The phase III MECCA study on metronomic chemo-endocrine therapy in advanced breast cancer—the results that so many have been waiting for

Access to novel anti-cancer therapies remains a global challenge, and many patients, even in high-income countries like the United States (US), are denied access to these therapies due to an inequitable health insurance system. Therefore, many agents introduced in the recent decade, which significantly improve patients’ outcomes, are still inaccessible to millions of cancer patients worldwide. Thus, wide, unlimited access to such therapies or similarly active strategies remains a substantial unmet need.

One such example is the access to novel endocrine therapy (ET)-based combination strategies involving cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), which have become a standard treatment for advanced estrogen receptor-positive (ER⁺)/human epidermal growth factor receptor 2-negative (HER2⁻) breast cancer (BC). However, the considerable total cost of therapy with these agents, regardless of the line of treatment (first or second), precludes a wide, global access to these drugs. Enough to say that a later use of these drugs (second line, instead of first line) decreases the total cost of therapy by $140,000 per patient. The global number of advanced BC patients who should receive CDK4/6i is estimated between 300,000 and 420,000 per year (1). However, in low- and middle-income countries (LMIC), far less than half of advanced BC patients have access to this class of agents at any stage of systemic treatment (2). Additionally, global access to CDK4/6i is unlikely to improve anytime soon, as the patent protection for palbociclib is set to expire in 2028, for abemaciclib in 2029, and for ribociclib in 2036 (3,4). These facts clearly demonstrate the critical importance of developing feasible and effective ET-based combination strategies, which can improve outcomes for advanced ER⁺/HER2⁻ BC patients to a similar extent as CDK4/6i.

For years, many experts have suggested that metronomic chemotherapy may represent an alternative to CDK4/6i. It may sound controversial, but indeed the ultimate mechanism of action of CDK4/6i—partners of choice for endocrine agents in advanced, ER⁺/HER2⁻ BC—is typical for phase-specific cytotoxic agents such as vinorelbine, paclitaxel, capecitabine, or methotrexate routinely used in various metronomic regimens (5-8). Classical chemotherapeutic agents administered in a low-dose, daily fashion inhibit cellular proliferation, induce apoptosis, impair tumor-induced angiogenesis, and improve anti-tumor immune responses (5-7), and the same biological effects are achieved with a metronomic use of CDK4/6i (9-12). The striking similarity in the biological effects of metronomically administered CDK4/6i and classical cytotoxic agents further supports the potential role of metronomic chemotherapy as an alternative to CDK4/6i (13-15).

Metronomic chemotherapy represents a unique concept of continuous cancer treatment with exceptionally high rationale in advanced disease settings, where long-term disease control with minimal toxicity-related impact on quality of life represents an ultimate goal. Metronomic chemotherapy based on a combination of several agents turned out to be a safe, feasible, and scalable approach in many cancer types, allowing not only the combination of various cytotoxic agents together to achieve a synergistic anticancer approach, but also combining chemotherapeutics with targeted therapies (antibodies, small-molecule kinase inhibitors) or immunotherapy (6,16-19). Although metronomic chemotherapy showed activity in various malignancies, it is predominantly used and evaluated in BC patients. However, even in BC, we lacked phase III data on the role of metronomic chemotherapy, except for CREATE-X study, which established the role of adjuvant capecitabine in patients with residual disease after neoadjuvant chemotherapy. Since metronomic chemotherapy is not a shiny, new strategy involving novel drugs, there is almost no incentive (not to mention financial) to conduct large, costly phase III studies on this therapeutic approach. Nonetheless, the available data strongly support the use of metronomic chemotherapy in advanced BC and even provide convincing data on its superiority to standard, intravenous chemotherapy-based approaches. METEORA-II, a phase II study, compared oral vinorelbine plus capecitabine plus cyclophosphamide (VEX) combination with weekly paclitaxel. The study demonstrated that VEX treatment significantly prolonged time-to-treatment failure and progression-free survival (PFS), albeit there was no difference in overall survival (OS) (20).

Over the last two decades, several phase II and cohort studies have shown that combining ET utilizing aromatase inhibitor (AI) or fulvestrant with metronomic chemotherapy improves activity (objective response rate, disease stabilization rate, and PFS) while maintaining a safety profile similar to ET alone (15,21). In our cohort study, a combination of fulvestrant with metronomic polychemotherapy, based on vinorelbine, cyclophosphamide, and capecitabine (FulVEC regimen), demonstrated significant activity in ER⁺/HER2⁻ BC patients regardless of the number of earlier lines of treatment (ET or chemotherapy) or earlier use of CDK4/6i (22). However, since none of the trials on metronomic therapy alone or in combination with endocrine treatment in advanced BC have been conducted as a phase III study, the strategies, despite promising results, have not entered mainstream use. The lack of robust survival data from phase III studies precluded the incorporation of metronomic-based chemo-endocrine strategies into key international guidelines, hence leaving many patients without access to this beneficial therapeutic approach.

Taking all the above into account, no doubt conducting the phase III MECCA trial, which compared the efficacy of metronomic chemo-ET (CET) with ET alone for advanced ER⁺/HER2⁻ BC (23), represents a significant achievement.

The authors compared metronomic CET with capecitabine [500 mg three times a day (tid)] plus AI with AI alone (ET) as first-line treatment for advanced ER⁺/HER2⁻ BC. The primary end point of the study was PFS, and secondary end points included OS, objective response rate, disease control rate (defined as disease controlled for ≥24 weeks), and safety.

A total of 263 patients were randomized in a 1:1 ratio to metronomic CET and ET. Pre- or perimenopausal women, who represented approximately 50% of patients, were also receiving gonadotropin-releasing hormone agonist (aGnRH) regardless of the arm assigned. Almost half of the patients presented with visceral involvement, and bone-only disease was observed in less than one-fifth of the population. The majority (>60%) of patients were considered endocrine sensitive, and the rest were diagnosed with secondary endocrine resistance (disease relapse after the first 2 years of adjuvant ET or within 12 months of completing adjuvant ET). Moreover, >60% of patients have been treated with chemotherapy as a part of perioperative treatment.

Metronomic CET resulted in a significant reduction in the relative risk of disease progression or death [hazard ratio (HR) for PFS =0.58; 95% confidence interval (CI): 0.43–0.76] with median PFS of 20.9 months (CET) and 11.9 months (ET). The median OS was not reached in the CET arm, and was 45.1 months in the ET arm (HR for OS= 0.58; 95% CI: 0.37–0.93). Additionally, CET was associated with a significantly higher probability of achieving an objective response compared to ET [odds ratio (OR) =1.79; 95% CI: 1.04–3.08].

Undoubtedly, the addition of capecitabine to AI increased CET toxicity compared with AI alone. Almost 30% of patients in the CET arm experienced palmar-plantar erythrodysesthesia, which represents a typical capecitabine-related AE. Grade 3 CTCAEs leading to capecitabine dose reduction were observed in 11.1% of patients, and in most of them, it resulted in treatment interruption. Discontinuation of study treatment due to AEs occurred in 16.7% of patients in the CET arm and 5.5% in the AI group.

Putting the MECCA study results into the context of current clinical practice makes them especially intriguing. Combined strategies, which are routinely used in first-line settings, involve AI plus CDK4/6i. Large, phase III clinical studies evaluated the role of AIs in combination with either palbociclib (PALOMA-2: 666 patients), abemaciclib (MONARCH-3: 493 patients), or ribociclib (MONALEESA-2: 668 patients; MONALEESA-7: 672 patients) (7,24-26). In all of these studies, the AI + CDK4/6i combination resulted in a significant decrease in the risk of disease progression or death compared to ET alone (HR =0.56 in PALOMA and MONALEESA-2; HR =0.55 in MONALEESA-7; and HR =0.54 in MONARCH-3) (24,27-31). However, only the MONALEESA studies demonstrated a significant improvement in OS with ribociclib in the first-line setting, with HRs for OS of 0.76 in both (7,25). The MECCA trial not only showed a significant improvement in PFS, with an HR similar to that of studies on CDK4/6i, but also demonstrated a considerable benefit in OS. Demonstrating a significant improvement in OS in a population of advanced BC patients who have access to several lines of active, systemic, sequential, postprogression treatment is a known, very challenging task. This is confirmed by the disappointing results of the aforementioned phase III studies (MONARCH-3 and PALOMA-2), which failed to achieve this crucial endpoint (30,31), unlike the MECCA study (Table 1).

Undoubtedly, the MECCA study should lead to updating current guidelines to introduce the CET combination as a new therapeutic standard in first-line settings, alongside CDK4/6i-based combinations. Such an immediate update is of critical importance for many patients worldwide who lack access to CDK4/6i-based therapies. The cost of 28-day treatment with metronomic capecitabine in the US is approximately $37–75. In contrast, the monthly cost of abemaciclib is $6,264, while ribociclib costs reach $10,950 (32).

The MECCA trial demonstrated that the cost-benefit ratio of CDK4/6i is inferior to that of an innovative therapeutic approach using the older, cheaper capecitabine. It also showed that treating ER⁺/HER2⁻ advanced BC patients with a therapy that is 80–150 times more affordable offers at least the same clinical benefits without profound financial toxicity. Moreover, the safety profile of the CET was better than that of CDK4/6i, particularly compared with ribociclib, the only drug to improve OS when combined with endocrine treatment in the first-line setting. The cumulative percentage of patients in the MECCA trial who experienced any grade 3 toxicity was 15.1% (no grade 3 neutropenia) compared to 66.2% and 15% of patients experiencing any grade 3 or grade 4 adverse event, respectively, in the MONALEESA-2 trial (grade 3 and grade 4 neutropenia in 49.7% and 9.6% patients, respectively) (23,27).

The MECCA trial is a groundbreaking study that finally confirmed the activity, feasibility, and safety of the CET combination in advanced BC. Some limitations of the MECCA study related to the homogenous Asian population (no representation of other populations) or lack of head-to-head comparison with CDK4/6i do not negatively impact the importance of the results. MECCA sheds a new, long-awaited light on metronomic chemotherapy, indicating that it is not just a niche strategy, but should be included in the mainstream of systemic treatment for advanced BC.

The capecitabine and AI combination represents a breakthrough treatment option for advanced ER⁺/HER2⁻ BC patients, not only in LMIC, but also in many high-income countries where limited access to modern therapies stems from inequities in health insurance systems

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-129/prf

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Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-129/coif). The author has no conflicts of interest to declare.

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