Purpose: Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately 8 months for metastatic disease. We report results for advanced MpBC treated with ipilimumab + nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013). Patients and Methods: Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1 mg/kg i.v. every 6 weeks) plus nivolumab (240 mg i.v. every 2 weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Results: Overall, 17 evaluable patients enrolled. Median age was 60 years (26–85); median number of prior therapy lines was 2 (0–5). ORR was 18%; 3 of 17 patients achieved objective responses (1 complete, 2 partial responses; 2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+, and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AE), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE), with adrenal insufficiency observed in all 3 responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1, and absent tumor-infiltrating lymphocytes. Conclusions: The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.

We reviewed preclinical data and clinical development of MDM2 (murine double minute 2), ALK (anaplastic lymphoma kinase) and PARP (poly [ADP-ribose] polymerase) inhibitors. MDM2 binds to p53, and promotes degradation of p53 through ubiquitin-proteasome degradation. JNJ-26854165 and RO5045337 are 2 small-molecule inhibitors of MDM2 in clinical development. ALK is a transmembrane protein and a member of the insulin receptor tyrosine kinases. EML4-ALK fusion gene is identified in approximately 3-13% of non-small cell lung cancer (NSCLC). Early-phase clinical studies with Crizotinib, an ALK inhibitor, in NSCLC harboring EML4-ALK have demonstrated promising activity with high response rate and prolonged progression-free survival. PARPs are a family of nuclear enzymes that regulates the repair of DNA single-strand breaks through the base excision repair pathway. Randomized phase II study has shown adding PARP-1 inhibitor BSI-201 to cytotoxic chemotherapy improves clinical outcome in patients with triple-negative breast cancer. Olaparib, another oral small-molecule PARP inhibitor, demonstrated encouraging single-agent activity in patients with advanced breast or ovarian cancer. There are 5 other PARP inhibitors currently under active clinical investigation.

Nivolumab is an immune checkpoint inhibitor targeting programmed death-1 protein and has been approved for the treatment of multiple advanced malignancies. Adverse effects of immune checkpoint inhibitors are distinct from conventional cytotoxic chemotherapy and can be life-threatening if left unrecognized. Here, we present a case of nivolumab-induced pericardial effusion successfully managed with high-dose corticosteroids. A 70-year-old Caucasian female with a history of 50-pack-year cigarette smoking was diagnosed of recurrent adenocarcinoma of lung after initial surgery. She progressed through multiple lines of chemotherapy and was eventually started on nivolumab. She developed a large pericardial effusion, grade 3 by Common Terminology Criteria for Adverse Events v4.0, about 4 days after receiving first nivolumab treatment. She was treated with oral prednisone at 1 mg/kg daily with gradual resolution of pericardial effusion over 5 weeks while she still received nivolumab every 2 weeks. Prednisone treatment was eventually tapered off about 10 weeks from initial nivolumab treatment. However 1 week after stopping prednisone, she again presented with shortness of breath and bilateral ankle edema, imaging confirmed recurrent pericardial effusion measuring 2.8 cm. Nivolumab was stopped and patient was again started back on prednisone 1 mg/kg daily which resulted in complete resolution of pericardial effusion in 3 weeks. Nivolumab was resumed 1 week afterwards while patient was on tapering dose of prednisone. There was no recurrent pericardial effusion when she continued low-dose prednisone during the remaining course of nivolumab treatment. With increasing use of immune checkpoint inhibitors, clinicians need to be aware of the unusual immune-related adverse events in order to provide timely management and effective patient care. To our knowledge, this is the first reported case of immune-related pericardial effusion from nivolumab successfully managed with high-dose corticosteroids. Furthermore, recurrent pericardial effusion was prevented by using low-dose corticosteroids as maintenance in order for patient to continue nivolumab treatment.

We have reviewed the pivotal presentations in non-small cell lung cancer (NSCLC) from the 2009 annual meeting of the American Society of Clinical Oncology. We have discussed the scientific data, the impact on standards of care, and ongoing clinical trials.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. Recent advancements in our understanding of the intricate relationship between inflammation and oncogenesis, particularly involving the IL-1β/PD-1/PD-L1 pathway, have shed light on their application in lung cancer development and clinical outcomes of patients. Targeting these pathways in cancers like NSCLC holds immense potential to revolutionize cancer treatment, particularly for patients lacking targetable genetic mutations. However, despite these promising prospects, there remain certain aspects of this pathway that require further investigation, particularly regarding treatment resistance. Therefore, the objective of this review is to delve into the role of IL-1β in NSCLC, its participation in inflammatory pathways, and its intricate crosstalk with the PD-1/PD-L1 pathway. Additionally, we aim to explore the potential of IL-1β as a therapeutic target for NSCLC treatment.