Faculty Bibliography

Tilsotolimod, an oligodeoxynucleotide TLR9 agonist, administered intra-tumorally, has been clinically evaluated. This compound has demonstrated the ability to induce changes within the tumor microenvironment, to convert non-inflamed cold tumors into inflamed hot tumors, with the hope that these tumors will be more responsive to immune checkpoint blockade.

Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered 'undruggable' owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRAS^G12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.

4-1BB has been considered a promising target in cancer immunotherapy for decades. Nevertheless, early 4-1BB-targeted agent demonstrated significant liver immuno-toxicity. A new wave of 4-1BB-based therapy is being developed to circumvent hepatotoxicity with bispecific molecule that directs 4-1BB agonism to the tumor microenvironment by targeting tumor-associated immune checkpoint molecule, PD-L1.

OBJECTIVES/OBJECTIVE:Treatment with epidermal growth factor receptor monoclonal antibodies extends life for patients with advanced colorectal cancers (CRCs) whose tumors exhibit wild-type KRAS, but KRAS testing may be underused. We studied the role of socioeconomic factors in the application of KRAS testing. MATERIALS AND METHODS/METHODS:We identified subjects with stage IV colorectal adenocarcinoma diagnosed 2010-2015 in the Surveillance, Epidemiology, and End Results (SEER) database. We used multivariable logistic regression models to evaluate associations between clinical/demographic factors and the rate of KRAS testing. We used multivariable-adjusted Cox proportional hazards models to assess survival. RESULTS:We identified 37,676 patients with stage IV CRC, 31.1% of whom were tested for KRAS mutations, of those who had documented KRAS testing, 44% were KRAS mutant. Patients were more likely to be tested if they were younger (odds ratio [OR]=5.10 for age 20 to 29 vs. 80+, 95% confidence interval [CI]: 3.99-6.54, P<0.01), diagnosed more recently (OR=1.92 for 2015 vs. 2010, 95% CI: 1.77-2.08, P<0.01), or lived in an area of high median household income (OR=1.24 for median household income of >$69,311 vs. <$49,265, 95% CI: 1.14-1.35, P<0.01). Patients were less likely to be tested if they had Medicaid (OR=0.83, 95% CI: 0.77-0.88, P<0.01) or were unmarried (OR=0.78, 95% CI: 0.75-0.82, P<0.0001). The risk of death was decreased in patients who received KRAS testing (hazard ratio=0.77, 95% CI: 0.75-0.80, P<0.01). CONCLUSIONS:We found a low rate of KRAS testing in CRC patients with those living in low-income areas less likely to be tested, even after controlling for Medicaid insurance. Our study suggests that socioeconomic disparities persist despite Medicaid insurance.

Immune checkpoint inhibitors (ICIs) are a class of medications targeting mostly the PD-1/PD-L1 and CTLA-4 immune pathways in the treatment of many cancers. Despite the encouraging success of ICIs, they are associated with immune-related adverse events as well as exacerbation of underlying autoimmune conditions. The treatment of these conditions often involves discontinuation of ICI in addition to the utilization of immunomodulatory agents. In this report, we discuss a case in which a patient with metastatic renal cell carcinoma experienced exacerbation of underlying paraneoplastic dermatomyositis after treatment with ICI. He was successfully continued on ICI with the use of intravenous immunoglobulin. The patient experienced adequate control of his myositis but also experienced deepening of his antitumor response.

Twenty to sixty percent of patients receiving immune checkpoint inhibitors (ICIs) experience high-grade immune-related adverse events (irAEs) which may prevent the continuation of treatment. Limited clinical evidence is available to guide treatment for these patients. Patients with stage IV or unresectable stage III melanoma at NYU Langone Health were reviewed from 1 January 2014 to 1 July 2019. Patients with first-line ICI systemic therapy, a high-grade irAE and a rechallenge with ICI therapy were included. Postrechallenge irAE recurrence, response rate, overall survival (OS) and progression-free survival (PFS) were evaluated. Postrechallenge irAEs recurred in 71.9% (n = 23/32) of patients at a median of 5.1 weeks from rechallenge, with 46.9% (15/32) recurring as high-grade events. Clinical response was achieved in 46.9% (15/32) of patients, including 40.6% (13/32) with a complete response and 6.3% (2/32) with partial response. Median OS from first ICI initiation was 85.4 weeks (45.7-140.7; 25th-75th percentile) and median PFS was 42.9 weeks (29.2-114.2; 25th-75th percentile). Patients with a shorter time to initial irAE and shorter time to postrechallenge irAE were at greater risk for disease progression [hazard ratio 7.80; 95% confidence interval (CI), 1.91-32.83; P = 0.004; hazard ratio 7.45, 95% CI, 1.57-35.35; P = 0.012). Those with greater duration to rechallenge (>10 weeks) were at lower risk for disease progression (hazard ratio 0.15, 0.03-0.68; P = 0.015). ICI rechallenge can be considered in patients with advanced melanoma, as the risk-benefit profile appears favorable. Treatment toxicity should be appropriately managed, as longer durations to rechallenge may lower the risk of disease progression.

Peritoneal carcinomatosis (PC) can occur as an advanced consequence of multiple primary malignancies. Surgical resection, radiation or systemic interventions alone have proven inadequate for this aggressive cancer presentation, since PC still has a poor survival profile. Photodynamic therapy (PDT), in which photosensitive drugs are exposed to light to generate cytotoxic reactive oxygen species, may be an ideal treatment for PC because of its ability to deliver treatment to a depth appropriate for peritoneal surface tumors. Additionally, epidermal growth factor receptor (EGFR) signaling plays a variety of roles in cancer progression and survival as well as PDT-mediated cytotoxicity, so EGFR inhibitors may be valuable in enhancing the therapeutic index of intraperitoneal PDT. This study examines escalating doses of benzoporphyrin derivative (BPD)-mediated intraperitoneal PDT combined with the EGFR-inhibitor cetuximab in a canine model. In the presence or absence of small bowel resection (SBR) and cetuximab, we observed a tolerable safety and toxicity profile related to the light dose received. Additionally, our findings that BPD levels are higher in the small bowel compared with other anatomical regions, and that the risk of anastomotic failure decreases at lower light doses will help to inform the design of similar PC treatments in humans.

OBJECTIVES/OBJECTIVE:Small studies suggest that a new entity of high-grade (HG) (G3, by Ki-67 or mitotic index) well-differentiated (histologically) gastrointestinal neuroendocrine tumors (NETs) exists, but prognosis and characteristics are unknown. We further characterized demographics and prognosis of patients with colorectal G3 NETs. MATERIALS AND METHODS/METHODS:We used the Surveillance Epidemiology and End Results (SEER) database to study colorectal NETs diagnosed from 2000 to 2015. We evaluated demographic, clinical, and tumor characteristics. We compared overall survival (OS) for G1-2 NET, G3 NET, and NEC (neuroendocrine carcinoma). We used logistic regression to detect grade associations and Cox proportional hazards models to examine predictors of survival. RESULTS:We identified 5894 cases with colorectal NET (5780 [98.1%] G1-2 and 114 [1.9%] G3); the cohort was 66% white, 47% male, and had a median age of 54. Patients with G3 NET were likely to be older (odds ratio [OR]: 2.23; 95% confidence interval [CI]: 1.19-4.19 for 60 to 69 vs. <50), unmarried (OR: 1.56; 95% CI: 1.02-2.38), and less likely to be diagnosed after 2010 (OR: 0.09; 95% CI: 0.06-0.15). OS for G3 NET (median, 36 mo; 95% CI: 13-92) fell between OS for NEC (median, 7 mo; 95% CI: 6-8), and G1-2 NET (median not reached, >120 mo). Among G1-3 NETs, black patients (hazard ratio [HR]: 1.30; 95% CI: 1.03-1.62), older patients (HR: 3.63; 95% CI: 2.63-5.01 for age 60 to 69 vs. <50), unmarried patients (HR: 1.40; 95% CI: 1.17-1.68), and those with HG features (HR: 3.97; 95% CI: 3.15-4.99) had worse survival. CONCLUSIONS:We defined a subset of G3 NETs that are HG and well differentiated, more common in older, unmarried patients, with a prognosis between that of NEC and G1-2 NETs. Our analysis adds the first national registry study in support of a new classification of nonpancreatic HG and well-differentiated NETs.