KADCYLA Powder for concentrate for solution for infusion Ref.[9013] Active ingredients: Trastuzumab emtansine

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, monoclonal antibodies
ATC code: L01XC14

Mechanism of action

Kadcyla, trastuzumab emtansine, is a HER2-targeted antibody-drug conjugate which contains the humanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.

Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumour cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1).

Trastuzumab emtansine has the mechanisms of action of both trastuzumab and DM1:

• Trastuzumab emtansine, like trastuzumab, binds to domain IV of the HER2 extracellular domain (ECD), as well as to Fcγ receptors and complement C1q. In addition, trastuzumab emtansine, like trastuzumab, inhibits shedding of the HER2 ECD, inhibits signalling through the phosphatidylinositol 3-kinase (PI3-K) pathway, and mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.
• DM1, the cytotoxic component of trastuzumab emtansine, binds to tubulin. By inhibiting tubulin polymerization, both DM1 and trastuzumab emtansine cause cells to arrest in the G2/M phase of the cell cycle, ultimately leading to apoptotic cell death. Results from in vitro cytotoxicity assays show that DM1 is 20-200 times more potent than taxanes and vinca alkaloids.
• The MCC linker is designed to limit systemic release and increase targeted delivery of DM1, as demonstrated by detection of very low levels of free DM1 in plasma.

Clinical efficacy

Early Breast Cancer

BO27938 (KATHERINE)

BO27938 (KATHERINE) was a randomized, multicenter, open-label trial of 1486 patients with HER2-positive, early breast cancer with residual invasive tumor (patients who had not achieved pathological complete response (pCR)) in the breast and/or axillary lymph nodes following completion of preoperative systemic therapy that included chemotherapy and HER2-targeted therapy. Patients may have received more than one HER2-targeted therapy. Patients received radiotherapy and/or hormonal therapy concurrent with study treatment as per local guidelines. Breast tumor samples were required to show HER2 overexpression defined as 3 + IHC or ISH amplification ratio ≥2.0 determined at a central laboratory. Patients were randomized (1:1) to receive trastuzumab or trastuzumab emtansine. Randomization was stratified by clinical stage at presentation (operable vs. inoperable), hormone receptor status, preoperative HER2-directed therapy (trastuzumab, trastuzumab plus additional HER2-directed agent[s]), and pathological nodal status evaluated after preoperative therapy.

Trastuzumab emtansine was given intravenously at 3.6 mg/kg on Day 1 of a 21-day cycle. Trastuzumab was given intravenously at 6 mg/kg on Day 1 of a 21-day cycle. Patients were treated with trastuzumab emtansine or trastuzumab for a total of 14 cycles unless there was recurrence of disease, withdrawal of consent, or unacceptable toxicity, whichever occurred first. Patients who discontinued trastuzumab emtansine could complete the duration of their intended study treatment up to 14 cycles of HER2-directed therapy with trastuzumab if appropriate based on toxicity considerations and investigator discretion.

The primary efficacy endpoint of the study was Invasive Disease-Free Survival (IDFS). IDFS was defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. Additional endpoints included IDFS including second primary non-breast cancer, disease-free survival (DFS), overall survival (OS), and distant recurrence-free interval (DRFI).

Patient demographics and baseline tumor characteristics were balanced between treatment arms. The median age was approximately 49 years (range 23-80 years), 72.8% were White, 8.7% were Asian and 2.7% were Black or African American. All but 5 patients were women; 3 men were included in the trastuzumab arm and 2 in the trastuzumab emtansine arm. 22.5 percent of patients were enrolled in North America, 54.2% in Europe and 23.3% throughout the rest of the world. Tumor prognostic characteristics including hormone receptor status (positive: 72.3%, negative: 27.7%), clinical stage at presentation (inoperable: 25.3%, operable: 74.8%) and pathological nodal status after preoperative therapy (node positive: 46.4%, node negative or not evaluated: 53.6%) were similar in the study arms.

The majority of the patients (76.9%) had received an anthracycline-containing neoadjuvant chemotherapy regimen.19.5% percent of patients received another HER2-targeted agent in addition to trastuzumab as a component of neoadjuvant therapy; 93.8% of these patients received pertuzumab. All of the patients had received taxanes as part of neoadjuvant chemotherapy.

A clinically meaningful and statistically significant improvement in IDFS was observed in patients who received trastuzumab emtansine compared with trastuzumab (HR = 0.50, 95% CI [0.39, 0.64], p<0.0001. Estimates of 3 years IDFS rates were 88.3% vs. 77.0% in trastuzumab emtansine vs. trastuzumab arms, respectively. See Table 6 and Figure 1.

Table 6. Summary of efficacy from study BO27938 (KATHERINE):

Data from first interim analysis 25 July 2018
Key to abbreviations (Table6): HR: Hazard Ratio; CI: Confidence Intervals,
¹ Hierarchical testing applied for IDFS and OS
² 3-year event-free rate and 5-year survival rate derived from Kaplan-Meier estimates
³ These secondary endpoints were not adjusted for multiplicity

Figure 1. Kaplan-Meier Curve of Invasive Disease-Free Survival in KATHERINE:

In KATHERINE, consistent treatment benefit of trastuzumab emtansine for IDFS was seen in all the pre-specified subgroups evaluated, supporting the overall result.

Metastatic Breast Cancer

TDM4370g/BO21977(EMILIA)

A Phase III, randomised, multicentre, international, open-label clinical study was conducted in patients with HER2-positive unresectable locally advanced breast cancer (LABC) or MBC who had received prior taxane and trastuzumab-based therapy, including patients who received prior therapy with trastuzumab and a taxane in the adjuvant setting and who relapsed during or within six months of completing adjuvant therapy. Only patients with Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 were eligible. Prior to enrolment, breast tumour samples were required to be centrally confirmed for HER2-positive status defined as a score of 3 + by IHC or gene amplification by ISH. Baseline patient and tumour characteristics were well balanced between treatment groups. Patients with treated brain metastases were eligible for enrollment if they did not require therapy to control symptoms. For patients randomised to trastuzumab emtansine, the median age was 53 years, most patients were female (99.8%), the majority were Caucasian (72%), and 57% had oestrogen-receptor and/or progesterone-receptor positive disease. The study compared the safety and efficacy of trastuzumab emtansine with that of lapatinib plus capecitabine. A total of 991 patients were randomised to trastuzumab emtansine or lapatinib plus capecitabine as follows:

• Trastuzumab emtansine arm: trastuzumab emtansine 3.6 mg/kg intravenously over 30-90 minutes on Day 1 of a 21-day cycle
• Control arm (lapatinib plus capecitabine): lapatinib 1250 mg/day orally once per day of a 21-day cycle plus capecitabine 1000 mg/m² orally twice daily on Days 1-14 of a 21-day cycle

The co-primary efficacy endpoints of the study were progression-free survival (PFS) as assessed by an independent review committee (IRC) and overall survival (OS) (see Table 7 and Figures 2 to 3).

Time to symptom progression, as defined by a 5-point decrease in the score derived from the Trials Outcome Index-Breast (TOI-B) subscale of the Functional Assessment of Cancer Therapy-Breast Quality of Life (FACT-B QoL) questionnaire was also assessed during the clinical study. A change of 5 points in the TOI-B is considered clinically significant. Kadcyla delayed patient-reported time to symptom progression for 7.1 months compared with 4.6 months for the control arm (Hazard Ratio 0.796 (0.667, 0.951); p-value 0.0121). The data are from an open-label study and no firm conclusions can be drawn.

Table 7. Summary of efficacy from study TDM4370g/BO21977 (EMILIA):

OS: overall survival; PFS: progression-free survival; ORR: objective response rate; OR: objective response; IRC: independent review committee; HR: hazard ratios; CI: confidence interval
* Stratified by: world region (United States, Western Europe, other), number of prior chemotherapeutic regimens for locally advanced or metastatic disease (0-1 vs. >1), and visceral vs. non-visceral disease.
** The interim analysis for OS was conducted when 331 events were observed. Since the efficacy boundary was crossed at this analysis, this is considered the definitive analysis.

A treatment benefit was seen in the subgroup of patients who had relapsed within 6 months of completing adjuvant treatment and had not received any prior systemic anti-cancer therapy in the metastatic setting (n=118); hazard ratios for PFS and OS were 0.51 (95% CI: 0.30, 0.85) and 0.61 (95% CI: 0.32, 1.16), respectively. The median PFS and OS for the trastuzumab emtansine group were 10.8 months and not reached, respectively, compared with 5.7 months and 27.9 months, respectively, for the lapatinib plus capecitabine group.

Figure 2. Kaplan-meier curve of IRC-assessed progression-free survival:

Figure 3. Kaplan-meier curve of overall survival:

In study TDM4370g/BO21977, consistent treatment benefit of trastuzumab emtansine was seen in the majority of pre-specified subgroups evaluated, supporting the robustness of the overall result. In the subgroup of patients with hormone receptor-negative disease (n=426), the hazard ratios for PFS and OS were 0.56 (95% CI: 0.44, 0.72) and 0.75 (95% CI: 0.54, 1.03), respectively. In the subgroup of patients with hormone receptor-positive disease (n=545), the hazard ratios for PFS and OS were 0.72 (95% CI: 0.58, 0.91) and 0.62 (95% CI: 0.46, 0.85), respectively.

In the subgroup of patients with non-measurable disease (n=205), based on IRC assessments, the hazard ratios for PFS and OS were 0.91 (95% CI: 0.59, 1.42) and 0.96 (95% CI: 0.54, 1.68), respectively. In patients ≥65 years old (n=138 across both treatment arms) the hazard ratios for progression-free survival (PFS) and Overall Survival (OS) were 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. In patients 65 to 74 years old (n=113), based on IRC assessments, the hazard ratios for PFS and OS were 0.88 (95% CI: 0.53, 1.45) and 0.74 (95% CI: 0.37, 1.47), respectively. For patients 75 years or above, based on IRC assessments, the hazard ratios for PFS and OS were 3.51 (95% CI: 1.22, 10.13) and 3.45 (95% CI: 0.94, 12.65), respectively. The subgroup of patients 75 years or above did not demonstrate a benefit for PFS or OS, but was too small (n=25) to draw any definitive conclusions.

In the descriptive follow-up overall survival analysis, the hazard ratio was 0.75 (95% CI 0.64, 0.88). The median duration of overall survival was 29.9 months in the trastuzumab emtansine arm compared with 25.9 months in the lapatinib plus capecitabine arm. At the time of the descriptive follow-up overall survival analysis, a total of 27.4% of the patients had crossed over from the lapatinib plus capecitabine arm to the trastuzumab emtansine arm. In a sensitivity analysis censoring patients at the time of cross-over, the hazard ratio was 0.69 (95% CI 0.59, 0.82). The results of this descriptive follow-up analysis are consistent with the confirmatory OS analysis.

TDM4450g

A randomised, multicentre, open-label phase II study evaluated the effects of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with HER2-positive MBC who had not received prior chemotherapy for metastatic disease. Patients were randomised to receive trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks (n=67) or trastuzumab 8 mg/kg intravenous loading dose followed by 6 mg/kg intravenously every 3 weeks plus docetaxel 75-100 mg/m² intravenously every 3 weeks (n=70).

The primary endpoint was investigator assessed Progression-Free Survival (PFS). The median PFS was 9.2 months in the trastuzumab plus docetaxel arm and 14.2 months in the trastuzumab emtansine arm (hazard ratio, 0.59; p=0.035), with a median follow-up of approximately 14 months in both arms. The objective response rate (ORR) was 58.0% with trastuzumab plus docetaxel and 64.2% with trastuzumab emtansine. The median duration of response was not reached with trastuzumab emtansine vs. 9.5 months in the control arm.

TDM4374g

A Phase II, single-arm, open-label study evaluated the effects of trastuzumab emtansine in patients with HER2-positive incurable, LABC or MBC. All patients were previously treated with HER2-directed therapies (trastuzumab and lapatinib), and chemotherapy (anthracycline, taxane, and capecitabine) in the neoadjuvant, adjuvant, locally advanced, or metastatic setting. The median number of anti-cancer agents that patients had received in any setting was 8.5 (range, 5-19) and in the metastatic setting was 7.0 (range, 3-17), including all agents intended for the treatment of breast cancer.

Patients (n=110) received 3.6 mg/kg of trastuzumab emtansine intravenously every 3 weeks until disease progression or unacceptable toxicity.

The key efficacy analyses were ORR based on independent radiologic review and duration of objective response. The ORR was 32.7% (95% CI: 24.1, 42.1), n = 36 responders, by both IRC and investigator review. The median duration of response by IRC was not reached (95% CI, 4.6 months to not estimable).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with trastuzumab emtansine in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).