A phase IB and randomised phase IIA trial of CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases: CARBON trial results.

Background: Approximately 70% of patients with metastatic breast cancer (MBC) develop bone metastases. Despite advances in systemic treatment options and the use of bone targeted agents in the management of bone metastases to reduce skeletal morbidity, there remains an unmet need for further treatment options. Radium-223 (Ra ²²³ ) is an alpha-emitting radiopharmaceutical that is preferentially taken up into bone at sites of increased osteoblastic activity where it emits high-energy, short-range alpha-particles that could provide a targeted anti-tumour effect on bone metastases. Here we evaluate the safety, feasibility and efficacy findings of the combination of Ra ²²³ with capecitabine chemotherapy in patients with MBC with bone involvement.
Methods: CARBON is a multi-centre, open-label phase IB/IIA study evaluating the combination of Ra ²²³ (55 kBq/kg day 1 given on 6 weekly schedule) and capecitabine (1000 mg/m ² bd days 4-17 every 21 days) in patients with bone metastases from MBC (± other disease sites). Other eligibility criteria included ECOG performance status 0-2, ≤2 lines of chemotherapy for MBC and current bisphosphonate or denosumab use for ≥ 6 weeks. The phase IB part of the trial (6 patients) was conducted to provide preliminary feasibility and safety of capecitabine + Ra ²²³ . Thereafter, 28 patients were randomised (2:1) to capecitabine + Ra ²²³ or capecitabine alone to further characterise the safety profile and evaluate efficacy, the primary efficacy endpoint being the bone turnover marker (urinary n-telopeptide of type I collagen) change from baseline to end of cycle 5 and secondary endpoints of time to first symptomatic skeletal event, and disease progression at extra-skeletal and bone disease.
Results: In addition to bone metastases, 10/23 [44%] and 13/23 [57%] capecitabine + Ra ²²³ and 2/11 [18%] and 9/11 [82%] capecitabine alone patients had soft tissue and visceral disease sites respectively. More capecitabine + Ra ²²³ patients had received prior chemotherapy for MBC: 11/23 [48%] vs 2/11 [18%]. The analysis populations comprise 34 patients (23 capecitabine + Ra ²²³ , 11 capecitabine); 2 patients randomised to capecitabine + Ra ²²³ received capecitabine alone and are included in the capecitabine arm. Median number of cycles received was 8.5 in capecitabine + Ra ²²³ (range 3-12) and 12 in the capecitabine arm (range 1-12). 94/95 prescribed Ra ²²³ cycles were administered. No dose limiting toxicities were seen in phase IB and no patients developed grade ≥ III diarrhoea. Gastrointestinal, haematological and palmer-planter erthyrodysesthesia adverse events were similar in both arms. Although formal statistical comparisons were not made, changes in bone turnover markers, the times to extra-skeletal progression and bone disease progression, and the frequency of symptomatic skeletal events were similar across the two treatment arms.
Conclusion: Capecitabine + Ra ²²³ at the planned dose was safe and feasible in MBC patients with bone metastases. However, no efficacy signals were seen that might suggest greater efficacy of the combination over capecitabine alone clinically or biochemically.
Competing Interests: Janet Brown declared research grants (to her institution) from Amgen, AstraZeneca and Bayer and personal fees from Amgen, Novartis, BMS, Ipsen, Sandoz, MSD and Bayer and support for attending meetings from Ipsen.  Matthew Winter declared consulting fees from Gilead, Novartis and Eli Lilly, payment for lectures/presentations/speakers bureaus from Eli Lilly, Pfizer, Novartis and Easai and support for attending meetings and/or travel from Eli Lilly, Gilead, Novartis and Easai. Robert Coleman declared consulting fees from AstraZeneca,  Boehringer Ingelheim, ITM and Sanofi; speaker fees from Amgen, ITM, Novartis and Pierre Fabre; and has a patent pending and share options with Inbiomotion.  Caroline Wilson declared consultancy fees from Pfizer, Novartis, Amgen and Roche Iain MacPherson declared consultancy fees from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, In3Bio, MSD, Novartis, Pfizer and Roche and travel support from Eisai and Roche. Richard Eastell declared consultancy funding from IDS, Sandoz, Samsung, Haoma Medica, CL Bio, Biocon, Takeda, meeting presentations from Pharmacosmos, Alexion and Amgen and grant funding from Amgen, Roche, Pharmacosmos and Alexion. Chris Twelves declared fees from AstraZenenca, Pfizer, Novartis, MSD and Eisai.  Sacha Howell declared speaker fees and advisory board fees from Pfizer. Carlo Palmieri declared grant funding from Daiichi Sankyo, Pfizer and Seagen, travel support from Gilead and Roche and honoraria from Astrazeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, Novartis, Pfizer and Roche. All other authors declared no conflicts of interests.
(© 2022 Published by Elsevier GmbH.)