The natural history of HER2-positive early breast was dramatically changed in 2005
by the results of 4 randomised phase III trials evaluating the combination of chemotherapy
with adjuvant trastuzumab, the first drug in the anti-HER2 class. HERA, BCIRG-006,
NCCTG 9831 and NSABP-B31 established 1 year of adjuvant trastuzumab as the standard
of care, and long term follow-up results of these trials (8 to 11 years) have underscored
the significant and prolonged improvement in outcomes patients derive from trastuzumab
use.([1]) Toxicity, mostly cardiac in nature, has proven to be low when patients are carefully
selected and followed. In addition, most cardiac events are reversible with interruption
of trastuzumab and prompt cardiac treatment.([2]) Though the cost associated with adjuvant trastuzumab can be a concern, especially
in developing countries, the development of biosimilar options will likely bring prices
down – making trastuzumab a safe, effective and relatively affordable treatment standard.([3]) Despite these improvements, HER2-positive patients still relapse in significant
numbers. The 11 year follow-up results of HERA show that approximately 30% of patients
in the trastuzumab containing arms eventually experienced a relapse.([5]) After a new generation of anti-HER2 agents successfully improved outcomes and changed
clinical practice in the advanced setting – including lapatinib, pertuzumab and T-DM1,
it was only logical to hope they would be similarly effective in early disease.([6]) The first results of lapatinib and pertuzumab in the neoadjuvant setting showed
significant improvement in pathologic complete response (pCR). NeoALTTO tested trastuzumab
+ lapatinib vs trastuzumab or lapatinib alone, first alone then with paclitaxel, followed
by surgery and further chemotherapy and the same anti-HER2 therapy for a year.([7]) Results showed the superiority of the dual blockade regimen (with an absolute improvement
in pCR of approximately 20%). The NEOSPHERE study tested docetaxel + trastuzumab,
docetaxel + pertuzumab or both monoclonal antibodies with or without docetaxel, also
showing superior results with the dual blockade regimen (absolute improvement in pCR
of approximately 16%).([8]) Both trials, however, failed to show an equivalent improvement in disease-free
survival (DFS)/event-free survival (EFS), though it must be said that neither trial
was adequately powered to show a significant improvement in long outcomes. To change
standards in the adjuvant setting, larger phase III studies were needed, leading to
the design of the dual blockade ALTTO and APHINITY trials.([10],[11]) Additionally, despite negative results in advanced disease, the ExteNET trial testing
an alternative strategy of extending anti-HER2 therapy to 2 years with neratinib after
the completion of trastuzumab was also launched.([12],[13])
The first evidence that the extent of success seen in the advanced setting would not
be easily replicated were the results of the ALTTO trial, which randomised 8381 patients
to 4 arms testing trastuzumab and lapatinib as single agents, in sequence (trastuzumab
followed by lapatinib) or in combination (trastuzumab + lapatinib). Though the reasons
for this trial proving statistically negative, despite some signal of efficacy, have
been extensively debated in recent years, it brought an end to the development of
lapatinib in the early setting. On the other hand, both APHINITY and ExteNET were
positive trials – showing a significant improvement in invasive disease-free survival
(IDFS), ultimately leading to approval by the FDA of both regimens tested in these
trials.
APHINITY tested chemotherapy (either anthracycline-based or anthracycline-free) combined
with trastuzumab or trastuzumab + pertuzumab for 1 year in 4805 patients. Results
of the primary analysis show a statistically significant yet small absolute improvement
in 3-year IDFS favouring the arm receiving dual blockade of 0.9% (hazard ratio, 0.81;
95% confidence interval [CI], 0.66 to 1.00; p=0.045), with absolute gains being somewhat
better at 4 years (1.7%). Subgroup analysis suggests that patients with node positive
disease benefitted more than node negative patients (1.8% absolute IDFs gain at 3-years),
as well as a non-significant trend towards higher benefit in estrogen receptor negative
(ER-negative) patients. The adverse event profile with the dual blockade regimen was
overall similar to the trastuzumab single agent regimen, with the exception of a significant
increase in the incidence of diarrhoea (Grade 3 or more 9.8% vs 3.7%), though it is
important to note that almost all cases occurred during the chemotherapy phase.([11]) Primary cardiac events were numerically increased in the combination group (17
vs 8), however the overall numbers were very low, highlighting the safety of the combination
regimen in a carefully selected patient population.
The ExteNET trial randomised 2840 patients to receive standard chemotherapy and trastuzumab
regimen followed either by one additional year of neratinib or placebo. 5-year IDFS
results show the relative superiority of the extended regimen with an absolute benefit
of 2.5% (HR 0.73, 95% CI 0.57–0.92, p=0.0083). Subgroup analysis suggest increased
efficacy in patients with ER-positive tumours. The toxicity profile was, however,
pronouncedly more intense in the extended treatment arm, notably with diarrhoea (40%
vs <1%), nausea (3% vs <1%) and vomiting (2% vs <1%) grade 3 or more, which was reflected
in reduced median dose intensity (82% in neratinib arm vs 98% placebo arm).([12])
Placing these results into the context of clinical practice, however, is likely to
prove challenging for clinicians. Though both dual blockade and extended therapy proved
to improve outcomes, these improvements are exceedingly small when compared to the
absolute improvement in disease free survival (DFS) of 6.8% in the HERA trial. Therefore,
most patients are still candidates for chemotherapy + 1 year trastuzumab and a clear
example are patients falling into populations well represented in APT (T1, node negative
patients with ER-positive disease) to whom paclitaxel + trastuzumab alone is a good
option.([4]) For patients who are not candidates to this regimen, clinicians must carefully
decide to either continue to use 1 year of trastuzumab alone, dual blockade with pertuzumab
or extended therapy with neratinib. For high risk patients, especially those who are
candidates for neoadjuvant therapy, node positive and/or ER-negative tumors, dual
blockade with pertuzumab should be considered. Extended therapy with neratinib can
be an option for patients at a high risk of relapse who did not receive neoadjuvant
chemotherapy, especially if ER+. However, proactive management of diarrhoeas, as per
the CONTROL (NCT02400476) trial, is needed to prevent low-adherence to such prolonged
oral treatment.
There is no doubt that progress was achieved in the HER2-positive breast cancer population,
with at least three treatment options in 2018: 1 year of trastuzumab, dual blockade
with trastuzumab and pertuzumab or neratinib after trastuzumab. However, a better
understanding on which population benefits the most from each of these approaches
is urgently needed to better fine-tune adjuvant treatment and can only be achieved
through better trial design that integrate biomarker research and selective escalation
strategies.
Bibliographical Record
Noam Pondé, Evandro de Azambuja. Improving the adjuvant treatment of HER2-positive
breast cancer: APHINITY and ExteNET trials. Brazilian Journal of Oncology 2018; 14:
e-20181447A188.
DOI: 10.26790/BJO20181447A188
