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https://www.pierre-fabre.com/en
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heading-Nerlynx-Neratinib--HER2-Breast-Cancer

Efficacy

Reading time: 7 min

ExteNET is a large trial designed to investigate the efficacy of extended adjuvant NERLYNX® after trastuzumab-based therapy in HER2+ early breast cancer

ExteNET study is a randomised phase III trial evaluating the addition of 1 year of NERLYNX® after trastuzumab therapy in HER2+ early breast cancer.#,1-4 Patients were treated with chemotherapy and trastuzumab. At the time of the ExteNET trial patient recruitment, pertuzumab and trastuzumab emtansine (TDM-1) were not available for adjuvant treatment in HER2+ early breast cancer. Patients included in the ExteNET trial only received prior trastuzumab.1

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Nerlynx-Neratinib--HER2-Breast-Cancer-Efficacy-schema-2

Primary endpoint
invasive disease-free survival (iDFS) at 2 years after randomisation*
 

Secondary endpoints
DFS-DCIS, time to distant recurrence, distant DFS, cumulative incidence of first occurrence of CNS recurrences, overall survival, safety
 

Other analyses
biomarkers, health outcome assessment (FACT-B, EQ-5D)
 

Stratification by
nodal status, HR status, concurrent vs sequential trastuzumab adjuvant regimen
 


CNS, central nervous system; DCIS, ductal carcinoma in situ; DFS, disease-free survival; EQ-5D, EuroQol5-Dimension Questionnaire; FACT-B, Functional Assessment of Cancer Therapy-Breast; HER2, human epidermal growth factor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridisation; T-DM1, trastuzumab emtansine.
#ExteNET is a double-blinded placebo-controlled study.
§Locally confirmed HER2 status (IHC 3+ or ISH).
*Patients were treated with chemotherapy and trastuzumab. Patient had not received treatment with T-DM1. Select exclusion criteria: clinically significant cardiac, GI or psychiatric comorbidities; inability to swallow pills.
†iDFS defined as the time between the date of randomisation to the first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distant recurrence or death from any cause, with 2 years and 28 days of follow-up.
‡Results of ExteNet study are supported by a descriptive analysis of 5-year follow-up, with 74.5% (2117/2840) of patients re-consented.

NERLYNX® significantly improves invasive disease-free survival (iDFS) vs placebo in patients with HER2+ early breast cancer2,3,5

ExteNET study met its primary endpoint and demonstrates the benefit of adding NERLYNX® after a trastuzumab-based therapy for patients with HER2+ early breast cancer (ITT population, n=2840).5

iDFS after adjuvant therapy at 2 years: 94.2% vs 91.9% NERLYNX® vs placebo; absolute benefit 2.3%.

33% relative reduction in the risk of disease recurrence* vs placebo in patients with HER2+ early breast cancer.5
HR: 0.67 (95% CI; 0.49-0.91); P=0.0115

See patient characteristics


CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; ITT, intention-to-treat; iDFS, invasive disease-free survival.
*“Recurrence” defined as the first occurrence of any of the following events: recurrence of ipsilateral invasive breast tumour, recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast cancer, a distant disease recurrence, or death from any cause at 2 years after randomisation.

NERLYNX® shows superior benefit in patients with HER2+/HR+ early breast cancer who have completed trastuzumab-based therapy less than 1 year ago, granting marketing EU authorisation in this specific population*†‡1,5

Invasive disease-free survival (iDFS) in HER2+/HR+ ≤ 1-year from completion of prior trastuzumab-based therapy population (n=1334)

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4,5% absolute benefit vs placebp at 2 years (1). 51% risk reduction at 2 years (1)

Graph adapted from Chan A, et al. Clin Breast Cancer 2021.

CI, confidence interval; EU, Europe; HER2+, human epidermal growth factor receptor 2 positive; HR, hazard ratio; HR+, hormone receptor positive; iDFS, invasive disease-free survival.
*Results of ExteNET are supported by a descriptive analysis of 5-year follow-up with 74.5% (2117/2840) of patients reconsented. 95% of the HER2+/HR+ study population received concurrent endocrine therapy. 5 years are the last updated results. iDFS results are expressed in Interactive Response Technology (IRT) based analysis.
†Recurrence is defined as an invasive disease event or death.
‡Unstratified.

See ExteNET final results publication

Some patients are at a heightened risk of recurrence*1,6-8

Risk considerations in early-stage HER2+ breast cancer patients

  • One or more positive nodes6

  • Tumor diameter ≥ 2cm8

  • Residual disease after neoadjuvant treatment1,7,8

  • High Ki-67

  • HR-status1

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Nerlynx-Neratinib--HER2-Breast-Cancer-Patient-Anna

Anna, pre-menopausal patient
with node-positive disease

Following surgery and adjuvant trastuzumab-based therapy together with endocrine therapy, Anna is disease-free

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Nerlynx-Neratinib--HER2-Breast-Cancer-Patient-Sofia

Sofia, postmenopausal non-pCR patient 
following neoadjuvant treatment

Sofia has undergone a number of cycles of neoadjuvant therapy, surgery and adjuvant therapy


HR, hormone receptor; HER2, human epidermal growth factor receptor 2; pCR, pathological complete response.
*“Recurrence” defined as the first occurrence of any of the following events: recurrence of ipsilateral invasive breast tumour, recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast cancer, a distant disease recurrence, or death from any cause.
KI-67 high/low classification should be according to the centers' local standards.

NERLYNX® can help reduce Anna’s risk of recurrence*1,4,6

Anna Node-positive patient

For HER2+ node-positive patients, like Anna, the risk of recurrence increases with the number of lymph nodes involved:*

  • 1-3 nodes involved: 25% relapse
  • ≥4 nodes involved: 45% relapse

at 10 years following 1 year trastuzumab*†6

Anna is HER2+/HR+ node-positive patient. Recurrence rates presented from HERA trial are according to node-positive status and without specified HR status.

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Nerlynx reduces the relative risk of invasive recurrence by 40% at 5 years

 

See ExteNET study results in the node positive subgroup of patients


CI, confidence interval; HR, hazard ratio; HER2, human epidermal growth actor receptor; HR+, hormone receptor positive.
Descriptive analysis from ExteNET study.
*“Recurrence” defined as the first occurrence of any of the following events: recurrence of ipsilateral invasive breast tumour, recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast cancer, a distant disease recurrence, or death from any cause.
†Dosage: once at 8 mg/kg body weight intravenously, then 6 mg/kg once every 3 weeks.
‡The ExteNET study enrolled a majority of patients that were node positive (1,079 out of 1,334 in the EU label population). This is from a forest plot of HER2+/HR+ ≤ 1 year from completion of trastuzumab-based treatment subgroup analysis from ExteNET study.

NERLYNX® can help reduce Sofia’s risk of recurrence*1,4,7

Sofia Non-pCR patient after neoadjuvant treatment

For patients like Sofia, who did NOT achieve a pCR and received trastuzumab-DM1, the recurrence rate is:

  • 9.3% at 3 years following 41 weeks of T-DM1*†7

In descriptive analysis of patients who did not achieve a pCR after trastuzumab-based adjuvant therapy, NERLYNX® demonstrates an absolute benefit vs placebo:‡1,4

 

In ExteNET study, patients were treated with trastuzumab, not with T-DM1 since T-DM1 was not available at that time.

CI, confidence interval; DDFS, distant disease-free survival; HR, hazard ratio; iDFS, invasive disease-free survival; NS, not significant; OS, overall survival; pCR, pathological complete response; T-DM1, trastuzumab emtansine.
Descriptive analysis from ExteNET study.
*“Recurrence” defined as the first occurrence of any of the following events: recurrence of ipsilateral invasive breast tumour, recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast cancer, a distant disease recurrence, or death from any cause.
†Dosage: Loading dose of 8 mg/kg body weight administered if more than 6 weeks had elapsed since preceding dose of trastuzumab, followed by 3.6 mg/kg body weight intravenously, once every 3 weeks for 14 cycles.
‡295 HER2+/HR+ patients who had residual disease after neoadjuvant treatment were included in the ExteNET study and received either NERLYNX or placebo.
 

See possible clinical scenarios

NERLYNX® improves iDFS in patients with residual disease (non-pCR)1

ExteNET study descriptive analysis: HER2+/HR+ ≤ 1-year from completion of trastuzumab with non-pCR after neoadjuvant therapy

Invasive disease-free survival at 5 years

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Invasive disease-free survival at 5 years

 

Of the 354 HER2+/HR+ ≤ 1-year from completion of trastuzumab population who had received neoadjuvant therapy in the ExteNET study, 295 had residual invasive disease (83%).1

In ExteNET study, patients were treated with trastuzumab only, not with T-DM1 since T-DM1 was not available at that time.2

CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor positive; iDFS, invasive disease-free survival; pCR, pathological complete response; T-DM1, trastuzumab emtansine.
Descriptive analysis from ExteNET study.
In ExteNET study HR+ label population, 93% of patients received endocrine therapy alongside NERLYNX.

NERLYNX® improves OS in patients with residual disease (non-pCR)1,4

ExteNET study descriptive analysis: HER2 +/HR+ ≤ 1-year from completion of trastuzumab with non-pCR after neoadjuvant therapy

Overall survival at 8 years

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Efficacy-Overall-survival-at-8-years

 

Of the 354 HER2+/HR+ ≤ 1-year population from completion of trastuzumab who had received neoadjuvant therapy in the ExteNET study, 295 had residual invasive disease (83%).1

In ExteNET study, patients were treated with trastuzumab only, not with T-DM1 since T-DM1 was not available at that time.2

CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor positive; OS, overall survival; pCR, pathological complete response; T-DM1, trastuzumab emtansine. 
Descriptive analysis from ExteNET study.
In ExteNET study HR+ label population, 93% of patients received endocrine therapy alongside NERLYNX®.

NERLYNX demonstrates a proven benefit for node-positive patients1

The ExteNET study includes a high proportion of lymph node positive patients (81%)*1

Stratification factors in the node positive subgroup HER2+/HR+ ≤ 1-year from completion of prior adjuvant trastuzumab-based therapy

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Efficacy-Stratification factors in the HER2+/HR

CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor positive.
Descriptive analysis from ExteNET study. Figure adapted from Chan A, et al. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial. Clin Breast Cancer. 2021;21(1):80–91.
*The ExteNET study enrolled a majority of patients that were node positive (1,079 out of 1,334 in the HER2+/HR+ population).
†Not statistically significant. Even if not statistically significant, a trend favouring NERLYNX was observed in Overall Survival, decreasing the risk of death by 21%.

Fewer CNS events as first site of metastases in the NERLYNX® arm compared to placebo at 5 years in HER2+/HR+ ≤ 1-year population and subgroups*1

Cumulative incidence of CNS recurrences at 5 years in patients with HER2+/HR+ early breast cancer who completed trastuzumab-based therapy less than 1 year ago (n=1334) and in the non-pCR subgroup of patients (n=295)*

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todo2
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todo3

 

CI, confidence interval; CNS, central nervous system; HER2, human epidermal growth factor 2; HR, hormone receptor-positive; pCR, pathologic complete response.
Descriptive analysis from ExteNET study. Both differences are not statistically significative. 
*Cumulative incidence of CNS recurrences (defined as time from randomisation to CNS recurrence as first distant recurrence either isolated CNS metastases or those diagnosed concurrently with other sites of metastatic disease).

NERLYNX® shows a 2.1% absolute benefit in overall survival at 8 years in the HER2+/HR+ ≤ 1-year population ​​​​​​​1

Overall Survival (OS) in HER2+/HR+ ≤ 1-year from completion of prior trastuzumab-based therapy population1

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Overal Survival


 

2,1% absolute benefit vs placebo. HR: 0.79 (95% CI: 0.53-1.13)1,4

OS data confirm the favourable benefit/risk profile for NERLYNX® in HER2+/HR+ early breast cancer patients ≤ 1-year from completion of trastuzumab-based treatment1,4

There is a numerical OS advantage in NERLYNX® arm (not statisticaly significative). After a median follow-up of 8 years, there were numerically fewer deaths in patients treated with NERLYNX®, 53 (7.9%), than in patients treated with placebo, 68 (10.2%). HR: 0.79 (95% CI: 0.53–1.13)1,4

CI, confidence interval; HER2, human epidermal growth factor 2; HR+, hormone receptor positive; NS, not significant; OS, overall survival.
Descriptive analysis from ExteNET study.

Patient characteristics are well balanced in the two arms of the ExteNET study1

Population baseline characteristics1 HER2+ (ITT population), n(%)
(N=2840)
HER2+/HR+ ≤ 1-year from last dose of trastuzumab to randomization, n(%)
(N=1334)

NERLYNX® group
(N=1420)

Placebo group (N=1420) NERLYNX® group (N=670) Placebo group
(N=664)

T stage
T1
T2
T3
Unknown or missing


440 (31)
585 (41)
144 (10)
251 (18)


459 (32)
555 (39)
117 (8)
289 (20)


218 (33)
270 (40)
61 (9)
121 (18)


209 (31)
250 (38)
65 (10)
140 (21)

Nodal status
Negative
1–3 positive nodes
4 positive nodes


335 (24)
664 (47)
421 (30)


336 (24)
664 (47)
420 (30)


130 (19)
339 (51)
201 (30)


125 (19)
334 (50)
205 (31)

Hormone receptor status
Hormone positive (ER+, PR+ or both)
Hormone negative (ER and PR negative)

816 (57)


604 (43)

815 (57)


605 (43)

670 (100)
 


664 (100)
 

Menopausal status at diagnosis
Premenopausal
Postmenopausal
 

663 (47)
757 (53)


664 (47)
756 (53)


350 (52)
320 (48)


342 (52)
322 (48)

Previous neoadjuvant or adjuvant therapy
Anthracycline-containing regimen
Non–anthracycline-containing regimen

1098 (78)


322 (22)

1100 (78)


320 (22)

502 (75)


168 (25)

503 (76)


161 (24)

Median time from the last adjuvant trastuzumab treatment to randomisation (months) – min/max

4.4 (0.2–30.9)

4.67 (0.3–40.6) 3.1 (0.2-12.0) 3.3 (0.3-12.0)
Concomitant endocrine therapy for hormone receptor-positive disease* 622 (93) 629 (95) 622 (93) 629 (95)

ER, estrogen receptor; ITT, itention-to-treat PR; progesterone receptor.
†The number of patients who received neoadjuvant chemotherapy in the ITT population was 342 (24%) in the NERLYNX® group and 379 (27%) in the placebo group; and in the HER2+/HR+ ≤ 1-year population was 162 (24%) in the NERLYNX group and 192 (29%) in the placebo group.
*Percentage is based on the number of hormone receptor-positive patients. Tumours were assessed as being ER or PR positive on the basis of local pathology laboratory cutoffs. There was no protocol specification as to whether a 1% or 10% threshold should be used.

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NERLYNX® shows a 4.7% absolute benefit in DDFS at 5 years in the HER2+/HR+ population*1
 

Distant disease-free survival (DDFS) in HER2+/HR+ ≤ 1-year from completion of prior trastuzumab-based therapy population1
 

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DDFS graph 2

 

4.7% absolute benefit vs placebo. HR: 0.57 (95% CI: 0.39-0.83)1


An additional year of extended adjuvant NERLYNX® prevents distant recurrences.

The 5-year DDFS rates were 92.4% (95% CI; 89.9%-94.4%) with NERLYNX® and 87.7% (95% CI; 84.8%-90.1%) with placebo, corresponding with an absolute benefit of 4.7% (HR: 0.57; 95% CI; 0.39-0.83), and confirmed the results from the primary 2-year analysis.1

CI, confidence interval; DDFS, distant disease-free survival; HER2+, human epidermal growth factor 2 positive; HR, hazard ratio; HR+, hormone receptor positive.
*Results of ExteNET are supported by a descriptive analysis of 5-year follow-up with 74.5% (2117/2840) of patients reconsented. 5 years are the last updated results. 95% of the HER2+/HR+ study population received concurrent endocrine therapy.
 

NERLYNX improves DDFS in patients with residual disease (non-pCR)1

ExteNET study descriptive analysis: HER2+/HR+ ≤ 1-year from completion of trastuzumab with non-pCR after neoadjuvant therapy

Distant disease-free survival at 5 years

Image
DDFS 5 Years graph

 

Of the 354 HER2+/HR+ ≤ 1-year from completion of trastuzumab population who had received neoadjuvant therapy in the ExteNET study, 295 had residual invasive disease (83%).1
In ExteNET study, patients were treated with trastuzumab only, not with T-DM1 since T-DM1 was not available at that time2

CI, confidence interval; DDFS, distant disease-free survival; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor positive; pCR, pathological complete response; T-DM1, trastuzumab emtansine.
Descriptive analysis from ExteNET study.
In ExteNET study HR+ label population, 93% of patients received endocrine therapy alongside NERLYNX.

NERLYNX® improves DDFS in patients with residual disease (non-pCR)1

ExteNET study descriptive analysis: HER2+/HR+ ≤ 1-year from completion of trastuzumab with non-pCR after neoadjuvant therapy

Distant disease-free survival at 5 years

Image
DDFS 5 ans 7% graph

 


Of the 354 HER2+/HR+ ≤ 1-year from completion of trastuzumab population who had received neoadjuvant therapy in the ExteNET study, 295 had residual invasive disease (83%).1
In ExteNET study, patients were treated with trastuzumab only, not with T-DM1 since T-DM1 was not available at that time.2

CI, confidence interval; DDFS, distant disease-free survival; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor positive; pCR, pathological complete response; T-DM1, trastuzumab emtansine.
Descriptive analysis from ExteNET study.
In ExteNET study HR+ label population, 93% of patients received endocrine therapy alongside NERLYNX®.