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memo - Magazine of European Medical Oncology

Open Access 20.12.2024 | review

Evolving treatment paradigms after CDK4/6 inhibitors in advanced breast cancer

Position paper on optimized sequencing

verfasst von: Prof. Michael Gnant, MD FACS FEBS, Marija Balic, Christian F. Singer, Gabriel Rinnerthaler, Georg Pfeiler, Christoph Suppan, Birgit Grünberger, Kathrin Strasser-Weippl, Vanessa Castagnaviz, Sonja Heibl, Rupert Bartsch

Erschienen in: memo - Magazine of European Medical Oncology

Summary

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment of hormone-receptor-positive, human epidermal growth factor receptor 2‑negative (HR+/HER2−) breast cancer, becoming the standard in first-line endocrine therapy (ET). However, evidence supporting the optimal sequencing post-CDK4/6i progression remains scarce. Liquid biopsy and comprehensive genomic profiling enable tracking of resistance and identifying actionable mutations like ESR1, PIK3CA, AKT or PTEN. So far, post-CDK4/6i therapies include PARP inhibitors, selective estrogen receptor degraders (SERDs), PI3K inhibitors, AKT inhibitors, mTOR inhibitors, chemotherapy, and antibody–drug conjugates (ADCs), while rechallenging CDK4/6 inhibitors also offers additional avenues for molecularly targeted care. This position paper emphasizes the importance of biomarker-driven, individualized treatment strategies, highlights the need for collaborative efforts to ensure broad access to innovative therapies, and provides guidance for clinical practice, paving the way for more precise and personalized care in HR+/HER2− advanced breast cancer.

Disclosures and declarations

The expert meeting, on which this publication is based, was held in July 2024 in an entirely virtual format, supported by the logo placement of Eli Lilly Austria Ges.m.b.H. without the company having a role in the design, execution, interpretation, or writing of the manuscript.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have significantly transformed the treatment landscape for patients with advanced hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancer, in both first- and second-line settings, and have been established as the standard of care for endocrine-responsive disease [1‐7]. Despite some remaining controversy whether they have to be used in first-line for all patients [8, 9], most guidelines recommend their upfront use in HR+ metastatic breast cancer (mBC) [10]. There are three approved CDK4/6i in the metastatic setting that showed remarkably similar progression-free survival (PFS) [1, 6, 11]. First-line (1L) approval of palbociclib was based on results from the phase III PALOMA-2 trial (NCT01740427) [1], ribociclib on the phase III MONALEESA-2 trial (NCT01958021) [11], and abemaciclib on the phase III MONARCH 3 trial (NCT02246621) [6]. As of today, limited data are available regarding the optimal therapeutic sequence after progression on CDK4/6i. While numerous options exist, evidence supporting the most effective sequence remains scarce. Nonetheless, “serial endocrine therapy” followed by cytotoxic agents is recommended by all contemporary treatment guidelines.

Therefore, this position paper aims to provide up-to-date information on potential strategies after progression on CDK4/6i by evaluating available data of second- and third-line therapy options following CDK4/6i treatment. Strategies are discussed for optimal sequencing, and novel agents are explored that are currently under investigation for patients with HR+ metastatic breast cancer (mBC).

Challenges of post-CDK4/6i treatment

Therapeutic advances in mBC have significantly improved patient outcomes, yet they have also raised important questions regarding the optimal sequencing of current and emerging treatments. Considering multiple factors (Fig. 1), the recent approvals of novel therapies with overlapping indications increasingly compel physicians to not only rely on the interpretation of clinical studies but also require indirect comparisons between published studies. In addition, it is necessary to integrate disease-related factors, and personal experience to optimally select targeted agents and combinations for HR+/HER2− mBC patients post-CDK4/6i therapy. Given the presence of several effective follow-up therapies [12], the key question is how to determine the most effective sequence of treatments.

While first-line CDK4/6i-based therapy provides relevant clinical activity, approximately 20% of tumors treated with combined CDK4/6i and endocrine therapy (ET) exhibit “primary resistance” (de novo), characterized by a lack of initial response or limited sustained benefit. Additionally, nearly all tumors will eventually develop acquired (secondary) resistance, requiring further lines of treatment [13‐15]. Due to reduced general condition, refusal of therapy or death, not every patient is treated with subsequent treatment lines. Data from the Austrian Study Group of Medical Tumor Therapy (AGMT) mBC-Registry show treatment attrition rates of 19.6% between the 1st and 2nd lines, 23.0% between the 2nd and 3rd lines, 29.6% between the 3rd and 4th and 30.6% from ≥ 4th to ≥ 5th line of therapy [16]. Interpreting all the scientific evidence together supports a “best treatment first” strategy, though this approach should be balanced with considerations of toxicity and patient preferences. For providing as many patients as possible with access to the most effective therapy, it has become critical to understand how exposure to endocrine therapy and CDK4/6i changes the phenotype and/or genomic landscape of metastatic tumors, in particular with respect to druggable mutations.

Continued importance of biomarker testing

While the assessment of tissue biopsies remains the diagnostic gold standard for identifying molecular changes, including HR and/or HER2 status as well as genomic alterations, on which diagnosis, classification and subsequent treatment decisions should be based, it is important to note that studies have shown up to 40% of tumors exhibit biological changes of potential therapeutic relevance—most likely promoted by “therapeutic pressure” [17‐25]. Given this dynamic nature, liquid biopsy (most commonly, circulating tumor DNA [ctDNA] in plasma) has emerged as a novel method to characterize and monitor the tumor genome, increasingly guiding clinical decision-making alongside traditional tissue biopsy [17, 21, 26‐28]. The AURORA trial has highlighted frequent alterations in several driver genes in metastatic lesions, including mutations in ESR1, PTEN, CDH1, PIK3CA, and RB1, as well as amplifications of MDM4 and MYC, deletions in ARID1A, and clonality in genes such as RB1 and ERBB2, by investigating both tissue and ctDNA. Additionally, a high tumor mutational burden (TMB) was associated with shorter time to relapse in patients with HR+ mBC [21, 29]. Moreover, in HR+ mBC, acquired resistance to previous ET has been linked to mutations in ESR1 [30], the MAPK pathway [31, 32], and various transcription factors such as ARID1A [31, 33, 34]. In this context, the occurrence of ESR1 mutations under the evolutionary pressure of aromatase inhibitor (AI) therapy has been shown to increase contiguously with each line of therapy. While ESR1 mutations rarely exist in primary tumors (~0–1%), they are relatively common in the metastatic setting and continuously increase with each line of therapy from approximately 5% in the first-line setting to 33% and approximately 40% in the second- and third-line setting, respectively [35‐39]. These observations indicate that serial testing of ctDNA represents a potentially viable tool for the early detection of resistance and the identification of newly emerged actionable targets [40‐43]. This emerging strategy holds promise for more personalized and timely interventions in the future as successfully demonstrated in the PADA-1 trial. In this study, a pioneering strategy was adopted by exchanging the endocrine partner of the CDK4/6i upon detection of an ESR1 mutation in patients with HR+/HER2− mBC. Specifically, switching from AI plus palbociclib to fulvestrant plus palbociclib nearly doubled PFS [44].

Although tissue can also be analyzed using next-generation sequencing (NGS), serial tissue biopsies are not routinely performed due to their invasiveness and or anatomical constraints (e.g., bone metastasis) [45]. This further underscores the relevance of plasma-based ctDNA analysis via NGS as an alternative.

Hence, the guidelines of the European Society for Medical Oncology (ESMO) advise somatic mutation testing using tissue or plasma sample and furthermore recommend testing of BRCA1/2 or PALB2 especially following progression on CDK4/6i [46]. Similarly, the American Society of Clinical Oncology (ASCO) recommends testing tissue or ctDNA for biomarkers including PIK3CA, BRCA1/2, and ESR1 mutations [47, 48]. While tumor-informed assays for ctDNA detection are mostly used in the early stage disease, tumor-naïve (tumor-agnostic) testing employing several parameters from the same ‘omics’ (e.g., multiple fragmentomics features) or features from different ‘omics’ (multi-omics; e.g., genomics, fragmentomics, nucleosomics, and methylomics) has demonstrated promising performance in the advanced/metastatic setting [45]. Increasingly, pan-cancer comprehensive genomic profiling (CGP) panels are typically employed to detect/identify clinically relevant biomarkers and actionable alterations that can indicate the usefulness of subsequent targeted therapies [49].

The authors point out that liquid biopsy analysis should be considered when metastatic disease is first detected and at each progression thereafter, especially when information about a molecular alteration could be treatment-relevant.

Genomic coverage and sensitivity of liquid biopsies can be further enhanced by combining several liquid biopsy analytes, including cell-free DNA and ctDNA, circulating tumor cells, exosomes, proteins, and metabolites. However, the analysis of numerous markers also adds to data complexity and increases the challenge of interpretation in a clinically relevant manner: The management of such a huge amount of data requires careful discussion in a multiprofessional team and supports the development of innovative machine learning algorithms. Also, continuous education and training of physicians and laboratory personnel as well as investments in laboratory and bioinformatic resources are crucial [45, 50]. In this regard, one should be aware that integrating the results of molecular testing into clinical practice necessitates a thorough understanding of the technical limitations and clinical implications of the underlying analytical tools, which can vary between different clinics [45]. With respect to the tests itself, it is recommended to use well-validated assays with established performance metrics (e.g. the AVENIO ctDNA Expanded kit with 77 genes) to ensure accurate interpretation of molecular findings [45, 51]. It is also important to state that a noninformative ctDNA test result should always be repeated, and eventually rechecked based on tissue-based testing [27, 45]. Additionally, evaluation of an untargeted assessment of tumor fractions can aid decision-making since very low tumor fractions point towards detection issues, whereas higher tumor fractions in blood correlate with a poorer prognosis and can, thus, also be used to evaluate therapy response [45]. In special cases such as bone-only metastatic disease, where the disease cannot be evaluated using RECIST criteria, mere ctDNA dynamics themselves may guide clinical decisions in the future [52].

For the sake of completeness, the “new field” of fusion RNAs needs to be addressed since researchers found that about one-third of metastatic breast cancers harbor highly expressed high-confidence and cancer-specific (HCCS) fusion RNAs, with 64.5% involving cancer-related genes like ESR1, which suggests potential cancer driver mutations. In addition, identifying HCCS fusions involving known cancer-driving kinases might offer new treatment options for patients with heavily pretreated disease. However, some of these fusions might be missed due to their low frequency with current testing standards, yet some are targetable and even have US Food and Drug Administration (FDA)-approved treatments available [53]. This could be one of many potentially interesting approaches, for example, for the subset of patients with ESR1 mutations who did not respond to elacestrant in the EMERALD trial (as indicated by an initial early drop in PFS curves), interpreted by some as suggestion of ‘total endocrine resistance’ [54]. Nonetheless, the EMERALD trial was the first to lead to the approval of the oral selective estrogen receptor degrader (SERD) elacestrant in palliative treatment [54], marking a significant milestone in the treatment armamentarium of HR+/HER2− mBC patients.

Since the molecular test must align with the therapy indication, costs, and reimbursement, all of which are crucial factors in selecting the assay, the authors suggest that—somewhat similar to the Austrian CAR-T-cell network [55, 56]—that validated laboratories and—optimally—molecular tumor boards should conduct and interpret these tests, ultimately resulting in important treatment recommendations. To ensure the health system’s readiness for liquid biopsies and optimal care for mBC patients, stakeholders must act now to collaboratively create an equal and sustainable nationwide access environment in Austria. At the same time, a framework should be considered to cover costs of molecular tests for patients from all regions. Currently, the additional financial burden is encumbered on the evaluating/treating center and its payer, sometimes also for patients from other states who undergo testing. Hence, the authors propose the establishment of a central Austrian funding and quality control system for liquid biopsy testing and interpretation.

As the reimbursement process for molecular biology analyses in mBC in Austria is not yet regulated, providers/institutions and payers (insurance companies, public health organizations) should be aware of cost implications. A genomic testing cost calculator has demonstrated that using NGS for a restricted set of genes resulted in lower costs per correctly identified patient compared to sequential single-gene testing (e.g., polymerase chain reaction for PIK3CA, immunohistochemistry [IHC] for HER2 amplification and high microsatellite instability, as well as fluorescence in situ hybridization [FISH] for NTRK fusions) [57]. As testing is increasingly becoming a part of the routine, it will certainly become even more cost-effective. Table 1 lists currently targetable mutations, detected by diverse molecular biology tests (NGS, IHC, FISH), along with their approved matched or breakthrough therapies.

Table 1

Mutation diagnosis—precision medicine for HR+ mBC targeted therapies, modified from [45, 58]

Genomic finding	Detection	Matched therapy
ESR1^mut	NGS, PCR (blood or tumor tissue)	Elacestrant^*,#
PIK3CA^mut	NGS, PCR (blood or tumor tissue if blood negative)	Alpelisib (+ fulvestrant)^,# Capivasertib (+ fulvestrant)^,# Inavolisib (+ palbociclib and fulvestrant) ^**
AKT1^mut	NGS (blood or tumor tissue if blood negative)	Capivasertib (+ fulvestrant)^*,#
PTEN^mut	NGS (blood or tumor tissue if blood negative)	Capivasertib (+ fulvestrant)^*,#
ERBB2^mut	NGS (tumor tissue or blood)	Neratinib^,#, Lapatinib^,#
gBRCA1/2	Germline sequencing	Olaparib^,#, Talazoparib^,#
sBRCA1/2	NGS (tumor tissue or blood)	Olaparib^§
gPALB2	Germline sequencing	Olaparib^§
NTRK fusion	FISH, NGS, PCR (tumor tissue or blood)	Larotrectinib^,#, Entrectinib^,#, Repotrectinib^*
Microsatellite instability-high or mismatch repair deficient	IHC, NGS, PCR (tumor tissue)	Pembrolizumab^,#, Dostarlimab-gxly^
Tumor mutational burden-high ≥ 10 mut/Mb	NGS (tumor tissue or blood)	Pembrolizumab^*,#
RET fusion	NGS (tumor tissue or blood)	Selpercatinib^*

IC tumor infiltrating immune cells, IHC immunohistochemistry, NGS next-generation sequencing, PCR polymerase chain reaction, FISH fluorescence in situ hybridization

^*FDA approved, ^#EMA approved, ^**FDA bbreakthrough therapy designation, ^§based upon lower-level evidence

Treatment sequencing postprogression on frontline CDK4/6 inhibitors plus endocrine therapy

The ESMO Metastatic Breast Cancer Living Guideline (v1.1, May 2023) recommends CDK4/6i for treating both de novo and recurrent mBC, irrespective of whether the resistance to ET is primary or secondary, and in both premenopausal and postmenopausal women if there is no imminent organ failure [46]. Although there are no direct comparisons between the three approved CDK4/6i, they generally appear to offer similar progression-free survival efficacy in the metastatic setting, with overall survival results favoring ribociclib and abemaciclib [1, 6, 11, 59‐61]. However, toxicity profiles differ slightly, allowing patients who experience severe side effects from one CDK4/6i to switch to another. Combining a CDK4/6i with ET is the standard first-line approach for patients with HR+/HER2− mBC, offering significant benefits regarding PFS and overall survival (OS), while also maintaining or improving quality of life (QoL) [I, A; ESMO-MCBS v1.1 scores: 3–5] [46].

Determining the best sequence of endocrine therapies after progression on CDK4/6 inhibitors is complex, involving factors such as previous treatments in the (neo)adjuvant or metastatic setting, duration of response to prior endocrine therapy, extent of disease, patient preferences, targetable mutations, and available treatment options [46]. Given the inevitable development of resistance, it is crucial to identify the optimal time of testing. Biomarkers can help to detect both de novo and acquired resistance mechanisms to CDK4/6 inhibitors and endocrine therapy. Of note, mutations with actionable potential can be acquired, subclonal, and/or vary under therapeutic pressure [62].

By drawing attention to a hypothetical patient with HR+/HER2− mBC whose ESR1 mutation was successfully suppressed with elacestrant but who developed a novel PI3KCA mutation (Fig. 2), we aim to highlight the importance of liquid biopsy for treatment sequence selection.

Therapeutic options in the absence of targetable alterations

Everolimus is an option for patients post-CDK4/6i without targetable alterations [46]. In the randomized phase 3 BOLERO-2 trial, the addition of everolimus to exemestane was shown to be effective in pretreated patients without prior CDK4/6i [63, 64]. However, real-world evidence indicates shorter time to next treatment for patients who received prior ET plus CDK4/6i, thus, limiting the applicability of these data in clinical practice (4.3 months vs 6.2 months with ET alone in the second line and 4.1 months vs 5.6 months with ET alone in the third line, respectively) [65]. Treatment discontinuations due to adverse events occurred in 19.0% vs 4.0% with everolimus vs placebo [63].

Regarding CDK4/6i in multiple lines, data from randomized phase 2 trials including MAINTAIN (NCT05207709) with ribociclib [66], PALMIRA (NCT03809988) with palbociclib [67], and PACE (NCT03147287) with palbociclib [68] have shown inconsistent findings regarding the benefit of continuing CDK4/6 inhibition while switching ET after tumor progression on frontline hormonal therapy and AI (Table 2). In the small cohort of patients with ESR1^mut in the MAINTAIN study, ribociclib + ET showed no benefit compared to placebo + ET [66]. While in the overall population addition of ribociclib to fulvestrant yielded a significant prolongation in patients progressing on prior CDK4/6i therapy, no benefit was seen the PALMIRA and the PACE study combining palbociclib with fulvestrant beyond progression on prior CDK4/6i + AI did not significantly improve PFS compared with using fulvestrant alone [67, 68]. However, there was at trend towards a longer median PFS when avelumab (a PD-L1 inhibitor) was added to fulvestrant plus palbociclib in the PACE trial (8.1 months; hazard ratio [HR], 0.75 vs fulvestrant; p = 0.23) [68].

Table 2

CDK4/6i in multiple lines

	postMONARCH [69]	MAINTAIN [66]	PALMIRA [67]	PACE [68]
Phase	3	2	2	2
Patients (n)	368	132	198	220
Prior chemotherapy	0%	9%	0%	16%
Prior palbociclib	59%	85%	100%	91%
Prior ribociclib	33%	12%	0%	4.5%
Prior abemaciclib	8%	2%	0%	4.1%
Second-line	100%	65%	100%	77%
> Second-line	0%	18.5%	0%	17%
CDKi on trial	Abemaciclib	Ribociclib	Palbociclib	Palbociclib
ET on trial	Fulvestrant	Fulvestrant or exemestane	Letrozole or fulvestrant	Fulvestrant
6‑months PFS (CDKi + ET vs ET)	50% vs 37%	41.2% vs 24.6%	40.9% vs 28.6%	32.9% vs 29.8%
mPFS in months (CDKi + ET vs ET)	6.0 vs 5.3	5.29 vs 2.76	4.2 vs 3.6	4.6 vs 4.8
	HR, 0.73	HR, 0.57	HR, 0.80	HR, 1.11
	(95% CI, 0.57–0.95)	(95% CI, 0.39–0.85)	(95% CI, 0.6–1.1)	(90% CI 0.79–1.55)
	p = 0.02	p = 0.006	p = 0.206	p = 0.62

CDKi Cyclin-dependent kinase inhibitor, CI confidence intervall, ET endocrine therapy, HR hazard ratio, mPFS median progression-free survival, PFS progression-free survival

The recently published postMONARCH study (NCT05169567) is the first randomized phase 3 trial demonstrating a statistically significant PFS improvement for abemaciclib in addition to fulvestrant in patients with mBC progressing on prior CDK4/6i-based therapy [69]. In more detail, patients eligible for postMONARCH had HR+/HER2− mBC and disease progression on a prior CDK4/6i and aromatase inhibitor in the advanced disease setting, or disease recurrence on or after a CDK4/6i plus ET in the adjuvant setting. At the primary analysis, abemaciclib improved the investigator-assessed PFS by 0.7 months (6.0 months with abemaciclib + fulvestrant vs 5.3 months with placebo + fulvestrant) with a 27% risk reduction for developing a PFS event. This small benefit was seen across all subgroups including patients with baseline ESR1, AKT or PIK3CA mutations, however—with all appropriate restraint of overinterpreting subgroup analyses (and in the absence of any significant heterogeneity testing)—the overall benefit appeared to be mainly driven by patients who received palbociclib in first line, and preferable occur in patients without visceral disease [69].

Moreover, the objective response rate (ORR) also improved with abemaciclib (17% vs 7% in patients with measurable disease). However, it appears that the observed benefit was mainly driven by the subgroup of patients who received palbociclib in 1L [69]. It is important to note that the absolute PFS numbers for patients with resistance mutations have not been reported yet. However, we would expect, as seen in the PALOMA-3 trial [70], that PFS would be shorter in both the abemaciclib + fulvestrant and the placebo + fulvestrant group. This suggests abemaciclib as a viable treatment option in the absence of other therapeutic targets.

PIK3CA mutations

For patients after CDK4/6i whose tumors harbor PIK3CA mutations, the PI3Kα-selective inhibitor and degrader alpelisib combined with fulvestrant is currently available in Austria. The approval is based on the cohort of patients with tumors having PIK3CA mutations of the SOLAR‑1 phase III trial in which alpelisib has shown a PFS benefit of 11.0 months versus 5.7 months (HR for PFS, 0.65; 95% confidence interval [CI] 0.50–0.85; p < 0.001). It is important to note that in SOLAR‑1, only a very small subset of patients had received prior CDK4/6i, leading to the European Medicines Agency (EMA) approval of alpelisib after previous single-agent endocrine therapy only [71]. Consequently, the three-cohort phase II BYlieve study was initiated following the release of the SOLAR‑1 data to assess the safety and, indirectly, the efficacy of alpelisib in a more diverse patient population, specifically those progressing on prior CDK4/6i-based therapy. The median 6‑month PFS rate was 50.4% (95% CI 41.2–59.6), with a median PFS of 7.3 months (95% CI 5.6–8.3) suggesting comparable activity with SOLAR‑1 [72‐74].

Capivasertib, a small-molecule inhibitor of all three AKT isoforms is indicated in HR+/HER2− mBC patients with tumors having one or more PIK3CA/AKT1/PTEN alterations following recurrence or progression on or after an endocrine-based regimen. The approval is based on the CAPItello-291 trial in which capivasertib + fulvestrant showed a PFS benefit of 7.3 months versus 3.1 months (HR for PFS, 0.50; 95% CI 0.38–0.65; p < 0.001) in patients with AKT pathway-altered tumors, of whom 70% had been previously treated with CDK4/6i [75, 76]. The safety profile of capivasertib + fulvestrant was generally manageable and consistent with prior data [75].

Comparing the toxicity of capivasertib and alpelisib across trials suggests that the percentages of patients who discontinued capivasertib owing to adverse events is lower than that seen with alpelisib, with 13.0% for capivasertib (vs 2.3% on placebo) and 25.0% for alpelisib (vs 4.2% on placebo), respectively. High rates of hyperglycemia were reported with alpelisib + fulvestrant treatment (36.6% vs 0.7% in the placebo group) compared to capivasertib + fulvestrant treatment (2.3% vs 0.3% in the placebo group). Therefore, hyperglycemia may not be the principle clinical concern with capivasertib [75, 77].

Another potential PI3Kα selective inhibitor that also facilitates the degradation of mutated PI3Kα isoform is inavolisib [78]. The US Food and Drug Administration (FDA) has already granted breakthrough therapy designation for the triple-combination of inavolisib plus palbociclib and fulvestrant for the treatment of patients with HR+/HER2− mBC harboring a PIK3CA mutation following recurrence on or within 12 months of completing adjuvant ET. Inavolisib + palbociclib + fulvestrant was associated with a sustained PFS benefit of 15.0 months compared to 7.3 months with placebo + palbociclib + fulvestrant (HR for PFS, 0.43; 95% CI 0.32–0.059; p < 0.0001) [78]. Regarding quality of life, a longer time without worsening pain severity was reported with the triplet combination, while day-to-day functioning and health-related quality of life were maintained. This was further supported by a proportion of patients of only 6.2% who discontinued treatment due to adverse events in the triplet combination arm compared to 0.6% in the palbociclib + fulvestrant arm [78].

ESR1 mutations

Elacestrant, the first oral SERD, is an option for patients with ESR1 mutations after CDK4/6i therapy based on the phase 3 EMERALD trial that compared elacestrant to standard ET in patients with HR+/HER2− mBC previously treated with other ET plus CDK4/6i [54]. PFS was improved across all patient subgroups (HR for PFS, 0.70; 95% CI 0.55–0.88; p = 0.002). Patients harboring ESR1 mutations experienced an even greater benefit, with an HR of 0.55 (95% CI 0.39–0.77; p = 0.0005). Specifically, the 12-month PFS rate for patients with ESR1-mutant tumors was 26.8% (95% CI 16.2–37.4) with elacestrant compared to 8.2% (95% CI 1.3–15.1) in the comparator group [54]. Notably, the Kaplan–Meier curves for all patients (including those with ESR1^mut) showed a steep drop after approximately 1–2 months of therapy, followed by a separation of the curves in both arms thereafter [54]. It has been hypothesized that this steep decline is due to participants whose cancers were resistant to any kind of endocrine monotherapy, which again highlights the need for better characterization of patients who will probably not benefit from single-agent elacestrant. Interestingly, a post hoc analysis of PFS based on the duration or prior CDK4/6i therapy demonstrated that patients with ESR1^mut tumors and prior exposure to CDK4/6i of at least 12 months achieved a median PFS of 8.61 vs 1.91 months with elacestrant vs the standard of care. In contrast, among patients with ESR1^mut tumors with shorter duration of first-line CD4/6i-based therapy of at least 6 months, median PFS was 4.14 months with elacestrant vs 1.87 months with standard of care [79]. Of note, in patients harboring ESR1^mut and PIK3CA^mut, median PFS was 5.45 months vs 1.94 months, suggesting numerically shorter absolute PFS in tumors harboring ESR1 and PIK3CA co-mutations [80, 81]. The ADELA trial (NCT06382948) will investigate elacestrant ± everolimus in ESR1^mut post CDK4/6i plus ET aiming to optimize the benefit of second-line elacestrant-based therapy and reducing the rate of patients with early progression.

Germline BRCA/PALB2 mutations

The majority of NGS panels incorporate BRCA mutations, and in most cases, the allele frequency of mutations enables conclusions regarding the origin of mutations (germline vs. somatic) [45]. In a meta-analysis including 7 studies, germline BRCA1 and BRCA2 mutations were present in 17% and 41% of estrogen-receptor-positive breast cancers, respectively [82]. PARP inhibitor monotherapy with either olaparib or talazoparib should be considered for patients with germline pathogenic BRCA1/2 mutations and may be an option, however based on lower-level evidence, in patients with tumors harboring germline PALB2 mutations or with somatic pathogenic or likely pathogenic BRCA1/2 mutations [46, 83]. Nonetheless, it should be mentioned that the phase II TBRCA 048 trial suggested limited activity of olaparib in tumors harboring somatic BRCA mutations [84].

HER2-low, HER2-ultralow and HER2− in high-risk ET “resistant” patients

The DESTINY-Breast04 and DESTINY-Breast06 studies investigated trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy in patients with HER2-low, and HER2-ultralow disease, respectively [85‐87].

In patients with HER2-low mBC who had received one or two previous lines of chemotherapy, T‑DXd improved median PFS (10.1 months vs 5.4 months; HR 0.51; p < 0.0001) and median OS (23.9 months vs 17.5 months; HR 0.64; p = 0.0028) in the DESTINY-Breast04 trial irrespective of HER2 IHC 1+ or 2+ expression (Table 3). While grade 3 adverse events were slightly less frequent with T‑DXd than with physician’s choice of chemotherapy (52.6% vs 67.4%), one must be aware of adjudicated drug-related interstitial lung disease (ILD) or pneumonitis that occurred in 12.1% of patients who received T‑DXd, with 0.8% being grade 5 [86, 87].

Table 3

Antibody–drug conjugates (ADCs) in metastatic breast cancer

	Destiny-Breast-06 in HR+/HER2-low and HER2-ultralow [85]	Destiny-Breast-04 HR+/HER2-low [86, 87]	TROPION-B01 HR+/HER2− [91]	TROPICS-02 HR+/HER2− [90]
Phase	3	3	3	3
Patients (n)	866	557	732	272
Prior lines of chemotherapy	0	1–2	1–2	2–4
Prior CDK4/6i	90.4%	64.1%	82%	99%
ADC on trial vs physician’s choice of chemotherapy	T‑DXd	T‑DXd	Dato-DXd	SG
PFS (months)	13.2 vs 8.1	10.1 vs 5.4	6.9 vs 4.9	5.5 vs 4.0
	HR, 0.63	HR, 0.51	HR, 0.63	HR, 0.66
	(95% CI, 0.53–0.75)	(95% CI, 0.40–0.64)	(95% CI 0.52–0.76)	(95% CI 0.53–0.83)
	p < 0.0001	p < 0.0001	p < 0.0001	p = 0.0003
OS	HR, 0.81^§	HR, 0.64	HR, 0.84^§	HR, 0.79
	(95% CI, 0.65–1.00)	(95% CI, 0.48–0.86)	(95% CI, 0.62–1.14)	(95% CI, 0.65–0.96)
	p = NR	p = 0.0028	p = NR	p = 0.02
ORR (%)	57.3 vs 31.2	52.6 vs 16.3	36.4 vs 22.9	21.0 vs 14.0

^§ data immature, ADC antibody-drug conjugate, CDK4/6i cyclindependent kinase 4/6 inhibitor, CI confidence interval, Dato-DXd datopotamab deruxtecan, HR hazard ratio, NR not reported, ORR objective response rate, OS overall survival, PFS progression-free survival, SG Sacituzumab govitecan, T-DXd Trastuzumab deruxtecan

The DESTINY-Breast06 trial (Table 3) evaluated T‑DXd in patients with HR+/HER2-low (defined as IHC2+/ISH- and IHC 1+) or HR+/HER2-ultralow (IHC 0 with membrane staining) mBC who were chemotherapy-naïve but had received ≥ 2 lines of ET ± targeted therapy or 1 line of ET for mBC if progression occurred ≤ 24 months of adjuvant ET or ≤ 6 months of ET + CDK4/6i (i.e., primary resistant disease). Median PFS in the intent-to-treat (ITT = HER2-low and -ultralow) population was 13.2 months vs 8.1 months (HR 0.63; p < 0.0001) and the ORR 57.3% vs 31.2%. Data were immature at the first interim analysis, with a 12-month OS rate of 87.0% vs 81.1% for T‑DXd vs chemotherapy (HR 0.81; 95% CI 0.65–1.00). In a subgroup analysis, patients whose tumors had a higher expression of HER2 (IHC2+) despite negative in situ hybridization (ISH) had a greater benefit compared to those with IHC1+. Median PFS was 15.2 months (vs 7.0 months in the chemotherapy group; HR 0.43) for those with IHC2+/ISH− but only 12.9 months (vs 8.2 months in the chemotherapy group; HR 0.74) for those with IHC1+. In an exploratory analysis of the DESTINY-Breast06 study, patients with tumors having HER2 ultralow expression had a similar benefit with the IHC1+ cohort (ORR 61.8% vs 26.3%; median PFS, 13.2 months vs 8.3 months; HR 0.78; 12-month OS rate 84.0% vs 78.7%; HR 0.75) [85]. The differences in outcomes between the two trials, DESTINY-Breast04 and DESTINY-Breast06 underscore the importance of patient selection and specific focus in clinical studies [85‐87]. While DESTINY-Breast04 demonstrated overall efficacy of T‑DXd in a broad HER2-low population without significant differences between IHC 1+ and IHC 2+ subgroups [86, 87], DESTINY-Breast06 revealed notable distinctions between IHC2+/ISH- and IHC1+ or IHC > 0 < 1+ expression [85], highlighting the nuanced nature of HER2 expression and its impact on treatment efficacy.

Of note, while the choice of chemotherapy in the DESTINY-Breast06 trial (i.e., taxane or capecitabine) did not affect the outcome in the control arm, 20.1% of patients received T‑DXd post treatment discontinuation. Regarding safety, adjudicated interstitial lung disease (ILD) or pneumonitis occurred in 11.3% of patients. There were three cases of grade 3 and three of grade 5 ILD or pneumonitis in the T‑DXd arm, whereas only 1 patient was observed with a grade 2 ILD or pneumonitis in the chemotherapy arm [85].

While the ESMO living guidelines recommend T‑DXd for patients with HER2-low mBC after at least one line of chemotherapy [46], the authors additionally suggest adding T‑DXd as potential option for asymptomatic patients with HER2-ultralow expressing mBC following ≥ 1 ET in this treatment algorithm based upon the activity demonstrated in DESTINY-Breast06 in this patient sample. In patients with mBC after ET, T‑DXd should be considered as first-line cytotoxic therapy for symptomatic disease without an increased risk of pneumonitis/ILD especially, if a taxane would be the treatment of choice. Regarding T‑DXd’s role as cyctotoxic first-line option for all patients with HER2-low/HER2-ultralow mBC, patient-reported outcomes as well as updated OS data of DESTINY-Breast06 must be awaited.

Sacituzumab govitecan (SG), an anti–TROP‑2 antibody-drug conjugate (Table 3) that has already been approved for metastatic triple-negative breast cancer patients with ≥ 2 prior lines of therapies (≥ 1 for mBC) as well as HR+/HER2− mBC patients who have received endocrine-based therapy, and ≥ 2 additional systemic therapies in the advanced setting, was investigated in the phase 3 randomized TROPICS-02 study in HR+/HER2− mBC [88‐90]. Inclusion criteria were ≥ 1 prior taxane, CDK4/6i, and ET in any setting. SG was shown to significantly improve median PFS and OS by 1.5 months and 3.2 months compared to chemotherapy, respectively [90]. According to the ESMO living guidelines for mBC SG should be considered for patients with HR+/HER2− (IHC 0) mBC after ≥ 2 prior lines of chemotherapy [46].

Another promising ADC in development is datopotamab deruxtecan (Dato-DXd; Table 3), which targets TROP2 in a similar fashion to SG and has the same payload as T‑DXd. In the TROPION-B01 trial, Dato-DXd was evaluated versus chemotherapy in HR+/HER2− mBC patients who had previously received one or two lines of chemotherapy. Median PFS in this heavily pretreated population was increased significantly by 2 months. While the OS data are still pending, an ORR of 36.4% vs 22.9% was reported [91].

The authors agree with the recently published update of the Advanced Breast Cancer Panel and support the opinion that the administration of T‑DXd in HR+/HER2-low disease followed by SG is the preferable sequence despite limited data on sequencing [92]. Some experts recommend this approach also in the HER2-ultralow disease setting (IHC > 0 < 1+ expression), whereas in HER2-IHC-zero disease, they suggest the use of SG before T‑DXd. However, this algorithm may eventually change with the potential approval of Dato-DXd, potentially being applicable before initiating treatment with SG.

Finally, chemotherapy options must also be mentioned here. Sequential single-agent chemotherapy is typically preferred over combination therapies. However, in cases requiring rapid responses due to imminent organ failure, combination chemotherapy may be considered. Several drugs are available for single-agent chemotherapy, including anthracyclines, taxanes, capecitabine, eribulin, vinorelbine, and platinum-based agents. Rechallenge with anthracyclines or taxanes is possible for patients with a disease-free interval greater than or equal to 12 months after adjuvant chemotherapy. When accessible, liposomal anthracyclines or protein-bound paclitaxel can be considered for this purpose. Alternatively, combining a taxane or capecitabine with bevacizumab is a viable option in the first-line of chemotherapy. Before starting capecitabine, patients should be tested for germline variants that give rise to deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme. Chemotherapy should generally be continued until disease progression or intolerable toxicity. This does not apply to anthracyclines, for which cumulative dose limits must be considered. The optimal sequencing of chemotherapies for mBC has not yet been established, and treatment options should be thoroughly discussed with the patient [46].

Selected new drugs on the horizon

Lasofoxifene, a selective estrogen receptor modulator (SERM), resulted in a median PFS of 6.04 months vs 4.04 months with fulvestrant (HR for PFS, 0.699; 95% CI 0.445–1.125; p = 0.138) in the randomized phase II ELAINE 1 trial that included patients with ESR1 mutant HR+/HER2− mBC after CDK4/6i therapy. Although only a trend towards an ORR benefit was observed, with 13.2% in the lasofoxifene arm vs 2.9% in the fulvestrant arm (p = 0.12), a phase 3 combination study of lasofoxifene and abemaciclib vs fulvestrant and abemaciclib (ELAINE 3) is ongoing [93].

The proteolysis targeting chimera (PROTAC) vepdegestrant was evaluated in the phase 1/2 VERITAC trial that enrolled patients with HR+/HER2− BC who had received a median of 4 prior lines of therapy including mandatory CDK4/6i pretreatment. In evaluable patients (n = 71), the clinical benefit rate was 37.1%, and median PFS was 3.5 months [94]. Based on the clinical activity reported for vepdegestrant, the randomized phase 3 VERITAC-2 study (NCT05654623) will compare the efficacy and safety of vepdegestrant vs fulvestrant in patients with HR+/HER2− mBC post-CDK4/6i plus ET [95].

Enobosarm, a novel, oral, selective androgen receptor modulator (SARM), was investigated in HR+/HER2− mBC patients in a randomized phase 2 study. Although only 6% of patients in the 9 mg group and 29% of patients in the 18 mg enobosarm dose group had received prior targeted therapy (mTOR inhibition and CDK4/6i), a median PFS of 5.6 months and 4.2 months was reported in the 9 and 18 mg groups, respectively [96]. When setting the results in context, it is important to stress that only 2% in both arms had received previous treatment with a mTOR inhibitor or CDK4/6i. Furthermore, it should be noted that the androgen receptor may have a tumor-suppressive role in HR+ breast cancer [97]. Still, results indicate that the role of SARMs warrants further investigation. Of note, the phase 1/2 VERU-024 study will analyze the efficacy of enobosarm + abemaciclib (NCT05065411) in patients post-CDK4/6i + ET.

General recommendations, discussion and conclusion

Improving outcomes of patients with mBC requires tailored and effective care based on individual patient needs and clinical progression patterns. Regardless of whether disease progression is smoldering, gradual, rapid, or whether patients have de novo extensive disease and/or a poor general health, it is crucial to emphasize that imaging results should always be compared to baseline scans rather than only sequentially from scan to scan, according to the response evaluation criteria in solid tumors (RECIST). Thus, an accurate assessment of disease progression or response to therapy can be ensured, preventing misinterpretations that might arise from minor fluctuations between consecutive scans. By consistently referring to baseline images, clinicians can better distinguish between true progression, therapeutic effects, and natural variations in disease presentation. Moreover, regular monitoring with liquid biopsies aids in accurate assessment of disease dynamics. In combination with clinical judgment, considering the patient’s overall health, symptoms, and preferences, remains vital in deciding whether to switch therapies or continue current treatment, or which drug to use postprogression. Finally, enrollment in clinical trials offers access to cutting-edge therapies, potentially improving disease management and patient survival. Integrating these strategies ensures a personalized and effective management plan for mBC patients. Therefore, in the following sections, we describe a selection of special situations.

In patients with smoldering disease characterized by very slow disease progression who often remain asymptomatic for longer periods [98], the evaluation of disease progression can be difficult and requires careful consideration of various clinical factors. There are situations where apparent disease progression might not warrant an immediate change of therapy. When patients exhibit increased bone metastases but demonstrate clinical benefit and stable or declining tumor markers, the situation is often characterized by increasing sclerosis and demarcation of bone metastases under therapy. This should be interpreted as a positive therapeutic effect rather than true disease progression. When 1–2 new metastases appear but there is evidence of sclerosis accompanied with declining tumor markers, it suggests scar formation rather than progression. Thus, continuing the current therapy for as long as a clinical benefit is observed can be justified. Nonetheless, therapy changes should be considered in the face of clear evidence of new metastases without corresponding sclerosis and tumor markers that are increasing, which indicates that the current therapy is no longer effective. Additionally, if the patient’s clinical condition deteriorates or there is rapid progression involving vital organs, these are clear signs that a change in therapy is necessary. Overall, these patient scenarios underscore the importance of a holistic assessment of patient condition, tumor markers, and imaging findings, balancing the need to maximize therapeutic benefit against the potential for over- or undertreating.

Managing mixed responses to CDK4/6i therapy in HR+/HER2− mBC characterized by some metastatic lesions progressing while others remain stable, or regress also requires careful evaluation. Due to the heterogeneous nature of the disease, tumor biology and biomarkers play a crucial role. Liquid biopsies and genomic testing can identify mutations such as ESR1 or PI3KCA, guiding targeted therapy decisions as outlined above. In this regard, combining ET with targeted agents like alpelisib, particularly for PIK3CA mutations, has shown significant efficacy, often doubling PFS [71]. Additionally, sequential use of CDK4/6i, as supported by the MAINTAIN [66] and postMONARCH [69] studies, can be beneficial. Switching to a different CDK4/6i postprogression can extend PFS for patients who initially responded to these inhibitors [66] unless patients exhibit loss of retinoblastoma protein expression as suggested by the BioPER trial [99].

The presence of ESR1 mutations, particularly when accompanied by PIK3CA co-mutations that commonly harbor aggressive behavior with high disease load and early progression [100, 101], significantly influences treatment decisions. In these cases, combination therapy may be the preferred approach over single-agent therapy. Hence, the choice between fulvestrant plus alpelisib, fulvestrant plus capivasertib, or elacestrant is often guided by the activity of the disease, allowing for a treatment strategy that is both effective and tailored to the patient’s specific needs, such as managing toxicity [71, 73, 75, 76]. Overall, targeted therapies like AKT inhibitors in combination with ET have shown promise in improving PFS and OS, also when additional mutations like PTEN loss or AKT mutations are present [75, 76, 102]. Personalized treatment plans based on comprehensive genomic profiling and molecular testing ensure that the therapy is optimally adapted to the unique genetic landscape of each patient.

When addressing special comorbidities such as cardiovascular disease, diabetes, or autoimmune conditions, patients require tailored treatment approaches. To minimize adverse effects and maximize therapeutic benefits, the ESMO Magnitude of Clinical Benefit Scale, representing an essential framework for evaluating the clinical benefits of new cancer therapies, can be used. This tool uses a validated scoring algorithm to quantify the clinical benefit of treatments, considering both relative and absolute prognostic advantages based on predetermined thresholds. Additionally, it accounts for adverse effects and the overall impact on quality of life, providing a comprehensive assessment to guide clinical decision-making [103].

For patients with HR+/HER2− mBC experiencing aggressive/rapid disease progression, an immediate and robust therapeutic approach is crucial. As outlined, first-line endocrine therapy plus CDK4/6i is the standard-of care first-line therapy for the vast majority of patients. In frail patients, single-agent endocrine therapy may remain an option, while in patients with an early relapse and life-threatening disease, upfront chemotherapy or ADCs may be preferred. In the second-line setting, another endocrine-based treatment line according to the biomarker profile is preferred, while in patients with high disease burden and primary endocrine resistance, chemotherapy or ADCs are recommended. The CAPItello-291 trial (NCT04305496) demonstrated significant improvements in PFS when the AKT inhibitor capivasertib was combined with fulvestrant, particularly benefiting patients with PI3K/AKT/PTEN pathway alterations [75, 76, 102]. For those with rapid disease progression despite initial therapies, chemotherapy regimens such as anthracyclines, taxanes, and platinum-based treatments might be required to achieve immediate tumor control [46].

In conclusion, the integration of novel treatment options for HR+/HER2− mBC and ctDNA monitoring represents a significant advancement in precision oncology. Nevertheless, questions about the optimal sequencing of therapies remain, prompting us to present a treatment algorithm based on the presented data and the ESMO [46], NCCN [58], and AGO [104] guidelines (Fig. 3), which will naturally evolve as new data emerge. However, a biomarker-first approach should be prioritized, ensuring that targeted therapies are employed before considering nonspecific treatments. With continued research, the field of breast cancer management is set to further refine and personalize treatments, ensuring the highest standard of care by tailoring approaches to individual genetic profiles and real-time tumor dynamics.

Conflict of interest

M. Gnant: Personal fees/travel support from Amgen, AstraZeneca, DaiichiSankyo, Eli Lilly, EPG Health (IQVIA), Menarini-Stemline, MSD, Novartis, PierreFabre, Veracyte; an immediate family member is employed by Sandoz. M. Balic: Research Funding, Advisory role, Speakers bureau: AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Pierre Fabre, Roche, Pfizer, Samsung, Menarini. Research Funding, Speakers bureau: Novartis. Research Funding, Advisory role: Seagen. Advisory Role: MSD. Advisory Role, Speakers bureau: Stemline. C.F. Singer: Personal fees, grants and travel support from Amgen, Seagen, AstraZeneca, Daiichi Sankyo, Menarini-Stemline, Novartis, Gilead, Roche and Pfizer. G. Rinnerthaler: Honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, Stemline, BMS; Consulting or Advisory Role: AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Stemline; Speakers bureau: none; Research Funding: none; Patents, Royalties; Travel, Accommodations, Expenses: Amgen, Daiichi Sankyo, Eli Lilly, Gilead, Merck, Pfizer, Roche; Other Relationship: none. G. Pfeiler: Honoraria and grants from Amgen, Seagen, AstraZeneca, Daiichi, Gilead, Roche, Novartis, Pfizer, Menarini, MSD, Accord, Lilly. C. Suppan: Consulting or Advisory Role: Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, Gilead, Daiichi Sankyo, Pierre Fabre. Speakers bureau: Roche, Novartis, Pfizer, Eli Lilly, Pierre Fabre, Astra Zeneca, Gilead, Daiichi Sankyo. Travel, Accommodations, Expenses: Roche, Novartis, Pfizer, Astellas, AstraZeneca, Daiichi Sankyo, Pierre Fabre. B. Grünberger: Honoraria for advisory role/Lecture honoraria from AstraZeneca, Daiichi, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen, Servier, Merck, Takeda, Taiho. K. Strasser-Weippl: Congress support from Roche, Pfizer, Novartis, MSD, Lilly. Speaker Fees/Advisory Boards: Roche, Pfizer, Novartis, Lilly, Daiichi, Myriad, MSD, Gilead, Seagen. V. Castagnaviz: Speaking Honoraria: Daiichi Sankyo, AstraZeneca. Advisory board/Consulting Honoraria: Novartis. Travel and conference attendance: Daiichi Sankyo, Gilead, Pierre Fabre, Lilly. S. Heibl: Honoraria, Advisory Board, Congress Support from AstraZeneca, Stemline, Novartis, Lilly, Roche, AbbVie, Takeda, BMS, Daiichi Sankyo, Gilead, Sanofi, GSK, Janssen, MSD. R. Bartsch: Advisory Role: AstraZeneca, Daiichi, Eisai, Eli Lilly, Gilead, Gruenenthal, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen, Stemline. Lecture Honoraria: AstraZeneca, BMS, Daiichi, Eisai, Eli Lilly, Gilead, Gruenenthal, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen, Stemline. Research Support: Daiichi, MSD, Novartis, Roche.

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Titel: Evolving treatment paradigms after CDK4/6 inhibitors in advanced breast cancer
Position paper on optimized sequencing
verfasst von: Prof. Michael Gnant, MD FACS FEBS
Marija Balic
Christian F. Singer
Gabriel Rinnerthaler
Georg Pfeiler
Christoph Suppan
Birgit Grünberger
Kathrin Strasser-Weippl
Vanessa Castagnaviz
Sonja Heibl
Rupert Bartsch
Publikationsdatum: 20.12.2024
Verlag: Springer Vienna
Erschienen in: memo - Magazine of European Medical Oncology
Print ISSN: 1865-5041
Elektronische ISSN: 1865-5076
DOI: https://doi.org/10.1007/s12254-024-01012-5

Springer Medizin Österreich

Summary

Disclosures and declarations

Publisher’s Note

Challenges of post-CDK4/6i treatment

Continued importance of biomarker testing

Treatment sequencing postprogression on frontline CDK4/6 inhibitors plus endocrine therapy

Therapeutic options in the absence of targetable alterations

PIK3CA mutations

ESR1 mutations

Germline BRCA/PALB2 mutations

HER2-low, HER2-ultralow and HER2− in high-risk ET “resistant” patients

Selected new drugs on the horizon

General recommendations, discussion and conclusion

Conflict of interest

Publisher’s Note

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