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heading-Nerlynx-Neratinib--HER2-Breast-Cancer

Efficacy

Reading time: 7 min

ExteNET is a large phase III trial designed to investigate the efficacy of neratinib as an extended adjuvant treatment post 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 in HER2+ early breast cancer.1-4 Patients were treated with chemotherapy and trastuzumab. At the time of the ExteNET trial patient recruitment, trastuzumab emtansine (TDM-1) was not licensed or available for adjuvant treatment in early breast cancer therefore patients included in the ExteNET trial only received prior trastuzumab.1

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Nerlynx-Neratinib--HER2-Breast-Cancer-Efficacy-schema-1

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.
*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.
†Invasive disease-free survival (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 an exploratory 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 the ITT population2,3,5

ExteNET study met its primary endpoint and demonstrated the benefit of adding NERLYNX after a trastuzumab-based therapy for HER2+ early breast cancer patients.5

Primary endpoint presented in the Summary of Product Characteristics (SmPC) is the 2-year data in ITT population, iDFS after adjuvant therapy at 2 years: 94.2% vs 91.9% NERLYNX vs placebo; absolute benefit 2.3%.

33% reduction of the relative risk of disease recurrence vs placebo in the ITT population*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.
*“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 HER2+/HR+ early breast cancer patients who have completed trastuzumab-based therapy less than 1 year ago, granting marketing autorisation in this specific population*†‡1,5

Invasive disease-free survival (iDFS) in HER2+/HR+ <1 year from completion of prior trastuzumab-based therapy population:

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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; HER2+, human epidermal growth factor receptor 2 positive; HR, hazard ratio; HR+, hormone receptor positive; iDFS, invasive disease-free survival
*NERLYNX EU label population: HER2+/HR+ patients completing prior trastuzumab-based treatment ≤1 year from randomisation. 5 years are the last updated results. Results of ExteNET are supported by an exploratory 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. 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 neoadjuvant1,7,8

  • High Ki-67

  • High BMI

  • Medium/High grading

  • Younger age

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

Anna, pre-menopausal patient
with node-positive disease

Anna is disease-free, following surgery, adjuvant trastuzumab-based therapy and hormone therapy.

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

Sofia, post-menopausal patient
with no pCR following neoadjuvant treatment

Sofia has undergone a number of cycles of neoadjuvant therapy, surgery and adjuvant therapy, and is currently disease-free


BMI, body mass index; 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.

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: 44% relapse

at 10 years following 1 year trastuzumab*†6

Anna is HER2+/HR+ and results presented from HERA trial are on HER2+ (HR status not specified, data not available).

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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; iDFS, invasive disease-free survival; OS, overall 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.
†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). NERLYNX showed a significant positive impact on N+ patient subgroup in iDFS with a reduction in the risk of recurrence of 40% at 5 years.

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

Sofia No pCR patient after neoadjuvant treatment

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

  • 11,7% at 3 years following 42 weeks of T-DM1*†7

Sofia is HER2+/HR+ and results presented from KATHERINE trial are on HER2+ (HR status not specified).
 

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


CI, confidence interval; HR, hazard ratio; iDFS, invasive disease-free survival; NS, not significant; OS, overall survival; pCR, pathological complete response; T-DM1, trastuzumab emtansine. *“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. In this exploratory subset analysis, NERLYNX showed 7.4% absolute benefit in iDFS at 5 years and 9.1% absolute benefit in overall survival at 8 years.

 

 

NERLYNX improves iDFS in patients with residual disease1

ExteNET study exploratory subset analysis: HER2+/HR+ ≤1 year from completion of trastuzumab with no 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 HR+ ≤1 year from completion of trastuzumab population who had received neoadjuvant therapy in the ExteNET study, 295 had residual invasive disease (83%).1

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.

NERLYNX improves OS in patients with residual disease1,4

ExteNET study exploratory subset analysis: HER2 +/HR+ ≤1 year from completion of trastuzumab with no pCR after neoadjuvant therapy

Overall survival at 8 years

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Efficacy-Overall-survival-at-8-years

 

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

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. 

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 HER2+/HR+ ≤1 year from completion of prior adjuvant trastuzumab-based therapy population

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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.
*The ExteNET study enrolled a majority of patients that were node positive (1,079 out of 1,334 in the EU label 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%.

CNS events data in EU label population

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

Population or subgroup CNS events (No. of patients) Cumulative incidence of CNS recurrences
at 5 years, % (95% CI)
Nerlynx Placebo Nerlynx Placebo
HR+ ≤1 year population 4 (670) 12 (664) 0.7 (0.2–1.7) 2.1 (1.1–3.5)
Nodal status        
Positive 4 (540) 10 (539) 0.8 (0.3–2.0) 2.2 (1.1–3.8)
Negative 0 (130) 2 (125) 0 (NE) 1.9 (0.4–6.0)
Prior trastuzamab regimen        
Concurrent 2 (411) 8 (415) 0.6 (0.1–1.9) 2.3 (1.1–4.3)
Sequential 2 (259) 4 (249) 0.9 (0.2–3.0) 1.8 (0.6–4.3)
Adjuvant or neoadjuvant therapy        
Adjuvant 3 (508) 6 (472) 0.7 (0.2–2.0) 1.5 (0.6–3.0)
Neoadjuvant 1 (162) 6 (192) 0.7 (0.1–3.3) 3.7 (1.5–7.4)
pCR status        
No 1 (131) 5 (164) 0.8 (0.1–4.0) 3.6 (1.3–7.8)
Yes 0 (17) 1 (21) 0 (NE) 5.0 (0.3–21.2)

CI, confidence interval; CNS, central nervous system; HR, hormone receptor-positive; NE, not estimable; pCR, pathologic complete response.
*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).
†Among the 354 patients who had received neoadjuvant therapy, 295 patients had no pCR, 38 patients achieved a pCR, and 21 patients had no outcome reported.

NERLYNX shows a 2.1% absolute benefit in overall survival at 8 years in EU label population4

NERLYNX demonstrates a 2.1% absolute benefit in overall survival in the HER2+/HR+ patients that completed prior trastuzumab-based treatment less than 1 year from randomization.4

Overall Survival

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Overal Survival

 

2,1% absolute benefit NERLYNX vs placebo. HR: 0.79 (95% CI: 0.53-1.12)4

OS data confirms the favourable benefit/risk profile for NERLYNX in HER2+/HR+ early breast cancer patients <1 year from completion of trastuzumab-based treatment4

Even though not statistically significant, there is a numerical OS advantage in NERLYNX arm: In EU label population, 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.
In the EU, NERLYNX is indicated for the extended adjuvant treatment of adult patients with early-stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who completed adjuvant trastuzumab-based therapy less than one year ago.5

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

Select ExteNET study intention-to-treat (ITT) population baseline characteristics1 NERLYNX group (N=1420) Placebo group (N=1420)
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)
Concomitant endocrine therapy for hormone
receptor-positive disease*
622 (93%) 629 (95%)
Menopausal status at diagnosis
Premenopausal
Postmenopausal
663 (47%)
757 (53%)
664 (47%)
756 (53%)
T stage
T1
T2
T3
Unknown or missing
440 (31%)
585 (41%)
144 (10%)
251 (18%)
459 (32%)
555 (39%)
117 (8%)
289 (20%)

Nodal status
Negative
1–3 positive nodes
4 positive nodes

335 (24%)
664 (47%)
421 (30%)
336 (24%)
664 (47%)
420 (30%)
Hormone receptor status
Hormone positive (ER+, PR+ or both)
Hormone negative (ER and PR negative)

816 (57%)
604 (43%)

815 (57%)
605 (43%)
Previous neoadjuvant or adjuvant therapy
Anthracycline-containing regimen
Non–anthracycline-containing regimen
1098 (78%)
322 (22%)
1100 (78%)
320 (22%)

ER, estrogen receptor; PR; progesterone receptor.
*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.
†The number of patients who received neoadjuvant chemotherapy was 342 (24%) in the NERLYNX group and 379 (27%) in the placebo group.

 

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