Gianni L, et al. - To test the synergistic effects of the combined pharmacological intervention directed to HER2 and oestrogen receptor (ER) signals on RB1, researchers here combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer. At 2 weeks and at surgery, the combination of palbociclib, fulvestrant, trastuzumab, and pertuzumab demonstrated a marked effect on the expression of Ki67. In HER2-positive and ER-positive breast cancer, triple targeting of ER, HER2, and RB1 might be an effective chemotherapy-free treatment strategy. Researchers highlighted the necessity for further clinical testing and additional molecular characterisation, not only in hormone receptor-positive tumours but also in tumours without HER2 amplification.

Methods

• Researchers performed a multicohort, open-label, exploratory, phase 2 study (NA-PHER2) at seven sites in Italy.
• For the first cohort, patients were eligible if they had previously untreated, histologically confirmed, unilateral, invasive, HER2-positive, ER-positive breast cancer and were suitable for neoadjuvant therapy.
• Treatment of patients comprised of receiving intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) every 3 weeks for 6 cycles plus oral palbociclib (125 mg once a day for 21 days in a 4-week cycle) and intramuscular fulvestrant (500 mg) every 4 weeks for 5 cycles.
• Change from baseline in Ki67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment) and changes in apoptosis from baseline to surgery were the coprimary endpoints.
• Clinical objective response (according to modified Response Evaluation Criteria in Solid Tumors) and pathological complete response were observed as the secondary endpoints.
• The primary and secondary endpoints were assessed in all patients who met eligibility criteria.
• Safety was assessed in all patients who received at least one cycle of therapy.

Results

• Researchers enrolled 36 patients from May 20, 2015 to Feb 8, 2016.
• Of these, 1 was deemed ineligible for the study and 5 were found to be HER2-negative on retrospective analysis.
• Thus, safety analyses included 35 patients and the primary and secondary endpoints were assessed in 30 patients.
• Geometric mean Ki67 expression was 31·9 (SD 15·7) at baseline compared to 4·3 (15·0) at week 2 (n=25; p < 0·0001) and 12·1 (20·0) at time of surgery (n=22; p =0·013).
• For apoptosis, the geometric mean was 1·2 (SD 0·3) at baseline compared to 0·4 (0·4; p=0·019) at surgery.
• Immediately before surgery, 29 (97%; 95% CI 83–100) of 30 patients achieved a clinical objective response.
• In breast and axillary nodes, 8 (27%; 95% CI 12–46) patients demonstrated a pathological complete response at surgery.
• Neutropenia (ten [29%]), diarrhoea (five [14%]), and stomatitis, increased alanine aminotransferase, and hypersensitivity reactions (one [3%] of each event) were identified as the most frequent grade 3 adverse events.
• In this study, researchers recorded no grade 4 or serious adverse events and no deaths.