrawal of consent or unacceptable toxicity. The primary efficacy endpoint was confirmed objective response rate (ORR) per RECIST v1.1 in the intent-to-treat (ITT) population assessed by independent central review (ICR). The secondary efficacy endpoint was duration of response (DOR). Among the 184 patients enrolled in DESTINY-Breast01, baseline demographics and medical history were as follows: median age 55 years (range: 28 to 96 years); 65 years and older (23.9%); women (100%); White (54.9%), Asian (38.0%), Black or African American (2.2%); Eastern Cooperative Oncology Group (ECOG) performance status 0 (55.4%) or 1 (44.0%); hormone receptor status (positive: 52.7%); presence of visceral disease (91.8%); previously treated and stable brain metastases (13.0%); median number of prior therapies for metastatic disease: 5 (range: 2 to 17); sum of diameters of target lesions (< 5 cm: 42.4%; ≥ 5 cm: 50.0%). An earlier analysis (median follow-up duration 11.1 months [range: 0.7 to 19.9 months]) demonstrated a confirmed objective response rate of 60.9% (95% CI: 53.4; 68.0) with 6.0% complete responders and 54.9% partial responders; 36.4% had stable disease, 1.6% progressive disease and 1.1% were not evaluable. At that time, the median duration of response was 14.8 months (95% CI: 13.8; 16.9) with 81.3% of responders having a response of ≥ 6 months (95% CI: 71.9; 87.8). Efficacy results at the updated data cut-off, with a median duration of follow-up for response of 20.5 months (range: 0.7 to 31.4 months), are presented in Table 6. Table 6: Efficacy results in the DESTINY-Breast01 study (intent-to-treat analysis population) DESTINY-Breast01 n = 184 Confirmed objective response rate (95% CI)* † 61.4% (54.0; 68.5) Complete response (CR) 6.5% Partial response (PR) 54.9% Duration of response ‡ Median, months (95% CI) 20.8 (15.0; NR) % with duration of response ≥ 6 months (95% CI) § 81.5% (72.2; 88.0) ORR 95% CI calculated using the Clopper-Pearson method; CI = confidence interval 95% CI calculated using the Brookmeyer-Crowley method *Confirmed responses (by blinded independent central review) were defined as recorded responses of either CR/PR, confirmed by repeat imaging at least 4 weeks after the visit at which the response was first observed. †Of the 184 patients, 35.9% had stable disease, 1.6% progressive disease and 1.1% were not evaluable. ‡Includes 73 patients with censored data §Based on Kaplan-Meier estimate NR = not reached Within the prespecified subgroups, antitumour activity was consistently observed based on prior pertuzumab therapy and hormone receptor status. HER2-low and HER2-ultralow breast cancer; DESTINY-Breast06 study (NCT04494425) The efficacy and safety of Enhertu were investigated in DESTINY-Breast06, a randomised, multicentre, open-label phase 3 study in which 866 adult patients with advanced or metastatic HR+ breast cancer with low HER2 expression (IHC 1+ or IHC 2+/ISH-) or ultralow HER2 expression, determined using PATHWAY/VENTANA anti-HER2/neu (4B5) as assessed in a central laboratory, were randomised. HER2-ultralow (IHC 0 with membrane staining, described in the study as IHC >0<1+) is defined as faint and incomplete HER2 membrane staining that is present in 10% or fewer tumour cells. The study enrolled patients who had experienced disease progression on (a) at least 2 lines of endocrine therapy in the metastatic setting or (b) one line of endocrine therapy in the metastatic setting and who had demonstrated progression within 24 months of starting adjuvant endocrine therapy or within 6 months of starting first-line endocrine therapy in combination with a CDK4/6 inhibitor in the metastatic setting. Patients with prior chemotherapy in the neoadjuvant or adjuvant setting were eligible for enrolment if their disease-free interval had lasted longer than 12 months. The study excluded patients with prior chemotherapy for advanced or metastatic disease, patients with a history of ILD/pneumonitis requiring steroid treatment or with ILD/pneumonitis at screening, uncontrolled or significant cardiovascular disease, untreated and symptomatic brain metastases or an ECOG performance status > 1. Patients were randomised 1:1 to treatment with Enhertu at a dose of 5.4 mg/kg (n = 436) administered by intravenous infusion every three weeks, or to single-agent chemotherapy of physician's choice (n = 430; capecitabine 60%, nab-paclitaxel 24% or paclitaxel 16%). Randomisation was stratified by prior CDK4/6 inhibitor use (yes or no), prior taxane use in the non-metastatic setting (yes or no) and by tumour HER2 IHC status (IHC 2+/ISH-, IHC 1+, IHC > 0 < 1+). Enhertu treatment was administered until disease progression, death, withdrawal of consent or unacceptable toxicity. The primary efficacy endpoint was progression-free survival (PFS) in patients with HER2-low breast cancer assessed by blinded independent central review (BICR) according to RECIST v1.1. The key secondary efficacy endpoints were BICR-assessed PFS based on RECIST v1.1 in the overall population (HER2-low and HER2-ultralow), overall survival (OS) in patients with HER2-low disease, and OS in the overall population. Secondary endpoints were ORR and DOR. Within the overall population, demographic characteristics and baseline tumour characteristics were similar across the treatment arms. Among the 866 randomised patients, the median age was 57 years (range 28 to 87 years); 31% were aged 65 years or older; 99.9% were women, 53% White, 35% Asian and 1% Black or African American. At baseline, patients had an ECOG performance status of 0 (59%) or 1 (39%); 18% had IHC > 0 <1+, 55% IHC 1+, 27% IHC 2+/ISH-; 67% had liver metastases, 32% lung metastases, 8% had brain metastases and 3% bone-only metastases. The median number of prior lines of endocrine therapy in patients was 2 lines in the metastatic setting (range 1 to 5), with 17% having received 1 line and 68% having received 2 lines. 89% of patients had received prior endocrine therapy in combination with CDK4/6i treatment in the metastatic setting, 47% of patients had received prior anthracycline treatment and 41% of patients had received prior taxane treatment in the non-metastatic setting. The efficacy results are summarised in Table 7 and in Figures 5 and 6. Table 7: Efficacy results in the DESTINY-Breast06 study Efficacy endpoint HER2-low cohort Overall population (HER2-low and HER2-ultralow cohorts) Enhertu (n = 359) chemotherapy (n = 354) Enhertu (n = 436) chemotherapy (n = 430) Progression-free survival by BICR Number of events (%) 225 (62.7) 232 (65.5) 269 (61.7) 271 (63.0) Median, months (95% CI) 13.2 (11.4; 15.2) 8.1 (7.0; 9.0) 13.2 (12.0; 15.2) 8.1 (7.0; 9.0) Hazard ratio (95% CI) 0.62 (0.52; 0.75) 0.64 (0.54; 0.76) p-value < 0.0001 < 0.0001 Overall survival* Number of events (%) 136 (37.9) 146 (41.2) 161 (36.9) 174 (40.5) Median, months (95% CI) 28.9 (25.7; 33.7) 27.1 (23.5; 29.9) 28.9 (26.4; 32.7) 27.4 (23.9; 29.9) Hazard ratio (95% CI) 0.83 (0.66; 1.05) 0.81 (0.66; 1.01) Confirmed objective response rate by BICR † n (%) 203 (56.5) 114 (32.2) 250 (57.3) 134 (31.2) 95% CI 51.2; 61.7 27.4; 37.3 52.5; 62.0 26.8; 35.8 Duration of response by BICR † Median, months (95% CI) 14.1 (11.8; 15.9) 8.6 (6.7; 11.3) 14.3 (12.5; 15.9) 8.6 (6.9; 11.5) Data cut-off: 18 March 2024; CI = confidence interval * First planned interim analysis † Results were not controlled for type 1 error and are to be interpreted descriptively A consistent PFS benefit was observed across several prespecified subgroups, including HER2 expression (IHC >0 <1+, IHC 1+, IHC 2+/ISH-), prior CDK4/6 inhibitor use (yes or no), prior taxane use in the non-metastatic setting (yes or no) and number of prior lines of endocrine therapy in the metastatic setting. In the HER2-ultralow subgroup (n = 152), median PFS was 13.2 months (95% CI: 9.8; 17.3) in patients randomised to Enhertu (n = 76) and 8.3 months (95% CI: 5.8; 15.2) in patients randomised to chemotherapy, with a hazard ratio of 0.78 (95% CI: 0.50; 1.21). Median OS was 29.5 months (95% CI: 27.9; not estimable) in patients randomised to Enhertu and 27.4 months (95% CI: 19.4; not estimable) in patients randomised to chemotherapy, with a hazard ratio of 0.75 (95% CI: 0.43; 1.29). The confirmed objective response rate was 61.8% (95% CI: 50.0; 72.8) in patients randomised to Enhertu and 26.3% (95% CI: 16.9; 37.7) in patients randomised to chemotherapy, respectively. Median duration of response was 14.3 months (95% CI: 9.2; 20.7) in patients randomised to Enhertu and 14.1 months (95% CI: 5.9; not estimable) in patients randomised to chemotherapy. Figure 5: Kaplan-Meier plot of progression-free survival (overall population) Figure 6: Kaplan-Meier plot of overall survival (overall population) DESTINY-Breast04 (NCT03734029) The efficacy and safety of Enhertu were studied in DESTINY-Breast04, a randomised, multicentre, open-label phase 3 study that enrolled 557 adult patients with unresectable or metastatic HER2-low breast cancer. The study comprised 2 cohorts: 494 patients who were hormone receptor-positive (HR+) and 63 patients who were hormone receptor-negative (HR-). HER2-low expression was defined as IHC 1+ (defined as faint, partial membrane staining in more than 10% of tumour cells) or IHC 2+/ISH- based on PATHWAY/VENTANA anti-HER2/neu (4B5) testing assessed by a central laboratory. Patients had to have received prior chemotherapy in the metastatic setting or had to have experienced disease recurrence during adjuvant chemotherapy or within 6 months of completing it. Per the inclusion criteria, patients who were HR+ had to have received at least one endocrine therapy and, at the time of randomisation, had to be ineligible for further endocrine therapy. Patients were randomised 2:1 to receive either Enhertu 5.4 mg/kg (n = 373) by intravenous infusion every three weeks, or chemotherapy of physician's choice (n = 184, eribulin 51.1%, capecitabine 20.1%, gemcitabine 10.3%, nab-paclitaxel 10.3%, or paclitaxel 8.2%). Randomisation was stratified by tumour HER2 IHC status (IHC 1+ or IHC 2+/ISH-), number of prior lines of chemotherapy in the metastatic setting (1 or 2) and HR status / prior CDK4/6i treatment (HR+ with prior CDK4/6 inhibitor treatment, HR+ without prior CDK4/6 inhibitor treatment, or HR-). Treatment was administered until disease progression, death, withdrawal of consent or unacceptable toxicity. The study excluded patients with a history of ILD/pneumonitis requiring steroid treatment or with ILD/pneumonitis at screening and clinically significant cardiac disease. Patients with untreated or symptomatic brain metastases or an ECOG performance status > 1 were also excluded. The primary efficacy endpoint in patients with HR+ breast cancer was progression-free survival (PFS) assessed by BICR based on RECIST v1.1. The key secondary efficacy endpoints were BICR-assessed PFS based on RECIST v1.1 in the overall population (all randomised HR+ and HR- patients), overall survival (OS) in HR+ patients and OS in the overall population. ORR, DOR and patient-reported outcomes (PRO) were secondary endpoints. Demographic characteristics and baseline tumour characteristics were similar across the treatment arms. The median age of the 557 randomised patients was 57 years (range: 28 to 81); 23.5% were aged 65 years and older; 99.6% were women and 0.4% men; 47.9% were White, 40.0% Asian and 1.8% Black or African American. At baseline, patients had an ECOG performance status of 0 (54.8%) or 1 (45.2%); 57.6% had IHC 1+, 42.4% IHC 2+/ISH-; 88.7% HR+ and 11.3% HR-; 69.8% had liver metastases, 32.9% lung metastases and 5.7% brain metastases. The percentage of patients who had previously received anthracyclines as part of (neo)adjuvant therapy was 46.3%, and 19.4% in the locally advanced and/or metastatic setting. In the metastatic setting, patients had a median of 3 prior lines of systemic therapy (range: 1 to 9), with 57.6% having received 1 and 40.9% 2 prior chemotherapy regimens; 3.9% were patients with early disease progression (progression during neo/adjuvant therapy). In HR+ patients, the median number of prior lines of endocrine therapy was 2 (range: 0 to 9) and 70% had received prior CDK4/6 inhibitor treatment. The efficacy results are summarised in Table 8 and in Figures 7 and 8. Table 8: Efficacy results in the DESTINY-Breast04 study Efficacy endpoint HR+ cohort Overall population (HR+ and HR- cohorts) Enhertu (n = 331) chemotherapy (n = 163) Enhertu (n = 373) chemotherapy (n = 184) Overall survival Number of events (%) 126 (38.1) 73 (44.8) 149 (39.9) 90 (48.9) Median, months (95% CI) 23.9 (20.8; 24.8) 17.5 (15.2; 22.4) 23.4 (20.0; 24.8) 16.8 (14.5; 20.0) Hazard ratio (95% CI) 0.64 (0.48; 0.86) 0.64 (0.49; 0.84) p-value 0.0028 0.001 Progression-free survival by BICR Number of events (%) 211 (63.7) 110 (67.5) 243 (65.1) 127 (69.0) Median, months (95% CI) 10.1 (9.5; 11.5) 5.4 (4.4; 7.1) 9.9 (9.0; 11.3) 5.1 (4.2; 6.8) Hazard ratio (95% CI) 0.51 (0.40; 0.64) 0.50 (0.40; 0.63) p-value < 0.0001 < 0.0001 Confirmed objective response rate by BICR* n (%) 175 (52.6) 27 (16.3) 195 (52.3) 30 (16.3) 95% CI 47.0; 58.0 11.0; 22.8 47.1; 57.4 11.3; 22.5 Complete response n (%) 12 (3.6) 1 (0.6) 13 (3.5) 2 (1.1) Partial response n (%) 164 (49.2) 26 (15.7) 183 (49.1) 28 (15.2) Duration of response by BICR* Median, months (95% CI) 10.7 (8.5; 13.7) 6.8 (6.5; 9.9) 10.7 (8.5; 13.2) 6.8 (6.0; 9.9) CI = confidence interval *Based on data from the electronic case report form for the HR+ cohort: n = 333 for the Enhertu arm and n = 166 for the chemotherapy arm. A consistent OS and PFS benefit was observed across prespecified subgroups, including HR status, prior CDK4/6i treatment, number of prior chemotherapies and IHC 1+ and IHC 2+/ISH- status. In the HR- subgroup, median OS was 18.2 months (95% CI: 13.6; not estimable) in patients randomised to Enhertu compared with 8.3 months (95% CI: 5.6; 20.6) in patients randomised to chemotherapy, with a hazard ratio of 0.48 (95% CI: 0.24; 0.95). Median PFS was 8.5 months (95% CI: 4.3; 11.7) in patients randomised to Enhertu and 2.9 months (95% CI: 1.4; 5.1) in patients randomised to chemotherapy, with a hazard ratio of 0.46 (95% CI: 0.24; 0.89). According to an updated descriptive analysis with a median follow-up of 32 months, the improvement in OS was consistent with the primary analysis. The hazard ratio in the overall population was 0.69 (95% CI: 0.55; 0.86) with a median OS of 22.9 months (95% CI: 21.2; 24.5) in the Enhertu arm versus 16.8 months (95% CI: 14.1; 19.5) in the chemotherapy arm. The Kaplan-Meier curve of the updated OS analysis is shown in Figure 7. Figure 7: Kaplan-Meier plot of overall survival (overall population) (updated analysis) Figure 8: Kaplan-Meier plot of progression-free survival by BICR (overall population) NSCLC DESTINY-Lung02 study (NCT04644237) The efficacy and safety of Enhertu were investigated in DESTINY-Lung02, a randomised phase 2 study that evaluated two dose levels. The assigned treatment dose was blinded to patients and investigators. The study enrolled adult patients with HER2-mutant metastatic NSCLC who had received at least one platinum-based chemotherapy-containing regimen. Identification of an activating HER2 (ERBB2) mutation was prospectively determined in tumour tissue by local laboratories using a validated assay such as next-generation sequencing, polymerase chain reaction or mass spectrometry. Patients were randomised 2:1 to receive Enhertu at a dose of 5.4 mg/kg or 6.4 mg/kg every 3 weeks. Randomisation was stratified by prior treatment against programmed cell death receptor 1 (PD-1) and/or programmed cell death receptor ligand 1 (PD-L1) (yes versus no). Treatment was administered until disease progression, death, withdrawal of consent or unacceptable toxicity. The study excluded patients with a history of ILD/pneumonitis requiring steroid treatment or with ILD/pneumonitis at screening and clinically significant cardiac disease. Likewise, patients with untreated and symptomatic brain metastases or an ECOG performance status > 1 were excluded. The primary efficacy endpoint was confirmed ORR assessed by BICR based on RECIST v1.1. The secondary efficacy endpoint was DOR. Demographics and baseline disease characteristics for the 102 patients enrolled in the 5.4 mg/kg arm were as follows: median age 59.4 years (range 31 to 84 years); women (63.7%); Asian (63.7%), White (22.5%) or other (13.7%); ECOG performance status 0 (28.4%) or 1 (71.6%); 97.1% had a mutation in the ERBB2 kinase domain, 2.9% in the extracellular domain; 96.1% had a HER2 mutation in exon 19 or exon 20; 34.3% had stable brain metastases; 46.1% were former smokers, none were current smokers; 21.6% had undergone prior lung resection. In the metastatic setting, 32.4% of patients had received more than 2 prior systemic therapies, 100% of patients had received platinum-based therapy, 73.5% of patients had received anti-PD-1/PD-L1 therapy and 50.0% of patients had received prior therapy with a combination of platinum and anti-PD-1/PD-L1 therapy. The efficacy results are summarised in Table 9. The median duration of follow-up was 11.5 months (data cut-off: 23 December 2022). Table 9: Efficacy results in the DESTINY-Lung02 study Efficacy endpoint DESTINY-Lung02 5.4 mg/kg n = 102 Confirmed objective response rate (ORR) by BICR n (%) 50 (49.0) (95% CI)* (39.0; 59.1) Complete response (CR) n (%) 1 (1.0) Partial response (PR) n (%) 49 (48.0) Duration of response Median, months (95% CI) † 16.8 (6.4; NE) *95% CI calculated using the Clopper-Pearson method; CI = confidence interval, NE = not estimable †95% CI calculated using the Brookmeyer-Crowley method Gastric cancer DESTINY-Gastric04 study (NCT04704934) The efficacy and safety of Enhertu were investigated in DESTINY-Gastric04, a randomised, multicentre, open-label, active-controlled study. The study enrolled adult patients with locally advanced, unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma who had experienced disease progression on or after a prior trastuzumab-based regimen. Patients were randomised 1:1 to treatment with either Enhertu (n = 246) or a combination of ramucirumab and paclitaxel (n = 248). Randomisation was stratified by HER2 status (IHC 3+ or IHC 2+/ISH-positive), geographic region (Asia [excluding mainland China] versus Western Europe versus mainland China/rest of the world) and time to disease progression on first-line treatment (< 6 months or ≥ 6 months). Tumour specimens had to have locally or centrally confirmed HER2 positivity, defined as IHC 3+ or IHC 2+/ISH-positive. The study excluded patients with a history of ILD/pneumonitis requiring steroid treatment or with ILD/pneumonitis at screening, patients with a history of clinically significant cardiac disease and patients with active brain metastases. Treatment was administered until disease progression, death or unacceptable toxicity. The primary efficacy endpoint was overall survival (OS). PFS, confirmed ORR and DOR were secondary endpoints. Patient demographics and baseline disease characteristics were similar across the treatment arms. Among the 494 patients enrolled in DESTINY-Gastric04, the median age was 63.7 years (range: 21.1 years to 87.0 years); 79.4% were men; 49.8% were White, 40.1% Asian and 0.4% Black or African American. Patients had an ECOG performance status of either 0 (37.4%) or 1 (61.9%); 61.1% had gastric adenocarcinoma and 38.9% GEJ adenocarcinoma; 84% were IHC 3+ and 16% were IHC 2+/ISH-positive; 70% of patients had two or more metastatic lesions, 61.7% had liver metastases, 6.9% had brain metastases; 15.6% of patients had been previously treated with immunotherapy. The efficacy results are summarised in Table 10 and in Figure 9. Table 10: Efficacy results in the DESTINY-Gastric04 study Efficacy endpoint Enhertu n = 246 Ramucirumab plus paclitaxel n = 248 Overall survival (OS) Number of events (%) 124 (50.4) 142 (57.3) Median, months (95% CI) 14.7 (12.1; 16.6) 11.4 (9.9; 15.5) Hazard ratio (95% CI) * 0.70 (0.55; 0.90) p-value† p = 0.0044 Progression-free survival (PFS) by investigator assessment Number of events (%) 166 (67.5) 156 (62.9) Median, months (95% CI) 6.7 (5.6; 7.1) 5.6 (4.9; 5.8) Hazard ratio (95% CI) * 0.74 (0.59; 0.92) p-value† p = 0.0074 Confirmed objective response rate (ORR) by investigator assessment †† n (%) 104 (44.3) 69 (29.1) 95% CI (37.8; 50.9) (23.4; 35.3) p-value§ p = 0.0006 Complete response n (%) 7 (3.0) 3 (1.3) Partial response n (%) 97 (41.3) 66 (27.8) Duration of response by investigator assessment Median, months (95% CI) 7.4 (5.7; 10.1) 5.3 (4.1; 5.7) CI = confidence interval *Two-sided p-value by stratified log-rank test and stratified Cox proportional hazards model adjusted for the stratification factors: HER2 status (IHC 3+ or IHC 2+/ISH+). †Based on a log-rank test stratified by HER2 status (IHC 3+ or IHC 2+/ISH+) ††Subjects eligible for ORR assessment are those who were randomised at least 77 days (i.e. 2 × 6 weeks – 1 week) before the data cut-off date for the interim analysis. Confirmed ORR is calculated using eligible subjects as the denominator: Enhertu = 235, ramucirumab plus paclitaxel = 237 §The p-value for the difference in ORR uses the Cochran-Mantel-Haenszel test adjusted for the stratification factor: HER2 status (IHC 3+ or IHC 2+/ISH+). Figure 9: Kaplan-Meier plot of overall survival (full analysis set) DESTINY-Gastric02 (NCT04014075) The efficacy and safety of Enhertu were investigated in DESTINY-Gastric02, a multicentre, open-label, single-arm phase 2 study conducted at sites in Europe and the United States. The study enrolled patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who had experienced disease progression on a prior trastuzumab-based regimen. Patients had to have centrally confirmed HER2 positivity, defined as IHC 3+ or IHC 2+/ISH-positive. The study excluded patients with a history of ILD/pneumonitis requiring steroid treatment or with ILD/pneumonitis at screening, patients with a history of clinically significant cardiac disease and patients with active brain metastases. Enhertu was administered by intravenous infusion at a dose of 6.4 mg/kg once every three weeks until disease progression, death, withdrawal of consent or unacceptable toxicity. The primary efficacy endpoint was confirmed ORR assessed by ICR based on RECIST v1.1. DOR and OS were secondary endpoints. Among the 79 patients enrolled in DESTINY-Gastric02, demographic and baseline disease characteristics were as follows: median age 61 years (range 20 years to 78 years); 72% were men; 87% White, 5.0% Asian and 1.0% Black or African American. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (37%) or 1 (63%); 34% had gastric adenocarcinoma and 66% GEJ adenocarcinoma; 86% were IHC 3+ and 13% were IHC 2+/ISH-positive; 63% had liver metastases. The efficacy results for ORR and DOR are summarised in Table 11. Table 11: Efficacy results in the DESTINY-Gastric02 study (full analysis set*) Efficacy endpoint DESTINY-Gastric02 n = 79 Data cut-off: 8 November 2021 Confirmed objective response rate † % (95% CI) ‡ 41.8 (30.8; 53.4) Complete response n (%) 4 (5.1) Partial response n (%) 29 (36.7) Duration of response; Median § , months (95% CI) ¶ 8.1 (5.9; NE) NE = not estimable * Includes all patients who received at least one dose of Enhertu. † Assessed by independent central review ‡ Calculated using the Clopper-Pearson method § Based on Kaplan-Meier estimate ¶ Calculated using the Brookmeyer-Crowley method. DESTINY-Gastric01 study (NCT03329690) The efficacy and safety of Enhertu were investigated in DESTINY-Gastric01, a multicentre, open-label, randomised phase 2 study conducted at sites in Japan and South Korea. This supportive study enrolled adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who had experienced disease progression after at least two prior regimens including trastuzumab, a fluoropyrimidine and platinum. Patients were randomised 2:1 to treatment with either Enhertu (n = 126) or chemotherapy of physician's choice: either irinotecan (n = 55) or paclitaxel (n = 7). Tumour specimens had to have centrally confirmed HER2 positivity, defined as IHC 3+ or IHC 2+/ISH-positive. The study excluded patients with a history of ILD/pneumonitis requiring steroid treatment or with ILD/pneumonitis at screening, patients with a history of clinically significant cardiac disease and patients with active brain metastases. Treatment was administered until disease progression, death, withdrawal of consent or unacceptable toxicity. The primary efficacy endpoint was unconfirmed ORR assessed by ICR based on RECIST v1.1. Overall survival (OS), progression-free survival (PFS), DOR and confirmed ORR were secondary endpoints. Patient demographics and baseline disease characteristics were similar across the treatment arms. Among the 188 patients, the median age was 66 years (range: 28 years to 82 years); 76% were men and 100% Asian. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 (49%) or 1 (51%); 87% had gastric adenocarcinoma and 13% GEJ adenocarcinoma; 76% were IHC 3+ and 23% were IHC 2+/ISH-positive; 54% had liver metastases; 29% had lung metastases; the sum of diameters of target lesions was < 5 cm in 47%, ≥ 5 cm to < 10 cm in 30% and ≥ 10 cm in 17%; 55% had received two and 45% three or more prior regimens in the locally advanced or metastatic setting. The efficacy results (as of the data cut-off date of 3 June 2020) for Enhertu (n = 126) versus chemotherapy of physician's choice (n = 62) were a confirmed ORR of 39.7% (95% CI: 31.1; 48.8) versus 11.3% (95% CI: 4.7; 21.9). The complete response rate was 7.9% versus 0% and the partial response rate was 31.7% versus 11.3%. Another efficacy result for Enhertu versus chemotherapy of physician's choice was a median DOR of 12.5 months (95% CI: 5.6; NE) versus 3.9 months (95% CI: 3.0; 4.9). Median PFS was 5.6 months (95% CI: 4.3; 6.9) versus 3.5 months (95% CI: 2.0; 4.3; hazard ratio = 0.47 [95% CI: 0.31; 0.71]). The OS analysis, prespecified at 133 deaths, demonstrated a survival benefit with Enhertu treatment compared with the chemotherapy of physician's choice group (hazard ratio = 0.60). Median OS was 12.5 months (95% CI: 10.3; 15.2) in the Enhertu group and 8.9 months (95% CI: 6.4; 10.4) in the chemotherapy of physician's choice group. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the paediatric population in the indications of breast cancer, NSCLC and gastric cancer (see section 4.2 for information on paediatric use). This medicinal product has been authorised under a so-called conditional approval scheme. This means that further evidence on its benefits is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this summary of product characteristics will be updated as necessary.