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`Fulvestra nt
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`>ub|ished Online
`November 28, 2016
`1ttp://dx.doi.org/10.1016/
`50140—6736(16)32418—7
`See Online/Articles
`ttp://dx.doi.org/10.1016/
`50140-6736(16)32389—3
`
`Metastatic breast cancer: focus on endocrine sensitivity
`
`Hormone receptor expression in breast cancer indicates
`disease subtypes that can be effectively managed with
`endocrine therapies?2 The use of selective oestrogen
`modulators or degraders
`showed efficacy in the
`
`What are the unique aspects of this trial? Patients
`enrolled in the study were not only endocrine—therapy
`naive, but most of them had diagnosis of less than
`1 year and only a third received chemotherapy. These
`
`management of metastatic and primary disease.1
`Aromatase inhibitors are a class of endocrine drugs that
`inhibit aromatase activity with an effect on oestradiol
`concentrations contributing to their efficacy primarily
`in postmenopausal breast cancer.2 Clinical
`resistance
`
`clinical characteristics might explain the high objective
`response rate and clinical benefit
`rate observed in
`the study. The most recent randomised phase 3 trials
`comparing standard letrozole alone with letrozole in
`combination with a CDK4 or CDK6 inhibitor as first—line
`
`to these drugs associated with progression of disease
`either during adjuvant
`therapy or
`in patients with
`advanced disease is a significant therapeutic challenge.3
`In the past few years several combination regimens,
`including
`drugs
`targeting
`endocrine—resistance
`
`treatment showed a large and significant improvement
`in progression—free
`survival with the combination
`regimens?8 Approximately a third of patients enrolled
`in both studies had de—novo diagnoses and the
`remaining patients had progressed after previous
`
`pathways and affecting cell cycles, showed efficacy
`as first—line therapy or after initial endocrine therapy,
`offering new therapeutic opportunities.4‘8 Despite these
`advancements, clinicians are still challenged by decisions
`about which criteria to use for the selection of the most
`
`adjuvant endocrine treatments. Despite such differences
`and the difficulty in cross—comparisons, the letrozole
`group in both studiesfi8 performed similarly in terms of
`disease control to the anastrozole (control) group ofthe
`FALCON study,9 confirming the benefit of aromatase
`
`appropriate initial endocrine treatment and what is the
`optimum treatment approach to substantially impact
`disease control and ultimately improve survival, a
`challenging goal in metastatic breast cancer.”8
`
`inhibitors in this setting. Nevertheless, the results of
`the current study support the outcome data of the
`CONFIRM study1 and indicate that fulvestrant should be
`considered as a potentially superior drug when a single
`
`John Robertson and colleagues9
`In The Lancet,
`report the results of the FALCON study, a randomised,
`multicentre, phase 3 clinical trial comparing fulvestrant
`anastrozole
`in
`with
`endocrine—therapy—naive,
`hormone receptor—positive postmenopausal patients
`
`agent treatment is preferred.
`Can we use only clinical criteria to select the most
`effective
`first—line
`regimen
`in
`newly
`diagnosed
`postmenopausal hormone receptor—positive metastatic
`breast cancer? Which patients can be treated with
`
`with metastatic breast cancer. 462 patients were
`randomly assigned to receive fulvestrant (n=230) or
`anastrozole (n=232) and progression—free
`survival,
`the primary endpoint, was
`significantly longer
`in
`the fulvestrant group than in the anastrozole group
`(hazard
`ratio
`[HR] 0797,
`95% CI 0637-0999,
`
`survival was
`progression—free
`p=0~0486). Median
`138 months (95% CI 1199—1699) with anastrozole
`and 166 months
`(95% CI
`1383—2099) with
`fulvestrant. Treatment with fulvestrant was
`also
`
`single drug endocrine therapy or otherwise require a
`combination regimen? Most patients with metastatic
`breast cancer develop a recurrence after being exposed
`to adjuvant endocrine therapy,
`in many cases an
`aromatase inhibitor or a sequence with tamoxifen. The
`
`FALCON study9 enrolled only endocrine—therapy—naive
`patients who are presumably endocrine—sensitive and,
`therefore, the results of the study might not necessarily
`be applicable to a standard metastatic breast cancer
`population that could also be offered a combination of
`
`associated with an improvement in overall response rate
`and clinical benefit rate. Perhaps the most intriguing
`result is the more marked improvement in patients with
`non—visceral metastasis (progression—free survival of
`223 months) than in patients with visceral metastasis
`
`endocrine drugs with a CDK4 or CDK6 inhibitor.“8 About
`20% of cases present with de—novo stage IV disease and
`this population is larger in developing countries, with
`bone frequentlythe only site of initial metastases, which
`might be an indication of more oestrogen—dependent
`
`(138 months), providing some indications when
`planning treatment for patients with de—novo disease.
`
`and indolent disease. The results of the FALCON study
`suggest that individuals with de—novo stage IV disease
`
`www.thelancet.com Published online November 28, 2016 http:lldxidoi.org/10.1016/50140-6736(16)32418-7
`
`AstraZeneca Exhibit 2155 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00905
`
`

`

`Comment
`
`
`
`are particularly sensitive to fulvestrant, but we should
`
`use caution in interpreting the data because this study
`was not powered to assess this question. It is possible
`that the presence of additional
`(visceral) metastasis
`indicates not only a more aggressive disease but also a
`larger tumour burden and heterogeneous oestrogen
`
`sensitivity, and for patients with visceral metastasis, a
`combination of fulvestrant and anastrozole might also
`be appropriate.10 Besides the clinical criteria, several
`additional factors should be considered when selecting
`the appropriate endocrine therapy, including the access
`
`to novel drugs based on regional regulatory availability,
`and the additional toxicity and higher costs typically
`associated with the combination regimens.
`Ultimately, we will need to integrate molecular
`diagnostics in our decision process because hormone—
`information
`
`little
`provides
`expression
`receptor
`about endocrine sensitivity and little opportunity
`for a less than empirical choice.”12 The detection of
`ESR1 mutations should now be considered a mandatory
`test
`in patients with disease progression during
`aromatase inhibitor treatment and we cannot assume
`
`that de—novo disease excludes intrinsic resistance to
`
`endocrine therapy}:12 The ability to effectively identify
`endocrine sensitivity using molecular diagnostics to
`
`complement clinical criteria would provide clinicians
`with the tools for a more rational and personalised
`approach to treatment selection, taking advantage of
`the manytherapeutic options currently available.
`
`Massimo Cristofanilli
`Department of Medicine, Division of Hematology and Oncology,
`Robert H Lurie Comprehensive Cancer Center, Feinberg School of
`Medicine, Northwestern University, Chicago, IL 60611, USA
`massimo.cristofanilli@nm.org
`
`I have received honoraria from Pfizer for speaking engagements on the current
`status and future development of endocrinetherapy in metastatic breast cancer.
`1
`Di Leo A,Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant
`500 mg vs 250 mg in the randomized CONFIRMtrial.jNatl Cancer inst 2014;
`106: djt337.
`Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole
`versustamoxifen as first-line therapy of advanced breast cancer in
`postmenopausal women: analysis of survival and update of efficacy from
`the International Letrozole Breast Cancer Group} Clin Oncol 2003;
`21: 2101—09.
`Musgrove EA, Sutherland RL. Biological determinants of endocrine
`resistance in breast cancer. Nat Rev Cancer 2009; 9: 631—43.
`Baselgaj, Campone M, Piccart M, et al. Everolimus in postmenopausal
`wormone-receptor-positive advanced breast cancer. N Engl} Med 2012;
`366: 520—29.
`:inn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor
`Jalbociclib in combination with letrozole versus letrozole alone as
`first-line treatment of oestrogen receptor-positive, HERZ-negative,
`advanced breast cancer (PALOMA-l/TRIO-18): a randomised phase 2
`study. Lancet Oncol 2015; 16: 25—35.
`:inn RS, Martin M, Rugo H, et al. PALOMA-2: Primary rsults from a phase
`II trial of palbociclib (P) with letrozole (L) compared with letrozole alone in
`aostmenopausal women with ER+/HER2—advanced breast cancer (ABC).
`Clin Oncol 2016; 34 (suppl): abstr 507
`Cristofanilli M,Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib
`versus fulvestrant plus placebo for reatment of
`wormone-receptor-positive, HERZ-negative metastatic breast cancerthat
`arog ressed on previous endocrine herapy (PALOMA-3): final analysis of
`he multicentre, double-blind, phase 3 randomised controlled trial.
`Lancet Oncol 2016; 17: 425—39.
`-lortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line
`herapy for HR-positive, advanced areast cancer. N Engl} Med 2016;
`375:1738—48.
`Robertson JFR, Bondarenko |M,Trishkina E, et al. Fulvestrant 500 mg
`versus anastrozole 1 mg for hormone receptor-positive advanced breast
`cancer (FALCON): an internationa , randomised, double-blind, phase 3
`rial. Lancet 2016; published online Nov 28. http://dx.doi.org/10.1016/
`SOl40-6736(16)32389-3-
`10 Mehta RS, BarlowWE, Albain KS, e al. Combination anastrozole and
`ulvestrant in metastatic breast cancer. NEngl} Med 2012; 367: 435—44.
`11 Chandarlapaty S, Chen D, HeW, et al. Prevalence of ESR1 mutations in
`cell-free DNA and outcomes in me
`astatic breast cancer: a secondary
`ialJAMA Oncol2016; 2: 1310—15.
`analysis ofthe BOLERO-2 clinical tr
`Drat A, Cheang MC, Galvan P, et al.
`3rognostic value of intrinsic subtypes in
`atic breast cancer treated with letrozole
`1ormone receptor-positive metast
`with or without lapatinibJAMA Oncol 2016; 2: 1287—94.
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`www.thelancet.com Published online November 28, 2016 http://dx.doi.org/10.1016/50140-6736(16)32418-7
`
`AstraZeneca Exhibit 2155 p. 2
`
`