2022 Prof. Hao Wang, ESMO |: After the advancement of the first-line treatment of HR+/HER2-ABC/MBC with fluvixamine monotherapy, pipexicil mPFS was added for up to 9.4 months

*For medical professionals only

Big coffee interprets the FUTURE study to explore the endocrine therapeutic value of

Hormone receptor-positive (HR+) breast cancer is one of the common subtypes of breast cancer, accounting for about 60%

The BCRG-M07 (FUTURE) study (abstract number: 228P) presented at the ESMO conference aims to investigate the effects of fluvixoside monotherapy (first- or second-line) in the treatment of HR+/HER2-advanced or metastatic breast cancer with fluvixamine in the sequential treatment of HR+/HER2-advanced or metastatic breast cancer ^[1].

Research interpretation

Fluvestrant is one of

▎Research methods

The FUTURE study is a multicenter, prospective study designed to evaluate the safety and efficacy

Fluvestran: 500 mg; That is, 250 mg intramuscularly injected twice on days 0, 14±3, 28 ± 3, and every 28 ±3 days thereafter

Pipercilide: 125 mg/day orally for 3 weeks, followed by discontinuation for 1 week

Figure 1.

▎ Research results

Between January 2018 and February 2020, 167 patients were enrolled in 55 institutions to receive floviestoran

Figure 2: Efficacy results

No new adverse events
were observed.

The results showed that the addition of pipexicil to patients with HR+/HER2-advanced breast cancer received fluvixazopron monotherapy for disease progression, and the addition of pipexil further improved the survival benefit of patients and was safe
.

Figure 3.
Security results

▎Research conclusion

This study reached the primary endpoint, and data suggest that pipexilil + fluvixazor may be effective and safe
in HR+/HER2-patient patients with disease progression with fluvixazone monotherapy.

This regimen may be a potential treatment option
for drug-resistant patients receiving flovisorptron monotherapy.

Expert reviews

The results of the FUTURE study have brought more guiding significance and thinking to the clinic:

Firstly, the FUTURE findings suggest that the addition of pipexicil after the progression of endocrine monotherapy can bring about nearly 10 months of mPFS benefit, which provides a reference for treatment options after the advancement of monotherapy

From the FUTURE study, we have seen that with the advancement of fluvixoside monotherapy with further treatment with pipexilid, mPFS
for 9.
4 months was obtained.

This is similar
to the results of the TREnd study reported in 2018.

In the TREnd study, researchers randomized HR+/HER2-advanced patients who had progressed prior to first- and second-line endocrine therapy (fluvixazole or AI monotherapy) and received a pipexil or pipexicil combined with a proendocrine regimen, and the results showed that the mPFS benefit of 6.
5 months in the combined group was 10.
8 months
compared with the 6.
5-month benefit of mPFS in the pipexilil monotherapy group.

TREnd researchers speculate that this may be associated with further endocrine therapy benefits after CDK4/6 inhibitors reverse endocrine resistance ^[2].

Based on the results of the FUTURE study, can it be concluded that advances in previous endocrine therapy, including advanced and adjuvant therapy, can be further benefited by the addition of CDK4/6 inhibitors? This requires further discussion
.

Combined with clinical practice, AI is the most commonly selected postoperative adjuvant therapy drug we choose, but with AI adjuvant therapy for about 5 years, some patients may already have the risk of endocrine resistance, how can these patients develop the best treatment strategy? The CSCO guidelines make clear recommendations for the first-level recommendation of fluvixoside plus CDK4/6 inhibitors, whether in patients with steroidal or nonsteroidal AI progression ^[3
].

In addition, considering that there is a approximately 30% to 50% probability of ESR1 activation mutations after AI advancement, resistance to endocrine therapy may develop in HR+ breast cancer patients carrying ESR1 mutations ^[4,5].


Referring to the results of the PADA-1 study, after the detection of ESR1 mutations, the conversion from Al+ pipexilil to fluvistol + pipeboxilil (11.
9 months) resulted in a doubling of the mPFS benefit, suggesting that when ESR1 mutations are detected, timely replacement of CDK4/6 inhibitors combined with AI to combined fluorovestrin can lead to greater benefit and early replacement of more benefits ^[6].

。
The CSCO guidelines also provide clear guidance for management after first-line endocrine progression, and for patients with Adjuvant Al therapy or advanced post-first-line endocrine therapy, switching to AI with another mechanism of action (e.
g.
, nonsteroidal swap for steroid-like AI) lacks results from
large randomized controlled clinical studies.

The choice of second-line endocrine therapy for advanced breast cancer should be combined with previous endocrine therapy and treatment response, and try not to repeat adjuvant therapy or drugs that have been used in relapse/metastatic endocrine therapy and defined as drug-resistant ^[3].

Second, whether alone or in combination, "fluorine"-based endocrine therapy benefits throughout the process

For HR+/HER2-metastatic breast cancer patients, the current domestic endocrine monodrugs mainly include fluvixan, nonsteroidal AI or steroidal AI and tamoxifen
.

Of these three drugs, whether from the mechanism or the benefit of efficacy, flovixamine is undoubtedly the most effective endocrine monotherapy
at present.

Mechanically, the affinity of flovestrane and ER is significantly higher
than that of tamoxifen.

Compared with AI inhibition of estrogen production, Flavissgroup induces degradation
by acting on the binding of cell keratin CK8 and CK18 to the nuclear matrix receptor cell keratin.

In addition, the flovist group also has the effect of downgrading ER, which neither TAM nor ^{AI has}
.

In terms of efficacy, mPFS in the third generation of AI is about 11 months, which is a significant increase in mPFS by about 3 months compared with ^{tamoxifen [8].}


Subsequently, the emergence of flavixogen further improved the benefit of HR+ advanced breast cancer, COMFIRM/CHinaCOMFIRM study [9,10], FIRST study ^[11] made flewavisan in the first-line endocrine treatment of advanced breast cancer, especially the FALCON study, comparing the efficacy of first-line flovixtrone and anastrozole^, With mPFS of 16.
6 months and 13.
8 months, respectively, flovistel has achieved the best efficacy of monotherapy ^{endocrine therapy to date [12].}


Based on the results of this study, major guidelines at home and abroad have revised treatment recommendations, and flovixazole has gradually established the status
of standard monotherapy for advanced first-line endocrine.

In light of the current situation, with the improvement of the accessibility of CDK4/6 inhibitors and the release of positive data for key phase III clinical studies, HR+/HER2-advanced breast cancer will still prefer the strengthening strategy
of endocrine combined CD4/6 inhibitors in more cases.

The main options for combination therapy are AI+CDK4/6 inhibitors and fluvestrant + CDK4/6 inhibitors
.

Phase III clinical studies such as PALOMA-2[13], MONALEESA-2[14], MONALEESA-7[15], and MONARCH-3^[16] confirm that first-line treatment with AI+^CDK4/6 inhibitors can enable HR+/ MPFS was extended by up to 24 months in patients with HER2-advanced breast cancer, compared with AI monotherapy by about
10 months.

Studies such as MONARCH-2[17], PALOMA-3 [18], and DAWNA-1 ^[19] have confirmed that flovixtan + CD4/6 inhibitors confer a higher survival benefit
than flovixone alone in patients with endocrine therapy.

In addition, MONALEESA-3[^20] and FLIPPER [21] studies have shown that first-line therapy with floviestamine + CD4/6 inhibitors can bring 33.
6 and ^31.
8 months of mPFS (floviristone monotherapy can also confer a benefit of mPFS of 19.
2 and 22 months, respectively
。
In particular, in the MONALEESA-3 study, the 2022 ESMO update results showed that flovistel+Ribociclib achieved the longest OS to date (67.
6 ^months).


For combination therapy, should AI+CDK4/6 inhibitors or fluvixtan + CDK4/6 inhibitors be used? In the PARSIFAL study, a head-to-head comparison of pipexilide + fluvixoride and pipercilliol + letrozole was compared, and although the results showed no significant difference, it was also seen that the use of pipexilil + fluviviril in people with previous AI-assisted therapy and sensitive relapses in the subgroup had a better benefit, resulting in mPFS for 27.
5 months compared to 19.
3 months for pipexil + letrozole ^[23
].

The choice of combination therapy in the 2022 CSCO guidelines defines the population, respectively, and the AI + CDK4/6 inhibitor is recommended for HR+ advanced breast cancer patients who have not undergone endocrine therapy or who have failed tamoxifen therapy
.

For populations after AI advancement, the flovixanine + CDK4/6 inhibitor regimen is preferentially recommended ^[3
].

Finally, after the addition of pipexili, how to choose the follow-up plan?

After the advancement of CDK4/6 inhibitors, the "endocrine +" protocol has gradually become more diverse, and more novel targeted drugs including PI3K inhibitors, mTOR inhibitors, and HDAC inhibitors are being used or have been explored in combination with
endocrine.

It is worth noting that in several key registered clinical studies, different target inhibitors have chosen flovistel as the basis for combination therapy, and it can be seen that flovixoside is the cornerstone
of future endocrine combined targeted therapy.

Phase II PrECOG0102 demonstrated the efficacy of flovirceptor plus mTOR inhibitor (everolimus) in patients with prior AI-resistant HR+/HER2-advanced stages, and showed that flovixone plus everolimus could nearly double the PFS benefit compared with flavixone alone (HR=0.
60; 95% CI 0.
40-0.
92; P=0.
02) compared with fluviazrant monotherapy (10.
4 months versus 5.
1 months, HR=0.
60; 95% CI 0.
40-0.
92; P=0.
02) ^[23]
。
For the PI3K/AKT pathway, FAKTION[24], BYLieve[25], and SOLAR-1^[26] studies explored the combination of flovisset in combination with AKT inhibitors (capivasertib) and PI3K inhibitors (Alpelisib) in AI or CDK4/^CDK4, respectively.
6 Benefits in the population after inhibitor therapy progression
.

The FAKTION study results confirm that combination therapy results in longer PFS (4.
8 months vs 10.
3 months)
than floviestone monotherapy.

BYLieve and SOLAR-1 studies have also confirmed that Alpelisib plus flovisset can achieve some PFS benefits in posterior therapy, especially in people with PIK3CA mutations
.

In addition, the endocrine combination with the HDAC inhibitor cedabenamide is also an option and is recommended in CSCO guidelines for people
after the progression of CDK4/6 inhibitors.

In addition to endocrine combination protocols, the ICON study also explored chemotherapy combined with immunity in populations with endocrine progression
.

However, the results released at this year's ESMO conference showed that chemotherapy plus ipimuzumab/navurizumab did not show a better benefit than chemotherapy ^[27], suggesting that the exploration of immunotherapy for breast cancer should be more cautious
.

In addition to different combination options, the ADC drugs that have emerged in the past two years will also provide more options
for the back line.

For example, the DESTINY-Breast04 study showed that for people with low expression of HR+/HER2, T-DXd can bring about 10.
1 months of PFS, significantly better than chemotherapy regimens (5.
4 months) ^[28].


The TROPiCS-02 study has also shown that gosatozumab has a significant benefit from chemotherapy (5.
5 vs.
4.
0, P=0.
0003) in patients with advanced HR+ (including HER2-negative and low-expressing populations) ^[29].

summary

In short, at present, for HR+ patients with advanced breast cancer, we have more and more
options available.

But in any case, endocrine therapy is still the basis
.

As the cornerstone drug in the endocrine treatment of HR+ advanced breast cancer, flovestrant runs through the entire management process
of first-line to post-line treatment.

With the publication of more clinical research results and more drugs on the market in the future, HR+ patients with advanced breast cancer will have longer survival and better quality of
life.

Hao

Ph.
D.
, Deputy Chief Physician, Master Supervisor

Sichuan Provincial Cancer Hospital, Deputy Director of the Department of Breast and Director of the First Ward

Graduated from Xiangya School of Medicine, Central South University,

Visiting Scholar, McGill University, Canada

Young expert of the Breast Cancer Committee of the Chinese Anti-Cancer Association

Young member of the Breast Surgeon Committee of the Chinese Medical Doctor Association

Young member of the Breast Oncology Group of the Oncology Branch of the Chinese Medical Association

He is the chairman of the Clinical Research and Translational Medicine Committee of Chengdu Anti-Cancer Association

JCO Chinese edition of the special journal on breast tumors is a member of the youth editorial board

References

[1] Watanabe K, et al.
Fulvestrant with additional palbociclib in advanced or metastatic hormone receptor-positive HER2-negative breast cancer after progression to fulvestrant monotherapy: JBCRG- M07 (FUTURE trial).
2022 ESMO Abstract.
#228P.

[2] Malorni L, et al.
Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: TREnd trial.
Ann Oncol.
2018; 29(8):1748-1754.

Chinese Society of Clinical Oncology.
Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Breast Cancer (2022).
2022.
07.
15.

[4] Jeselsohn R, et al.
Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.
Clin Cancer Res.
2014; 20(7):1757-1767.

[5] Jeselsohn R, et al.
ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer.
Nat Rev Clin Oncol.
2015; 12(10):573-83.

[6] FC Bidard, et al.
Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial.
2021 San Antonio Breast Cancer Symposium, GS3-05.
2021 SABCS GS-3-5.

[7] Hyder SM, et al.
Selective inhibition of estrogen-regulated gene expression in vivo by the pure anti-estrogen fulverstrant.
Cancer.
1997; 57:2547-2549.

[8] Baum M, et al.
Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.
Lancet.
2002; 359(9324):2131-9.

[9] Di Leo A, et al.
Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer.
J Clin Oncol.
2010; 28(30):4594-6.

[10] Zhang Q, et al.
Fulvestrant 500 mg vs 250 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer: a randomized, double-blind registrational trial in China.
Oncotarget.
2016; 7(35):57301-57309.

[11] Robertson JFR, et al.
Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study.
J Clin Oncol.
2009; 27(27):4530-5.

[12] Robertson JFR, et al.
Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial.
Lancet.
2016; 388(10063):2997-3005.

[13] Finn RS, et al.
Palbociclib and Letrozole for Advanced Breast Cancer.
N Engl J Med.
2016; 375(20):1925-1936.

[14] Hortobagyi GN, et al.
Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer.
N Engl J Med.
2022; 386(10):942-950.

[15] Im SA, et al.
Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer.
N Engl J Med.
2019; 381(4):307-316.

[16] Goetz MP, et, al.
MONARCH 3: Interim overall survival (OS) results of abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+, HER2- advanced breast cancer (ABC ).
Ann Oncol.
2022; 33(S7): #LBA15.

[17] Sledge Jr GW, et al.
MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy.
J Clin Oncol.
2017; 35(25):2875-2884.

[18] Cristofanilli M, et al.
Overall Survival With Palbociclib And Fulvestrant in Women With HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-Blind, Phase 3 Randomized Study.
Clin Cancer Res.
2022; 28(16):3433-3442.

[19] Zhang P, et al.
Dalpiciclib plus fulvestrant in HR+/HER2− advanced breast cancer (ABC): updated analysis from the phase 3 DAWNA-1 trial.
2022 ESMO.
Abstract #229P.

[20] Slamon DJ, et al.
Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.
N Engl J Med 2020; 382(6):514-524.

[21] Albanell J, et al.
GEICAM/2014-12 (FLIPPER) study: First analysis from a randomized phase II trial of fulvestrant (F)/palbociclib (P) versus (vs) F/placebo (PL) as first-line therapy in postmenopausal women with HR (hormone receptor)+/HER2– endocrine sensitive advanced breast cancer (ABC).
2020 ESMO LAB19.

[22] Neven, et al.
Updated Overall Survival Results From the First Line Population in t he Phase III MONALEESA 3 Trial of Postmenopausal Patients With HR+/HER2− Advanced Breast Cancer Treated With Ribociclib + Fulvestrant.
2022ESMO Abstract #LBA4.

[23] Jones RH, et al.
Fulvestrant plus capivasertib versus fulvestrant plus placebo after relapse or progression on an aromatase inhibitor in metastatic, estrogen receptor–positive breast cancer (FAKTION): Overall survival and updated progression-free survival data with enhanced biomarker analysis.
2022ASCO Abstract #1005.

[24] Howell SJ, et al.
Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial.
Lancet Oncol.
2022; 23(7):851-864.

[25] Rugo HS, et al.
Alpelisib (ALP) + fulvestrant (FUL) in patients(pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), humanepidermal growth factor receptor 2-negative (HER2–) advanced breast cancer(ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) +aromatase inhibitor (AI): BYLieve study results.
JCO.
2020; 38(15_suppl):1006.

[26] André EM, et al.
Alpelisib Plus Fulvestrant for PIK3CA-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2–Negative Advanced Breast Cancer: Final Overall Survival Results From SOLAR-1.
Ann Oncol.
2021; 32(2):208-217.

[27] Kyte JA, et al.
ICON –a randomized phase IIb study evaluating chemotherapy combined with ipilimumab and nivolumab in metastatic hormone receptor positive breast cancer.
2022ESMO Abstract #215MO

[28] Modi S, et al.
Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.
N Engl J Med.
2022; 387(1):9-20.

[29] Rugo HS, et al.
Health-related quality of life (HRQoL) in the phase III TROPiCS-02 trial of sacituzumab govitecan (SG) vs chemotherapy in HR+/HER2- metastatic breast cancer (MBC).
2022ESMO Abstract #1553O.