Mini Oral 2: mBC

Dr Laure-Anne Teuwen, a medical oncologist at the University Hospital of Antwerp, provided insights from the second mini oral session on metastatic breast cancer at ESMO 2024.

In the HR+/HER2- advanced breast cancer (ABC) setting, the standard first-line treatment is endocrine therapy with a CDK4/6 inhibitor, unless there is visceral crisis, in which case paclitaxel chemotherapy is used. The phase 2 ABIGAIL trial evaluated abemaciclib plus endocrine therapy, with or without a short induction course of paclitaxel, in patients with untreated HR+/HER2- ABC and aggressive disease (defined by visceral metastases, grade 3 tumours, negative progesterone receptor, elevated LDH or early recurrence after adjuvant therapy). Notably, patients with visceral crisis were excluded. The trial’s primary endpoint was ORR at 12 weeks, with PFS and OS as secondary endpoints. Of 160 patients enrolled, the ORR was 60% in the abemaciclib plus endocrine therapy arm, compared to 40% in the paclitaxel arm. Non-inferiority was demonstrated, followed by superiority testing, which confirmed that abemaciclib was superior to paclitaxel chemotherapy.

In the HR+/HER2+ breast cancer setting, the standard first-line treatment includes chemotherapy with trastuzumab and pertuzumab, followed by maintenance with trastuzumab-pertuzumab and endocrine therapy, unless chemotherapy is contraindicated. The DETECT V trial explored whether chemotherapy could be omitted in some patients, by comparing the standard regimen (chemotherapy with trastuzumab-pertuzumab, followed by endocrine therapy) with an upfront endocrine therapy-based regimen (trastuzumab-pertuzumab plus endocrine therapy). After enrolment of 124 patients, the protocol was amended to include ribociclib in both treatment arms. The primary endpoint was tolerability, with secondary endpoints of PFS and OS. In 270 patients, severe adverse events and grade 3-5 adverse event rates were similar across groups. While the trial was not powered for PFS and OS, an exploratory analysis suggested improved outcomes with the addition of ribociclib, though further studies are needed to confirm this. 

There are several concerns regarding the DETECT V trial. First, although it was positioned as a first-line setting, only 75% of patients received treatment in the first-line, while 25% had previously undergone up to two chemotherapies and two anti-HER2 therapies, resulting in a heterogeneous population. Second, chemotherapy selection was at the physician’s discretion, and no data were provided on the distribution of chemotherapy regimens used, leaving uncertainty about whether patients received the most effective early-line treatments. Third, the choice of tolerability as the primary endpoint for a phase 3 trial is suboptimal; PFS or OS would have been more appropriate to evaluate whether chemotherapy could be safely omitted. To definitively address whether chemotherapy can be omitted and if CDK4/6 inhibitors add value in this setting, a more robust trial design is required.

The TIFFANY trial is a phase 3 randomized study conducted in China, evaluating the novel CDK4/6 inhibitor tibremciclib in HR+/HER2- ABC in the second-line setting after progression on endocrine therapy. The trial compared tibremciclib plus fulvestrant versus fulvestrant alone, with PFS as the primary endpoint and OS as a secondary endpoint. Among the 270 patients included, PFS was significantly longer in the tibremciclib arm (11 months) compared to the control arm (5 months), with a hazard ratio of 0.31. Neutropenia was the most common grade 3 adverse event. While tibremciclib demonstrated efficacy similar to other CDK4/6 inhibitors, the trial raised concerns as it began in 2022, when three other CDK4/6 inhibitors were already approved, also in China. Patients in the control arm received fulvestrant alone, considered a substandard treatment given the availability of these CDK 4/6 inhibitors, which could have been avoided in a phase 3 trial.