The KATHERINE trial evaluated the efficacy of trastuzumab emtansine (T-DM1) compared to trastuzumab in patients with HER2-positive early breast cancer who had residual invasive disease following neoadjuvant therapy. Results showed T-DM1 significantly reduced the risk of invasive disease-free survival (idfs) events by 50%, with three-year idfs rates of 88.3% for T-DM1 versus 77.0% for trastuzumab. The study supports the use of T-DM1 as a recommended adjuvant therapy for patients with poor prognoses post-surgery due to residual disease.

1. KATHERINE Trial
Trastuzumab Emtansine (TDM-1)
for Residual Invasive HER2-Positive
Breast Cancer
By:
Dina Barakat
Clinical Fellow in Clinical Oncology
Weston Park Hospital
June 2021

2. Background

3. • Breast cancer was the most common type of cancer and the fourth most
common cause of cancer death in the UK in 2016, accounting for 15% of all
new cancer cases.
• Approximately 14% of patients with early breast cancer (eBC), in which the
disease is still localised to the breast and regional lymph nodes, have HER2-
positive disease. If untreated, HER2-positive breast cancer is associated with
increased tumour size, increased risk of disease recurrence and poorer
clinical outcomes compared to HER2-negative disease.
• The treatment goal in early breast cancer is cure.
• Treating patients with the most effective regimens in the first instance is the
best opportunity to prevent metastatic relapse. Metastatic breast cancer
(mBC) is incurable (treatment is palliative with the goal of delaying
progression) and is associated with high healthcare costs and societal
burden.
• Treating eBC effectively to reduce the risk of metastatic relapse reduces the
burden of breast cancer overall.

4. • Systemic HER2-targeted treatment is the standard of care (SoC) for HER2-
positive eBC in the UK, and has already transformed the treatment and
prognosis of patients with HER2-positive eBC.
• Systemic treatment can be given in the neoadjuvant (pre-surgery) and
adjuvant (post-surgery) settings as part of a complete eBC treatment
regimen, to reduce the risk of disease recurrence.

5. What is TDM-1?
• Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate of trastuzumab
and the cytotoxic agent emtansine (DM1), a maytansine derivative and
microtubule inhibitor.
• T-DM1 retains trastuzumab activity while providing intracellular delivery of
DM1 to HER2-overexpressing cells.
• In two phase 3 trials involving patients with HER2-positive advanced breast
cancer who had previously received HER2-targeted therapy including
trastuzumab and chemotherapy, T-DM1 showed superior efficacy and a
favorable risk–benefit profile as compared with capecitabine plus lapatinib or
treatment of the physician’s choice.
• T-DM1 is approved for use in patients with HER2-positive metastatic breast
cancer who previously received treatment with trastuzumab and a taxane.

7. Why TDM-1 in the adjuvant setting?
• Neoadjuvant therapy may reduce the size of a tumour to the extent that no invasive tumour is detected
in the surgically excised breast specimen (and axillary lymph node[s], depending on the definition),
described as a pCR, whilst patients who do not achieve a pCR are described as having RID.
• Neoadjuvant HER2-targeted agents + chemotherapy have generated pCR rates of 29.0–66.2% in proof-
of-concept clinical trials.
• In current UK clinical practice the majority of patients with HER2-positive eBC eligible for neoadjuvant
therapy receive neoadjuvant pertuzumab + trastuzumab + chemotherapy, which is associated with pCR
rates of approximately 60%.
• The 40% of patients who do not achieve pCR, and therefore have RID at surgery, are at high risk of
recurrence and have been consistently demonstrated to have poorer prognosis than those who achieve
a pCR.
• Little guidance is available to inform the optimal treatment approach after surgery based on tumour
response to neoadjuvant therapy, and adjuvant treatments for patients who may benefit from a change
of systemic therapy are lacking. As a result, patients with RID at surgery currently receive the same
adjuvant treatment as those achieving a pCR, despite their significantly poorer prognosis.

11. Trial Design

12. Phase III, open-label, randomised, prospective study
involving 1,486 patients at 273 sites across 28 countries.

13. • Study population:
Patients with HER2-positive early breast cancer and residual invasive disease in the breast and/or axillary
lymph nodes at surgery, after completion of neoadjuvant chemotherapy plus HER2-targeted therapy.
• Intervention:
Trastuzumab emtansine, with radiation and endocrine therapy per protocol and local guidelines
• Comparator arm:
Trastuzumab, with radiation and endocrine therapy per protocol and local guidelines.
• Primary outcomes:
IDFS (excluding second primary non-breast cancers), defined as the time from randomisation to the first
occurrence of one of ipsilateral invasive breast tumour recurrence, ipsilateral local-regional invasive breast
cancer recurrence, distant recurrence, contralateral invasive breast cancer or death of any cause.
• Secondary outcomes:
OS
DFS
Adverse effects of treatment
HRQoL

14. Trial Methodology and Statistical Analysis

15. • International: 273 sites across 28 countries, of which 14 were in the UK.
• Prospective, phase III, open-label, randomised, multicentre study
• Patients were randomised in a 1:1 ratio using a permuted-block randomisation scheme through
an interactive voice response system/interactive web response system.
• Key inclusion Criteria:
 Histologically confirmed HER2-positive invasive breast cancer
 (stage T1–4/N0–3/M0 except T1a/bN0).
 HER2-positivity was confirmed by a central laboratory.
 Pathological evidence of RID in the breast and/or axillary
 lymph nodes following completion of taxane-based
 neoadjuvant therapy administered with trastuzumab ±additional HER2-targeted agents.
 Patients must have completed ≥6 cycles (16 weeks) of neoadjuvant chemotherapy including ≥9 weeks of
trastuzumab and ≥9 weeks of taxane-based therapy.
 Surgical removal of all clinically evident disease in the breast and axillary lymph nodes.
 Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1.
 LVEF ≥50% after neoadjuvant treatment and no decrease in LVEF by >15% from pre-neoadjuvant therapy
LVEF.

16. • Key Exclusion Criteria:
 Stage IV (metastatic) breast cancer.
 Gross residual disease remaining after mastectomy or positive margins after breast-conserving surgery.
 Progressive disease during neoadjuvant therapy.
 Cardiopulmonary dysfunction (heart failure of NYHA class II or higher or a history of a reduction in LVEF to <40%
with previous therapy).
 Current Grade ≥2 peripheral neuropathy (according to National Cancer Institute Common Terminology Criteria
for Adverse Events, [NCI CTCAE]).
 Any known active liver disease (e.g. due to hepatitis B virus [HBV], hepatitis C virus [HCV], autoimmune hepatic
disorders or sclerosing cholangitis).
 Treatment with anti-cancer investigational drugs within 28 days prior to commencing study treatment.
 Exposure to cumulative doses of anthracyclines exceeding:
o Doxorubicin: 240 mg/m2
o Epirubicin or liposomal doxorubicin-hydrochloride: 480 mg/m2
o Other anthracyclines: exposure equivalent to doxorubicin >240 mg/m2

17. • Preplanned subgroups:
 Subgroup analyses of IDFS were performed for randomisation
 Stratification factors (underlined below) as well as other disease or patient related prognostic
or predictive factors for the primary endpoint, as outlined below:
• Hormone receptor status
• Pathological nodal status after neoadjuvant therapy
• Clinical stage at presentation
• Neoadjuvant HER2-directed therapy type
• Age
• Race
 Subgroup analyses are planned based on the same factors for OS
• Duration of the study:
 The study began on 3rd April 2013, with a primary completion date of 25th July 2018 and an
estimated study completion date of 4th April 2023.
 Median follow-up duration in the ITT population was 41.4 months (range 0.1–62.7) in the
trastuzumab emtansine arm and 40.9 months (range 0.1–62.6) in the Trastuzumab arm.

18. • Study Power:
 384 invasive disease events and 1,484 patients were required for 80% power to detect
a HR of 0.75 with a two-sided significance level of 5% for the primary analysis of IDFS.
 This would correspond to a 6.5% improvement in 3-year IDFS from 70.0% in the
trastuzumab arm to 76.5% in the trastuzumab emtansine arm.
 A sample size of 1,484 patients and approximately 10 years of followup from the date
of randomisation of the first patient gave this study 56% power to detect a HR of 0.80
in OS with a two-sided significance level of 5%.
 This would correspond to a 2.8% improvement in 3-year OS from 85.0% in the
trastuzumab arm to 87.8% in the trastuzumab emtansine arm

20. Results

21. Patient Characteristics

23. Primary end-point
50% reduction

24. Secondary outcomes

25. Quality of life analysis

28. Adverse Events

31. Summary Statistics
• The KATHERINE study met its primary objective; trastuzumab emtansine reduced the risk
of an IDFS event by 50% compared to trastuzumab (HR=0.50; 95% CI: 0.39–0.64; p<0.001)
at a median follow up of 41.4 months in the trastuzumab emtansine arm and 40.9 months in
the trastuzumab arm.
• Estimates of IDFS at three years were 77.0% (95% CI: 73.8–80.3) for the trastuzumab arm
and 88.3% (95% CI: 85.8–90.7) in the trastuzumab emtansine arm.
• Secondary efficacy outcomes were supportive of the substantial treatment benefit observed
in the primary IDFS analysis: clear between-group differences in favour of trastuzumab
emtansine were observed in IDFS (STEEP definition), DFS and DRFI.
• The OS data were immature at the clinical cut-off date, but are supportive of the IDFS
analysis with a separation of the survival curves from 30 months, continuing up to 60
months (HR=0.70; 95% CI: 0.47–1.05; p=0.0848).
• Mean population change from baseline scores on the EORTC QLQ-C30 and EORTC QLQ-
BR23 were small and similar in each treatment arm, indicating no clinically meaningful
deterioration and suggesting that baseline functioning and HRQoL levels were maintained
over the course of treatment.
• Subgroup analyses were performed for the primary outcome according to factors including
clinical stage at presentation, hormone receptor status, neoadjuvant HER2-directed therapy
type and pathological nodal status after neoadjuvant therapy. These analyses demonstrated
the consistency of the overall result across pre-specified patient subpopulations, further
demonstrating the robustness of the primary result.

32. • No new safety signals for trastuzumab emtansine were observed in the
KATHERINE study. As expected, adverse events (AEs) of any grade were
more common in the trastuzumab emtansine arm than in the trastuzumab
arm (98.8% vs 93.3%, respectively), as were AEs of ≥Grade 3 (25.7% vs
15.4%, respectively).
• Side effects were generally reversible and could be well managed.

34. Trastuzumab emtansine is recommended, within its marketing
authorisation,
as an option for the adjuvant treatment of human epidermal
growth factor receptor 2 (HER2)-positive
early breast cancer in adults who have residual invasive disease
in the breast or lymph nodes after neoadjuvant taxane-based
and HER2-targeted therapy.
“NICE Guidelines, June 2020”

36. • Given the inclusion of pertuzumab + trastuzumab as a relevant
comparator (in the node-positive population) in the final scope for this
appraisal, the Company acknowledges that some form of comparison
between trastuzumab emtansine and pertuzumab + trastuzumab in this
setting must be presented.
• Despite the trial design and population differences, it was deemed most
appropriate to use the APHINITY trial data to inform the comparison. The
APHINITY study was judged to be most appropriate since it includes a
large sample size, the comparator of interest (pertuzumab +trastuzumab),
and the same primary outcome as the KATHERINE study (IDFS).
• A Bucher analysis has subsequently been performed by the Company.

37. Dr. M B Mukesh MBBS, FRCR, MSc, MD
Consultant Clinical Oncologist
East Suffolk & North Essex NHS Foundation Trust
mmukesh@nhs.ne
• There is no published data looking at the “relative effect of pertuzumab & trastuzumab versus trastuzumab and
relative effect of trastuzumab emtansine versus trastuzumab” in early breast cancer setting.
• The indirect comparison between APHINITY and KATHERINE study is not appropriate as both study looked at a very
different patient population with different interventions.
• The APHINITY study did not include patients receiving NACT and the high risk was defined based on baseline node
positivity.
• There was no information about tumour sensitivity to treatment. The study included addition of pertuzumab to
trastuzumab in adjuvant setting for more effective Her-2 pathway blockade. KATHERINE study was based on patients
who had received NACT and Her-2 directed therapy and had residual disease post neo-adjuvant treatment.
• The study did not select patients Clarification questions based on baseline tumour size or nodal status but included
patients who had demonstrated in vivo resistance to chemotherapy and Her-2 directed therapy (80% trastuzumab and
20% with trastuzumab & pertuzumab).
• The high risk feature was residual disease post neo-adjuvant therapy. The study looked at switching adjuvant Her-2
directed antibodies (trastuzumab ± pertuzumab) with antibody drug conjugate (trastuzumab emtansine) in patients
with residual disease.”

38. Dr Duncan Wheatley Clinical Oncologist Clinical
Lead for Peninsula cancer research network,
Member of NIHR breast clinical studies group and executive member of the UK
breast cancer Group.
Recruiter to TRYPHAENA, APHINITY, KAITLIN, and KATHERINE Studies.
• “In the aphinity study, her2+ breast cancer patients were post surgically treated
with adjuvant chemotherapy and trastuzumab and randomised to receive a year
of pertuzumab/placebo. At 3 years the invasive event free survival was 94.1% for
those receiving pertuzumab vs 93.2% for those who didn’t. In the slightly higher
risk node positive population (63% of trial population), the invasive cancer event
rate was 92% vs 90.2%.
• These differences were statistically significant , but small. 40% of the patients in
Aphinity had small, less than 2cm tumours and 47% were node negative.
• Therefore overall these patients in Aphinity were a good prognostic group, as
seen by the excellent 3 year survival of both groups. However further follow up is
needed to see if the long term benefits change over time. Certainly more patients
will relapse over time.

39. • In the Katherine study, the hypothesis was that we already knew that patients
who don’t achieve a pathological complete response have a worse outcome,
switching to alternative her2 based therapy might give them a better outcome.
• The bigger the residual cancer burden after neoadjuvant therapy, the higher the
risk of relapse.
• Therefore the patients in Katherine study were biologically predetermined to be
a much higher risk group than in Aphinity. This is both because they had residual
disease after her2 antibody containing chemotherapy (some with trastuzumab,
some (19%) with 2 her2 containing regimes, mainly pertuzumab) and because
patients receiving neoadjuvant chemotherapy will usually have a much higher
stage at diagnosis than most of the patients in aphinity.

40. • Patients who have pertuzumab added to trastuzumab, have almost double the chance of
achieving a pathological complete response, so those with residual disease will be rarer
and presumably even more resistant. Pathological CR is more likely in the er- her2+
subgroup than the er+her2+ group (as shown by the fact 25% of patients in Katherine
study were er-, 75% er+, whereas overall there is a 50/50 split for er-/er+ patients in
her2+ breast cancer In the results of Katherine, overall the event rate for relapses is
higher than Aphinity because of these facts, that a poorer prognostic group had been
selected via higher initial stage and resistance to standard her2 based chemotherapy. The
3 year event free survival was 88.3% for the T-DM1 group, versus 77.0% for those
continuing with trastuzumab, with a hazard ratio of 0.50.
• The standard of care for most larger (over 2cm/node positive) her2+ breast cancer
patients would be neoadjuvant chemotherapy with pertuzumab and trastuzumab, as per
NICE guidance. For those with nodal involvement, adjuvant pertuzumab and trastuzumab
would be the standard of care adjuvantly. The addition of pertuzumab neoadjuvantly
roughly doubles the path cr rate, so would half the number of patients not achieving a
pathological cr, and therefore potential candidates for Kadcyla. I would therefore strongly
support neoadjuvant dual antibody containing neo adjuvant chemotherapy for these
patients, with kadcyla for those not achieving a pathological complete response. This
would be instead of the much less effective therapy of continuing the antibodies (as per
standard of care) post surgery, with their costs anyway.”

41. Committee Conclusion
• Therefore, in conclusion, it seems fair to say that the indirect comparison
trastuzumab emtansine versus pertuzumab may be biased; however, it is
unclear in what direction or to what extend there is a bias. Given the
available evidence, the indirect comparison presented by the company
seems the best estimate of the relative effectiveness of trastuzumab
emtansine versus pertuzumab.