A Multicenter Phase II Trial of Ipilimumab and Nivolumab in Unresectable or Metastatic Metaplastic Breast Cancer: Cohort 36 of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART, SWOG S1609).

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.

Philosophical oncology: on being needed--thoughts of a deathwatcher.

The ultimate bond that connects the patient and the physician requires an understanding of the human drama we call illness. Medical oncology is a specialty filled with the uncomfortable experiences of people facing fear, anxiety, and loss. The caregiver must share in the distress, be troubled by the patient's troubles, but keep a safe distance, so as not to be wounded as well. The physician is not only a deathwatcher for the sickest of patients, but, by necessity, must be self-reflective--a doctorwatcher.

Palliative care in pancreatic cancer.

BACKGROUND: Pancreatic cancer is a formidable health problem, representing the 10th most common malignancy in the United States and the 4th most common cause of all cancer deaths. The overall 5-year survival rate is 4%, making this disease a model tumor in which to address the specialized care issues of palliative medicine. METHODS: General considerations in both medical decision-making and symptom management are reviewed. Treatment of patients with locally unresectable, recurrent, or metastatic disease is individualized, based on considerations that include patient age, patient wishes, family influence, insurance constraints, and geographic practice variations. RESULTS: Success in managing progressive symptoms is needed to palliate patients with advanced pancreatic cancer. Common problems include biliary obstruction, depression, pain, intestinal obstruction, and fatigue. CONCLUSIONS: Relief of pain and suffering associated with critical illness is required in managing patients with cancer. Pancreatic cancer is a model illness that mandates this need.

Philosophical oncology: calling on the principle of double effect.

Reasonable human behavior is based on doing something for a consequence that is perceived as good. Ethical medical decision-making is based on prioritizing values after understanding the relevant facts. There is an ethical obligation to do no harm. This is especially true in relieving the pain and suffering of dying patients; in these cases, treatment has the risk of contributing to a patient's death. The principle of double effect has been helpful as a moral guide in troubling cases to discern what actions are acceptable, even though the action could lead to an end that would seem as immoral as if the effect were directly intended. This principle, though, is not without problems and critics, and some have pointed out its shortcomings as an ethical guide.

Semi-allogeneic vaccines for patients with cancer and AIDS.

Interest in semi-allogeneic vaccines has been increasing, as demonstrated by the publication of successful preclinical and clinical studies by others and us that validate this immunotherapeutic approach to cancer and HIV-infection. We now report that lymphocytes from an HLA-A2+ melanoma patient, stimulated with a GP100-derived epitope and semi-allogeneic hybrids, lysed target cells presenting this peptide more efficiently than lymphocytes stimulated with GP100 peptide alone. Phenotypic analysis with GP100/HLA-A2 tetramer complexes also demonstrated a significant increase in the size of the GP100-specific CD8+ lymphocyte pool when PBMC were stimulated with both peptide and semi-allogeneic hybrids. Analyses of PBMC from other donors further suggest that this stimulatory effect of semi-allogeneic hybrids results from an increase in the HLA-restricted recall response of CD8+ cytotoxic T lymphocytes against melanoma-derived antigens. Likewise, lymphocytes from an HIV-infected patient that had been stimulated with a mixture of HIV-derived peptides and semi-allogeneic hybrids also demonstrated significantly greater antigen-specific cytotoxicity and tetramer reactivity compared with those lymphocytes that had been stimulated with peptides alone. Our approach should provide useful information for the design of future clinical studies treating patients with melanoma or HIV with therapeutic vaccines consisting of a combination of semi-allogeneic hybrids and immunodominant antigenic peptides.