Introduction
After the establishment of CDK4/6 inhibitors, PARP inhibitors, and the PI3K inhibitor
alpelisib, a whole series of new substances and studies have become the focus of interest
in the
treatment of patients with advanced HRpos/HER2neg breast carcinoma, including selective
estrogen receptor degraders (SERD), new Akt kinase inhibitors, and the antibody-drug
conjugates (ADC)
trastuzumab deruxtecan and sacituzumab govitecan. Some of these drugs (sacituzumab
govitecan and trastuzumab deruxtecan) are also relevant in patients with triple-negative
breast carcinoma. In
HER2-positive breast carcinoma, trastuzumab deruxtecan and tucatinib have set new
standards. This review summarizes the latest findings that have been published in
the past months, either as a
full-length publication or at one of the major congresses, for example at the 2022
San Antonio Breast Cancer Symposium.
Patients with Advanced HRpos/HER2neg Disease
RIGHT Choice study – chemotherapy vs. ribociclib in first-line therapy
For patients with advanced HRpos/HER2neg breast carcinoma, the national and international
guidelines uniformly recommend that all endocrine therapy options should be exhausted
before
chemotherapy is chosen as the treatment [1 ]. Only if there is a visceral crisis should chemotherapy be chosen as the treatment
option
[2 ]. Nevertheless, before the introduction of CDK4/6 inhibitors, 40–50% of advanced
HRpos/HER2neg patients were treated with
chemotherapy in the first line of therapy [3 ]
[4 ]
[5 ]. After the introduction of CDK4/6 inhibitors, this decreased to 10%–20% [6 ]. Based
on these data from real-world surveys, analyses were also provided for the prognosis
and comparison of the therapy groups (endocrine therapy vs. chemotherapy). All of
these evaluations
showed that patients treated with chemotherapy have a worse prognosis [5 ]
[6 ]
[7 ]. A representation of these comparisons is shown in [Fig. 1 ]. The multivariate analyses showed
that the choice of treatment had an independent influence on the prognosis [5 ]
[6 ].
Nevertheless, these studies concluded that the poorer prognosis of patients with chemotherapy
is attributed to selecting patients with a poorer prognosis when determining the treatment.
This
interpretation was put to the test by the publication of the RIGHT Choice study [8 ].
Fig. 1 Representation of progression-free survival (PFS) in the two studies, a RIBANNA [7 ] and b PRAEGNANT [6 ].
The RIGHT Choice study included patients with advanced HRpos/HER2neg breast carcinoma
in the first line of therapy. A requirement was that patients had either symptomatic
visceral
metastases, a visceral crisis, rapid disease progression, or a clearly symptomatic,
non-visceral disease [8 ]. According to the medical
assessment, it should be a patient cohort for which polychemotherapy is indicated.
Patients were randomized to treatment with ribociclib + letrozole (± goserelin) or
a combination
chemotherapy with one of the following chemotherapies: docetaxel + capecitabine, paclitaxel
+ gemcitabine, or capecitabine + vinorelbine. The primary study goal was progression-free
survival
(PFS). A large proportion of the 222 patients included in the study had symptomatic
visceral metastases (67.6%), and most patients had de novo metastatic disease (64.9%)
[8 ]. The median follow-up period was 24.1 months. When comparing the two randomization
arms, the median PFS was significantly better in the
ribociclib arm (24.0 months) than in the chemotherapy arm (12.3 months). The hazard
ratio was 0.54 (95% CI: 0.36–0.79, p < 0.007) [8 ]. The time to response to therapy was very similar in both randomization arms (4.9
months in the ribociclib arm and 3.2 months in the chemotherapy arm). As expected,
treatment-related severe adverse events were less frequent in the ribociclib arm (1.8%)
than in the chemotherapy arm (8%) despite prolonged treatment. Quality of life analyses
have not yet
been reported.
The RIGHT Choice study challenges the paradigm of requiring chemotherapy for a rapid
response in an aggressive disease. It underscores once again that all endocrine therapy
options should
be exhausted before using chemotherapy and that combination therapy with ribociclib
and letrozole results in better PFS than chemotherapy.
The efficacy of certain ADC therapies seems to be independent of target expression
– analyses using sacituzumab govitecan in the TROPiCS-02 study as an example
The TROPiCS-02 study had already reported that progression-free survival and overall
survival could be improved with treatment with sacituzumab govitecan compared to chemotherapy.
The
TROPiCS-02 study included HRpos/HER2neg patients who had already received several
preliminary therapies. These included at least endocrine therapy, taxane therapy,
and therapy with a CDK4/6
inhibitor. Study participants had to have completed at least two and no more than
four chemotherapy lines for metastatic disease. Thus, only HRpos/HER2neg patients
who had clearly undergone
preliminary therapy were included in this study [9 ]. Patients were randomized 1 : 1 to receive either treatment with sacituzumab
govitecan or chemotherapy of the physician’s choice (capecitabine, vinorelbine, gemcitabine,
eribulin). The aim of studies of this kind should be to improve efficacy while providing
a more
favorable side effect profile.
In some ADCs, it is suspected that efficacy can be achieved even at low expression
of the target through a so-called bystander effect. This has already been shown for
trastuzumab deruxtecan
in HRpos/HER2neg, HER2-low-expressing tumors [10 ], and for sacituzumab govitecan in triple-negative tumors [11 ]. Now, the corresponding results for Trop2 expression have also been reported for
the TROPiCS-02 study [12 ]. [Fig. 2 ] shows the hazard ratios for the various subgroups for progression-free survival
and overall survival. The patients were divided into groups with an h-score (possible
values 0–300) [0–10], [11–99], and [100–300]. For the two groups [11–99] and [100–300],
the comparisons
between the randomization arms were very similar. In the smaller group of patients
with an h-score [0–10], the hazard ratio for progression-free survival was 0.89, which
is higher than in
the other two groups. However, in terms of overall survival, the hazard ratio was
lower at 0.61 [12 ]. However, this group was small
(n = 79) and also included 25 patients entirely without Trop2 expression [12 ]. These data show that efficacy does not appear to depend
on Trop2 expression and that some effects of ADC need to be better understood.
Fig. 2 Hazard ratios for the subgroups of the TROPiCS-02 study stratified according to Trop2
expression (HR = hazard ratio; OS = overall survival; PFS = progression-free survival).
Camizestrant also improves progression-free survival
The substance group of oral selective estrogen receptor degraders (SERDs) is of particular
interest because these therapies are better bioavailable than the SERD fulvestrant
and may have
better efficacy than aromatase inhibitors, especially in patients with a somatic ESR1 mutation. For the oral SERD elacestrant, it has already been reported in the EMERALD
study that
in previously treated patients with advanced HRpos/HER2neg disease and endocrine resistance,
progression-free survival can be improved with elacestrant compared to standard endocrine
therapy
[13 ]
[14 ]. For the two SERDs giredestrant (acelERA study) and amcenestrant
(AMEERA-3 study), no superiority compared to standard endocrine therapy could be demonstrated
in a similar therapy situation [15 ]
[16 ].
Due to the mechanism of action [17 ]
[18 ] of SERDs, these substances are thought
to have superiority over other endocrine therapy options in patients with an ESR1 mutation. This was the case for the SERD elacestrant, so that elacestrant has only
been approved in
the USA in cases of a proven ESR1 mutation [19 ].
Another study has now been published with positive results with camizestrant and the
Serena-2 study [20 ]. The study included patients
who had relapse or progression under endocrine therapy and thus showed signs of endocrine
resistance. Patients were randomized to receive treatment with either fulvestrant
or camizestrant
75 mg or camizestrant 150 mg. A total of 220 patients were included. Approximately
one third of the patients were enrolled with progression in adjuvant therapy and two
thirds with
progression in the first line of endocrine therapy [20 ]. Approximately one third of patients (36.7%) also had an ESR1
mutation. Both the group of patients, who were treated with 75 mg camizestrant (HR = 0.58;
95% CI: 0.41–0.81), as well as the patients who were treated with 150 mg camizestrant
(HR = 0.67; 95% CI: 0.48–0.92) had longer progression-free survival compared to fulvestrant
therapy [20 ]. This was also the case for
the group of patients who had been pretreated with a CDK4/6 inhibitor. No treatment
benefit could be demonstrated in patients without an ESR1 mutation, whereas the benefit was
considerable in patients with an ESR1 mutation ([Table 1 ]). In the group of patients with an ESR1 mutation and treatment with
camizestrant 150 mg, the median PFS was extended from 2.2 months with fulvestrant
to 9.2 months [20 ]. With regard to side effects,
grade 1 and grade 2 sinus bradycardia occurred more frequently with camizestrant,
with 75% mg of camizestrant in 5.4% of patients and 150% for camizestrant mg in 25%
of patients.
Table 1
Comparison of progression-free survival times between the randomization arms of the
Serena-2 study in the total population and stratified
according to ESR1 mutation stats [20 ].
Population
n
HR (95% CI)
Camizenstrant 75 mg vs. fulvestrant
HR (95% CI)
Camizenstrant 150 mg vs. fulvestrant
Total population
220
0.58 (0.41–0.81)
0.67 (0.48–0.92)
Patients with ESR1 mutation at baseline
83
0.33 (0.18–0.58)
0.55 (0.33–0.89)
Patients without ESR1 mutation at baseline
134
0.78 (0.50–1.22)
0.76 (0.48–1.20)
In particular, the results in the group of patients with an ESR1 mutation motivate support for relevant study concepts investigating whether patients
with an ESR1 mutation are
more likely to benefit from a SERD in combination with a CDK4/6 inhibitor or the continuation
of treatment with a CDK4/6 inhibitor and aromatase inhibitor, such as the SERENA-6
study [21 ].
PROTAC SERDs with initial efficacy data from a phase II study
The active substance platform PROTAC (Proteolysis Targeting Chimera) has been introduced
as a new concept in the degradation of proteins. With ARV-471, a SERD is available
as one of the
first PROTAC substances. On the one hand, the hetero-bifunctional molecule has a ligand
for the protein of interest (in this case the estrogen receptor), and on the other
hand another ligand
that serves as a substrate for the E3 ubiquitin ligase complex. This binds the protein
to be degraded with the ubiquitin-proteasome system, which triggers degradation [17 ]
[22 ]. Initial efficacy data on a small cohort have already been presented in the
past [22 ]. Further data on a larger cohort in the form of a phase II study have now been presented
[23 ]. The VERITAC study included 71 patients with severely pretreated, advanced HRpos/HER2neg
breast carcinoma. On median, the patients had
already received three lines of therapy in the metastatic situation. All had received
preliminary therapy with a CDK4/6 inhibitor, 79% with fulvestrant and 45% with chemotherapy
in the
metastatic situation. Overall, 57.7% of patients had ESR1 mutations after the extensive preliminary therapies. The median PFS was 3.7 months
(95% CI; 1.9–8.3) for the overall
population and 5.7 months (95% CI: 3.6–9.4) for patients with an ESR1 mutation. The clinical benefit rate (stable disease and remissions) was 38.0% (95%
CI: 26.8–50.3) for the overall
cohort and 51.2% (95% CI: 35.1–67.1) for patients with an ESR1 mutation. With extensive preliminary treatment, these results are very promising.
The substance is being further
developed in both the metastatic situation and the neoadjuvant situation [24 ]
[25 ]
[26 ]. The neoadjuvant TACTIVE-N/ TRIO-048 study is already recruiting, including in Germany
among other
countries.
First randomized trial of capivasertib (Akt kinase inhibitor) published
The CAPItello-291 study presented the first large-scale randomized phase III trial
of the Akt kinase inhibitor capivasertib [27 ]. It
is thought that genomic alterations in the PI3K/Akt kinase signaling pathway ([Fig. 3 ]) lead to activation and subsequent tumor growth,
proliferation, and metastasis. These genomic alterations are thought to be in the
AKT1 , PIK3CA , and PTEN genes. However, it is also known that the activation of the
signaling pathway can occur without a genomic alteration in one of these genes [28 ].
Fig. 3 Illustration of the PI3K-AKT kinase signaling pathway and its crosstalk with the estrogen
signaling pathway (source: Alves CL, Ditzel HJ. Drugging the PI3K/AKT/mTOR Pathway
in ER+
Breast Cancer. Int J Mol Sci 2023; 24. doi:10.3390/ijms24054522 , red marking and labeling supplemented with capivasertib,
Creative Commons Attribution [CC BY] license, https://creativecommons.org/licenses/by/4.0/ ).
Capivasertib is an inhibitor of all isoforms of Akt kinase (AKT1/AKT2/AKT3). In the
phase II FAKTION study of 140 patients, it was already shown that adding capivasertib
to fulvestrant
improved progression-free survival and overall survival [29 ]. However, no patients with a CDK4/6 pretreatment were included in this
study, and testing for genomic alterations was performed at different points in time
using different methods.
The CAPItello-291 study included a total of 708 patients with advanced HRpos/HER2neg
breast carcinoma who had relapse during or up to 12 months after adjuvant aromatase
inhibitor therapy or
who had progression during aromatase inhibitor therapy in the metastatic situation.
Up to two lines of endocrine therapy were allowed in the advanced therapy situation,
and a maximum of one
chemotherapy. Patients were randomized to either therapy with capivasertib and fulvestrant
or therapy with fulvestrant monotherapy. Progression-free survival was the primary
study objective,
and overall survival was one of the secondary study objectives. Of the patients included
in the study, most patients (> 80%) had already received at least one endocrine therapy
for
advanced disease, and approximately 70% had taken a CDK4/6 inhibitor prior to inclusion
in the study [27 ]. Genomic alterations were
investigated using FoundationOne or Burning Rock assays. A total of 40.8% (n = 289)
of the patients had an alteration in PIK3CA , AKT1 , or PTEN. Most of the patients had
a mutation exclusively in the PIK3CA gene (219 out of 289 patients with a genomic alteration) [27 ].
In the overall population, the addition of capivasertib improved the median PFS from
3.6 months (95% CI: 2.8–3.7) to 7.2 months (95% CI: 5.5–7.4). The hazard ratio was
0.60 (95% CI:
0.51–0.71, p < 0.001). The therapeutic effect was consistent across all subgroups,
especially in the group of patients pretreated with CDK4/6 inhibitors (HR = 0.62;
95% CI: 0.51–0.75).
With regard to the abovementioned genomic alterations, although a slightly lower hazard
ratio was found in the group of patients with an AKT pathway alteration (HR = 0.50;
95% CI 0.38–0.65),
an effect was also detectable in the group of patients without alteration (HR = 0.70;
95% CI: 0.56–0.88). An exploratory analysis of overall survival showed an initial
indication of an
overall survival benefit with 87 events in the capivasertib arm and 108 events in
the fulvestrant monotherapy arm, with a hazard ratio of 0.74 (95% CI: 0.56–0.98).
This trend was even
slightly lower in the group of patients with an alteration in the AKT signaling pathway
(HR = 0.69; 95% CI: 0.45–1.05). With regard to side effects, additional diarrhea,
nausea/vomiting,
rash, and fatigue have mainly been reported. The rate of treatment discontinuation
due to side effects was 13% in the capivasertib arm.
With capivasertib, a new substance has now been established in a phase III trial after
everolimus, the CDK4/6 inhibitors, and alpelisib, which can overcome endocrine resistance
through a
combination with endocrine therapy for a relevant proportion of patients. The trend
in terms of overall survival is promising. However, overall survival can only be adequately
assessed when
more events have occurred and the first planned analysis with regard to this endpoint
is performed.
Patients with HER2-Positive Advanced Disease
Destiny Breast 03 study – overall survival data positive
The Destiny Breast 03 study has already established in the first analysis the superiority
of T-DXd over T-DM1 in terms of progression-free survival [30 ]. Although the overall survival data indicated that the T-DXd arm was superior to
T-DM1, no statistically significant superiority could be demonstrated with regard
to
this analysis [30 ].
A further evaluation with a longer follow-up period has now been presented [31 ]
[32 ]. The median follow-up times were 28.4 months in the T-DXd arm and 26.5 months in
the T-DM1 arm. The median OS was not achieved in any of the two randomization arms.
The
24-month survival rates were 77.4% (71.7–82.1%) in the T-DXd arm and 69.9% (63.7–75.2%)
in the T-DM1 arm. The hazard ratio was 0.64 (95% CI: 0.47–0.87, P < 0.0037). This
difference was
statistically significant and largely consistent in the subgroup analyses performed.
A new analysis was also performed for progression-free survival. With the longer follow-up
period, the results were very similar to those of the previous analysis. The hazard
ratio was 0.33
(95% CI: 0.26–0.43, p < 0.000001). The median PFS was 28.8 months (95% CI: 22.4–37.9
months) in the T-DXd arm and 6.8 months (95% CI: 5.6–8.2 months) in the T-DM1 arm
[31 ]
[32 ].
In the previous analysis, no deaths have occurred to date as a consequence of interstitial
lung disease. This could be confirmed in the analysis with the longer follow-up period.
Furthermore, no deaths were observed due to this side effect.
With the excellent data in terms of overall survival, a new question arises in this
and similar studies. In the T-DXd arm, clinical complete remission could be seen in
21.1% of cases
(n = 55). Given the high frequency, the question arises as to whether this clinical
response can be used to predict long-term survival. Appropriate analyses should be
planned for the
future.
Destiny Breast 02 study – trastuzumab deruxtecan after T-DM1 treatment
The Destiny-Breast 02 study was conducted in parallel with the Destiny-Breast 03 study
[33 ]. However, this study included patients who
had already completed treatment with T-DM1. Thus, in terms of the study population,
all patients had preliminary therapy with T-DM1 and approximately 80% had preliminary
therapy with
pertuzumab and trastuzumab. Randomization was performed with a 2 : 1 ratio. 406 patients
received T-DXd and 202 patients received treatment of the physician’s choice (TPC
arm), which was
either capecitabine + trastuzumab or capecitabine + lapatinib. Most patients were
treated as part of the study in the third (45%) or fourth line of therapy (30%). The
important subgroup of
patients with brain metastases consisted of 18.2% in the T-DXd arm and 17.8% in the
TPC arm [33 ].
The median PFS was 17.8 months (95% CI: 14.3–20.8) in the T-DXd arm and 6.9 months
(95% CI: 5.5–8.4) in the TPC arm. This corresponded to a hazard ratio of 0.36 (95%
CI: 0.28–0.45). There
was no difference in efficacy in patients with (HR = 0.35; 95% CI: 0.20–0.61) and
without brain metastases (HR = 0.38; 95% CI: 0.29–0.48) [33 ].
There was also a clear difference in terms of overall survival. The median overall
survival in the T-DXd arm was 39.2 months (95% CI: 32.7–NE) and 26.5 months (95% CI:
21.0–NE). This
corresponded to a hazard ratio of 0.66 (95% CI: 0.50–0.86) in favor of T-DXd [33 ].
In the context of this study, no new safety signals were seen, in particular no deaths
as a consequence of interstitial pneumonitis. Nevertheless, it is important to consistently
diagnose
respiratory symptoms under T-DXd, to consider corticosteroid treatment, and to make
appropriate dose changes and interruptions if necessary.
Outlook
With elacestrant and camizestrant, two SERDs, especially with an ESR1 mutation, have shown that they have high efficacy compared to standard endocrine
therapy. They would have the
potential to establish themselves as new combination partners for the CDK4/6 inhibitors
or after treatment with CDK4/6 inhibitors after corresponding results. With capivasertib,
endocrine
resistance could be overcome for a relevant proportion of HRpos/HER2neg patients after
everolimus, the CDK4/6 inhibitors, and alpelisib for further combination therapy.
The next important step
must be to gain a better understanding of the resistance mechanisms and the chronological
sequence of the resistance mechanisms. For this purpose, data must be collected from
a large number of
patients under the appropriate therapies. This task will mainly involve studies in
the real-world setting. Two of these studies, which are active in Germany, are the
CAPTOR-BC and the MINERVA
study [34 ]
[35 ]
[36 ]. The
prospective collection of the necessary clinical and molecular data will provide an
opportunity to better understand the mechanisms of progression and be able to plan
the ideal treatment
sequencing for patients.
