CHEOPS trial: a GINECO group randomized phase II assessing addition of a non-steroidal aromatase inhibitor to oral vinorelbine in pre-treated metastatic breast cancer patients

Through their mitogenic effects via the estrogen-receptor alpha (ERα), estrogens play a fundamental role in the carcinogenesis process. Blocking estrogenic signaling is therefore the basic principle of hormone therapy for the treatment of hormone receptor-positive (HR +) breast cancer. Despite the undeniable efficacy of molecules used in endocrine therapy, many tumors have intrinsic or acquired resistance, despite their positive tumor status for ERα. It is nevertheless interesting to note that some clinical studies have shown that 43% and 30% of patients who have relapsed, respectively, on tamoxifen or aromatase inhibitor will respond to fulvestrant treatment, indicating the interest of continuing endocrine therapy beyond neoplastic progression [1, 2].

Systemic chemotherapy with cytotoxic agents remains a standard treatment for metastatic cancer. "Metronomic" chemotherapy is a repeated reduced-dose chemotherapy treatment administered daily for antineoplastic purposes. These effects involve anti-angiogenic impact, interference with immune response and conventional cytotoxic activity [3]. The impact of metronomic chemotherapy on angiogenesis would be explained by the inhibition of the mobilization of endothelial cell progenitors and/or the activation of apoptosis by endothelial cells [4]. There may also be a reactivation of the immune system through a reduction in the number of regulatory T cells, a decrease in their inhibitory function of T and NK lymphocyte activity and a maturation of dendritic cells, thus stimulating the antitumor immune response [5].

Metronomic chemotherapy was initially evaluated in 64 metastatic breast cancer patients by an Italian Phase II study. The treatment included methotrexate and cyclophosphamide and interesting results were reported, with 20% response rate, a 30% clinical benefit rate and no significant toxicity [6]. Regarding metronomic administration of vinorelbine, several regimens with multiple dosages were tested in metastatic breast cancer treatment. Oral vinorelbine according to a 50 mg metronomic regimen, three times a week continuously, was evaluated as monotherapy in a phase I study with pharmacokinetic data [7] and in combination with bevacizumab [8]. These studies showed that administration of 50 mg of oral vinorelbine three times a week was feasible and well tolerated with an interesting clinical benefit in advanced refractory cancers.

The combination of endocrine therapy and metronomic chemotherapy with vinorelbine could therefore be of interest for HR + /HER2− (Hormone receptor positive, human epidermal growth factor receptor 2 negative) breast cancers in a metastatic hormone-resistance setting.

We hypothesized that maintaining HR-targeted therapy after progression in combination with chemotherapy may improve disease control. The CHEOPS study aims to confirm the clinical benefit of a combination of an anti-aromatase and metronomic chemotherapy treatment, oral vinorelbine (OV), 50 mg, three times per week for AI pre-treated, HR + /HER2− metastatic breast cancer patients. It would have the theoretical advantage of being well tolerated and more effective than chemotherapy alone even after an anti-aromatase therapy.

The limiting factor in this study was the number of toxic deaths induced by oral vinorelbine dose and administration scheme. Indeed, adverse effects of metronomic chemotherapy are most often mild or non-existent and are generally represented by grade 1 toxicities: leukopenia, moderate neutropenia, nausea and vomiting, increased transaminases and asthenia. Serious grade 3–4 toxicities are rare [9, 10]. Several studies have confirmed that metronomic oral vinorelbine can safely be administered at doses up to 50 mg three times a week, especially in advanced breast cancer [11, 12]. Patients with recurrent metastatic breast (BC), prostate (PC) or non-small cell lung cancer (NSCLC) and adequate organ functions were randomly assigned to 30, 40 or 50 mg vinorelbine, taken orally three times a week. With maximum response duration achieved at 50 mg, adverse events were mild and negligible and did not differ between the three arms. Considering the antitumor activity and response duration, the negligible toxicity of the highest dose investigated and the lack of drug accumulation over time, the authors suggest that 50 mg given three times a week is the optimal dose for metronomic oral vinorelbine [11].

The toxic deaths observed here may be the result of poor management of oral oncology drugs at home, for example, by maintaining chemotherapy during periods of neutropenia, infection or hospitalization, despite protocol recommendations. Recommendations for close biological monitoring have been strengthened accordingly (Appendix Table 6). Serious grade 3–4 toxicities would be better managed today through better knowledge of adverse reactions and learning by mistake. The management of per os cancer drugs requires patient autonomy, training of paramedical staff and the knowledge of all health-care providers in contact with the patient. This experience shows that it is now necessary to train non-specialized staff to provide the best possible support to patients treated at home [13‐15]. The other possibility is to introduce progressively oral vinorelbine with dose escalation scheme or reduce the dose of oral vinorelbine administered three times a week to minimize the risk of toxic death. Oral form of vinorelbine 70 mg/m² (fractionated on days 1, 3, and 5 for 3 weeks, on and 1 week off, every 4 weeks, for a maximum of 12 cycles) has been experimented in 34 elderly metastatic breast cancer patients and an OR of 38% was reported. Neutropenic infection was evident in two patients (6%). In all instances, these complications resolved during antibiotic therapy [16]. Another study with an alternative on and off metronomic regimen, vinorelbine 30 mg (total dose), one day on and one day off, was given to 32 elderly patients with metastatic breast cancer; a 50% CB was reported, without grade 3 or 4 toxicity [17]. Adamo et al. reported the biological effect of oral metronomic vinorelbine alone or in combination with endocrine therapy in 61 post-menopausal women with untreated stage I–III HR + /HER2-negative breast cancer. Two cases (3.4%) of grade 3 adverse event, both in the oral metronomic vinorelbine alone arm, were observed after completing the 3-week treatment. One case was an acute pancreatitis and the other was an acute gastroenteritis. Overall, no discontinuations due to toxicity was observed. However, the study population was treatment naive, whereas patients in the CHEOPS trial were already at an advanced stage of their metastatic disease (average of 3.2 years since diagnosis of metastatic disease) and had already received one or two lines of chemotherapy [18].

Other combinations may then be possible such as capecitabine and endocrine therapy or oral cyclophosphamide and endocrine therapy. Some studies evaluating combinations were carried out in the 1980s. These randomized trials compared chemotherapy most often with CMF (cyclophosphamide, methotrexate and 5 fluorouracil) as monotherapy with the same chemotherapy in combination with tamoxifen. These different studies showed significant benefit in terms of neoplastic response rate (74% versus 51%, respectively; P < 0.01; 75% versus 49% p = 0.0001) and progression-free survival. However, there was no significant difference in terms of overall survival (111 weeks versus 78 weeks p = 0.25 [19]; 24 months versus 19 months p = 0.07 [20, 21]), mainly due to side effects including thromboembolic effects induced by tamoxifen. However, in patients with metastatic breast cancer, aromatase inhibitor (AI) has been shown to be superior in terms of tamoxifen survival and significantly reduce thromboembolic complications [22]. A randomized phase II clinical trial evaluated the combination of letrozole and cyclophosphamide (50 mg/d for 6 months) compared to letrozole alone in 114 patients with hormone-sensitive metastatic breast cancer. The authors concluded that metronomic cyclophosphamide associated with hormone therapy was beneficial with an objective response rate of 87% in the combination arm versus 71% in the letrozole arm alone [23]. However, these trials mainly excluded patients resistant to concomitant endocrine therapy. In contrast, all patients enrolled in the CHEOPS trial were resistant to AI. This difference may be associated with the small benefit of adding AI to chemotherapy reported here. For HR + /HER2− pre-treated metastatic breast cancer, efficacy of endocrine therapy in combination with chemotherapy remains an open question.

The underlying question is then the interest of maintaining endocrine therapy throughout the treatment, including successive chemotherapy lines. To finish, maintenance endocrine therapy (MET) after chemotherapy could be another way to combine endocrine therapy and chemotherapy. Sutherland et al. discussed four trials addressing the question of whether there is a benefit from introducing endocrine therapy following chemotherapy for metastatic breast cancer [24]. Berrutti et al. investigated the factors influencing response rate and overall survival in 207 MBC patients responding to first-line chemotherapy with epirubicin administration, followed or not by MET. Patients receiving MET survived significantly longer than those submitted to observation in univariate and multivariate analysis [25]. In a phase III randomized trial, Kloke et al. investigated the use of medroxyprogesterone acetate (MPA) maintenance treatment in 90 advanced breast cancer patients with a disease controlled after six cycles of induction chemotherapy. A longer median time to progression (TTP) was reported in the MET arm compared to the observation arm (4.9 months versus 3.0 months), but no difference in OS was observed (17.4 months versus 18.0 months) [26]. Montemmuro et al. retrospectively analyzed the effect of MET after high-dose chemotherapy with hematopoietic progenitor cell transplant (HDCT) on the progression-free survival (PFS) on 109 patients with hormone-dependent MBC who remained progression free for at least 4 months after HDCT. Of these patients, 55 were non-randomly submitted to MET. In multivariate analysis, MET appeared to be a significant factor with improvement of PFS with MET (HR 0.58; 95% CI: 0.362–0.931) [27]. Finally, Dufresne et al. retrospectively identified factors which influence PFS and OS after the first line of chemotherapy in 560 patients with HR + MBC. Administration of MET was shown to improve both PFS (16.3 versus 7.8 months; p < 0.001) and OS (48.1 versus 30 months; p < 0.0001) in multivariate analysis [28]. When chemotherapy for MBC was discontinued due to toxicity, in the absence of progression, the use of ET, with its relatively low toxicity, is a reasonable option, although this approach has not been assessed in randomized trials.

Concerning prior treatment, only a minority of patients had previously received anti-CDK4/6 therapy. This treatment is now the gold standard for first-line treatment of HR + metastatic breast cancer. The results of the CHEOPS trial are therefore not applicable to current daily practice. However, these results do provide a proof of concept on a trend toward an improvement of outcomes with a combination of endocrine therapy and chemotherapy compared to chemotherapy alone. This concept should persist after exposure to anti-CDK4/6.

The addition of aromatase inhibitor to oral vinorelbine over oral vinorelbine alone in aromatase inhibitor resistant metastatic breast cancer was associated with a non-significant improvement of PFS. The study has been prematurely stopped due to treatment toxicity. Several unexpected SAEs were reported. Metronomic oral vinorelbine schedule, at 50 mg three times a week, requires close biological monitoring. The question of hormonal treatment and chemotherapy combination remains open.