Attrition and withdrawal in multiple myeloma randomized controlled trials: A systematic review.

OBJECTIVES: Patients with multiple myeloma (MM) enrolled in randomized control trials (RCTs) discontinue treatment for various reasons; however, no prior study has analyzed reasons for discontinuation. We performed a systematic review of MM RCTs to investigate reasons for treatment discontinuation, imbalances between trial cohorts, and reporting practices. METHODS: A comprehensive search for RCTs in MM from 2015 to 2021 identified 45 studies meeting inclusion criteria. RESULTS: Of 21 236 randomized patients, 10 161 (47.8%) discontinued therapy by primary endpoint ascertainment. Causes of discontinuation included progression (n = 4790; 22.6% of randomized patients); toxicity (n = 2569; 12.1%); patient/physician withdrawal (n = 1200; 5.7%) and death (n = 495; 2.3%). Of randomized patients, 20 914 (98.5%) were included in the RCT analysis. Imbalances of attrition, defined as trials with greater than 5% absolute difference in discontinuation rate for reasons other than death, progression, and toxicity between intervention and control arms, were found in 11 (24.4%) studies. CONCLUSIONS: Although progression is the most common reason for RCT treatment discontinuation in patients with MM, over 10% discontinued due to toxicity. Furthermore, 24.4% of trials showed substantial imbalances between trial cohorts; raising concern for informative censoring and emphasizes the importance of detailed characterization of withdrawal in MM RCTs.

Tumor Molecular and Microenvironment Characteristics in EBV-Associated Malignancies as Potential Therapeutic Targets: Focus on Gastric Cancer.

Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of Indoleamine 2,3-Dioxygenase 1 (IDO1), synergism between H. pylori and EBV co-infection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism.

Targeted and Immunotherapy Approaches in HER2-Positive Gastric and Gastroesophageal Junction Adenocarcinoma: A New Era.

HER2-targeted therapy with the HER2 monoclonal antibody trastuzumab has achieved impressive outcomes in the first-line settings of patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma overexpressing HER2. However, considering that a substantial proportion of those patients eventually relapses, as well as the relatively limited performance of those agents in second-line settings, a deeper understanding of resistance mechanisms is needed for enhanced guidance for patients' therapeutic selection in the second-line setting and beyond. In this review, we highlight trastuzumab's (HER2-targeting agent) performance in patients with gastric or GEJ cancer, with insight into mechanisms of resistance. We also discuss the new integration of PD-1 inhibitor pembrolizumab into the trastuzumab for gastric cancer frontline regimen, the latest addition of trastuzumab deruxtecan to the treatment armamentarium, and the potential of pipeline HER2-targeting approaches and combinations in patients with gastric or GEJ adenocarcinoma.

Real world outcomes in patients with neuroendocrine tumor receiving peptide receptor radionucleotide therapy.

Aim: 177Lu-Dotatate (Lu-177), a form of peptide receptor radionuclide therapy (PRRT), was approved by Food and Drug Administration (FDA) for the treatment of somatostatin-receptor-positive neuroendocrine tumors (NETs) in 2018. Clinical trials prior to the FDA approval of Lu-177 showed favorable outcomes but there is limited published real world outcomes data. This study aims to describe and analyze real world outcomes of patients with NET who received Lu-177. Methods: After obtaining institutional review board approval, retrospective evaluation was performed to analyze the efficacy of Lu-177 for somatostatin receptor-positive gastro-entero-pancreatic NETs (GEP-NETs) patients at the University of Kansas Cancer Center between June 2018 and September 2021. This study aims to determine the response rate to the treatment of the entire cohort and subgroups. Results: A total of 65 patients received Lu-177 of which 58 completed treatment. The 58 patients had a median age of 61.5 years, 24 females and 34 males, 86% Caucasian and 12% black. The origins of NETs were primarily small bowel (n = 24) and pancreatic (n = 14). Pathology showed grades 1 (n = 21), 2 (n = 25), and 3 (n = 4) and were primarily well-differentiated tumors (n = 4). Among the cohort, 52 patients had imaging to assess response with 14 (26.9%) patients with partial response (PR), 31 (59.6%) with stable disease (SD), and 7 (13.5%) with progressive disease (PD). In a subset analysis, patients with non-functional disease (n = 29) had higher rates of PR 42.3% (compared to 11.5%, P = 0.0147) and higher disease control rate of 96% (compared to 78%, P = 0.042) than patients with functional disease (n = 29). Patients with non-functional disease had a lower PD of 3.85% (compared to 23%, P = 0.0147) than those with functional disease. Conclusions: This real world outcomes analysis of NETs treated with Lu-177 shows improved PR when compared to the initial clinical trials and is promising for patients. In addition, patients with non-functional tumors were found to have a statistically significant improved response rate which has not been described in the literature before. If these study findings are validated in a larger cohort they may guide patient selection for Lu-177 therapy in the future.

Characterization of Age-Associated, Neutrophil-to-Lymphocyte Ratio (NLR) and Systemic Immune-Inflammatory Index (SII) as Biomarkers of Inflammation in Geriatric Patients with Cancer Treated with Immune Checkpoint Inhibitors: Impact on Efficacy and Survival.

BACKGROUND: Geriatric patients (≥80 years) are underrepresented in immune checkpoint inhibitor (ICIs) clinical trials. However, their unique biology may affect their response to ICIs. There are currently no established biomarkers of the response to ICIs in adult patients with cancer that can help with patient selection. METHODS: We built a multicenter, international retrospective study of 885 patients (<80 years: n = 417, 47.12%; ≥80 years: n = 468, 52.88%) with different tumor types treated with ICIs between 2011 and 2021 from 11 academic centers in the U.S. and Europe. The main outcome measures were objective response rates (ORR), progression-free survival (PFS) and overall survival (OS) stratified by age and circulating inflammatory levels (neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammatory index (SII)). RESULTS: Patients ≥80 years with low NLR (NLR-L) and SII (SII-L) had significantly higher ORR (vs. high NLR [NLR-H], p < 0.01 and SII-H, p < 0.05, respectively). At median follow-ups (13.03 months), and compared to SII-H, patients with SII-L had significantly longer median PFS and OS in patients <80 (p < 0.001), and ≥80 years (p < 0.001). SII-L was independently associated with longer PFS and OS (HR: 0.61 and 0.62, respectively, p < 0.01). CONCLUSION: Lower inflammation pre-ICI initiation may predict an improved response and survival in geriatric patients with cancer.

Oncolytic Viruses as an Adjunct to Immune Checkpoint Inhibition.

Utilizing viruses in the treatment of cancer, or oncolytic viral therapy (OVT), began in the 1950s with the idea that viruses could invade and destroy cancer cells. Barriers to this approach included a lack of specificity towards cancer cells and intolerable toxicities. However, it was discovered that OVT increases cytokines such as interferon gamma and interleukins within the tumor microenvironment. This "priming" of the tumor microenvironment can lead to an improved innate immunologic response to tumor cells. An "OVT-as-monotherapy" approach has led to modest tumor response rates that have unfortunately not translated well in clinical trials. Currently, only one OVT agent-talimogene laherparevec (TVEC)-has been approved by the FDA for unresectable melanoma with limited visceral metastases. Further advancements in immunotherapy combined with improved viral engineering over the last decade have paved the way for a renewed focus on OVT. For example, various viruses have been modified to infiltrate and upregulate PD-L1 signaling within tumor cells. Upregulation of PD-L1 on tumor cells can increase tumor cell response to immunotherapies that utilize the interaction between PD-L1 on tumor cells and PD-1 on lymphocytes to allow for immune cell destruction of cancer cells. Combining OVT and immunotherapy offers more promise than OVT as monotherapy. Currently, several are actively investigating the combinatorial approach of OVT and immunotherapy in treating non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer, melanoma, pancreatic cancer, multiple myeloma, and head and neck squamous cell carcinoma. In this review, we will discuss the history of OVT including its limitations as a monotherapy. We will also discuss the background of combining OVT and immunotherapy including possible benefits and pitfalls of this approach. Lastly, we will review current clinical trials investigating OVT and immunotherapy in multiple cancers.

Immunoglobin A Deficiency and Squamous Cell Carcinoma With a Rare Presentation as Anal Cancer.

Selective immunoglobin A deficiency (IgAD) is the most common immunodeficiency disorder in the western world. Cancer is the most common cause of death in these individuals. Various cases have been reported of squamous cell carcinoma (SCC) in IgAD at sites like skin, oral cavity, and lung. Here we present a rare case of SCC occurring as anal cancer. No other reports to our knowledge describe this rare presentation. A 54-year-old Caucasian woman with asymptomatic partial IgAD presented with a palpable anal mass. Further evaluation showed stage IIIa SCC anal cancer (T1N1M0). Additional workup showed positive human papilloma virus (HPV) serology and positive HPV immunohistochemistry studies. The patient achieved complete response with chemoradiation with her most recent imaging and anorectal exam showing no evidence of cancer recurrence at 3 years follow-up. This case highlights the association between IgAD and malignancy. Although IgAD is the most common primary antibody deficiency, this patient's case presents a rare instance of anal SCC in an IgA-deficient individual. Studies show an association between HPV infection and SCC, but few include IgA-deficient individuals. Patients with IgAD and other immunodeficiencies are at higher risk for HPV infection and therefore may be at a higher risk of SCC. With widespread use of the HPV vaccine, the medical community should be aware of its importance in cancer prevention for these patients. Further studies are needed to evaluate relationships between IgAD, HPV infections, SCC cancer, and the role that the HPV vaccine has in cancer prophylaxis.