Nature Reviews Clinical Oncology最新文献

Over the past few years, several novel systemic treatments have emerged for patients with treatment-refractory metastatic colorectal cancer, thus making selection of the most effective later-line therapy a challenge for medical oncologists. Over the past decade, regorafenib and trifluridine–tipiracil were the only available drugs and often provided limited clinical benefit compared to best supportive care. Results from subsequent practice-changing trials opened several novel therapeutic avenues, both for unselected patients (such as trifluridine–tipiracil plus bevacizumab or fruquintinib) and for subgroups defined by the presence of actionable alterations in their tumours (such as HER2-targeted therapies or KRAS^G12C inhibitors) or with no acquired mechanisms of resistance to the previously received targeted agents in circulating tumour DNA (such as retreatment with anti-EGFR antibodies). In this Review, we provide a comprehensive overview of advances in the field over the past few years and offer a practical perspective on translation of the most relevant results into the daily management of patients with metastatic colorectal cancer using an evidence-based algorithm. Finally, we discuss some of the most appealing ongoing areas of research and highlight approaches with the potential to further expand the therapeutic armamentarium.

Chimeric antigen receptor (CAR) T cells are revolutionizing cancer therapy, particularly for haematological malignancies, conferring durable and sometimes curative responses in patients with advanced-stage disease. The CAR T cell products currently approved for clinical use are all autologous and are often effective; however, in patients who are lymphopenic and/or heavily pretreated with chemotherapy, autologous T cells can be difficult to harvest in sufficient numbers or have functional impairments that might ultimately render them less efficacious. Moreover, autologous products take several weeks to produce, and each product can be used in only one patient. By contrast, allogeneic CAR T cells can be produced for many patients using T cells from a single healthy donor, can be optimized for safety and efficacy, can be instantly available for ‘off-the-shelf’ use and, therefore, might also be more cost-effective. Despite these potential advantages, the development of allogeneic CAR T cells has lagged behind that of autologous products, owing to the additional challenges such as avoiding graft-versus-host disease and host-mediated graft rejection. Over the past few years, the development of advanced genome-editing techniques has facilitated the generation of novel allogeneic CAR T cell products. Furthermore, CAR cell products derived from other cell types such as induced pluripotent stem cells and natural killer cells are being investigated for clinical use. In this Review, we discuss the potential of allogeneic CAR cell products to expand life-saving immunotherapy to a much broader population of patients in the coming years, the progress made to date and strategies to overcome remaining hurdles.

Approximately 40% of hormone receptor-positive (HR⁺), HER2-negative (HER2^–) breast cancers harbour activating mutations in PIK3CA (encoding the catalytic subunit of PI3Kα); these mutations are generally associated with a poor prognosis but also responsiveness to inhibitors of the PI3K–AKT pathway. Now, data from the phase III INAVO120 trial demonstrate that addition of the selective PI3Kα inhibitor and degrader inavolisib to standard-of-care first-line endocrine plus CDK4/6 inhibitor therapy for advanced-stage disease is feasible and increases efficacy.

In INAVO120, 325 patients with metastatic recurrence of PIK3CA-mutant HR⁺, HER2^– breast cancer during, or within 12 months of completing, adjuvant endocrine-based therapy were randomly assigned (1:1) to receive palbociclib and fulvestrant plus either inavolisib or placebo. The requirement for early disease relapse enriched for patients with a poor prognosis: 83% had received chemotherapy, 80% had visceral metastases, 52% had liver metastases and 51% had ≥3 metastases. Notably, however, only 1% of patients had received a CDK4/6 inhibitor as part of adjuvant therapy. Progression-free survival (PFS) was the primary end point.

The standard-of-care (SOC) first-line treatment for patients with recurrent or metastatic cervical cancer is chemotherapy with a platinum-based agent and paclitaxel, with or without bevacizumab, and with addition of an anti-PD-1 antibody in those with a PD-L1 combined positive score (CPS) ≥1. Now, data from the phase III COMPASSION-16 trial show that addition of the PD-1 × CTLA4 bispecific antibody cadonilimab to chemotherapy plus bevacizumab improves outcomes in this setting.

In this trial, conducted in China, 445 women were randomly allocated (1:1) to receive first-line chemotherapy with or without bevacizumab plus either cadonilimab or placebo. Progression-free survival (PFS) and overall survival (OS) were the co-primary end points.