A Phase 2 Trial of Nab-paclitaxel in Combination With Anti-PD1 Therapy in Advanced Urothelial Cancer.

PURPOSE: Immune checkpoint inhibitor therapy and nab-paclitaxel have each shown efficacy in platinum-refractory advanced urothelial cancer. We conducted a single-arm phase 2 trial of the combination of nab-paclitaxel and pembrolizumab in platinum-refractory or cisplatin-ineligible advanced urothelial cancer (NCT03240016). MATERIALS AND METHODS: Eligible patients had RECIST 1.1 measurable and cisplatin-ineligible or platinum-refractory advanced urothelial cancer. Patients received nab-paclitaxel at starting dose of 125 mg/m2 intravenously on days 1 and 8 and pembrolizumab 200 mg intravenously on day 1 in 21-day cycles until progression, intolerable toxicity, or death. Nab-paclitaxel was permitted to be discontinued after 6 cycles. The nab-paclitaxel starting dose was reduced to 100 mg/m2 after planned interim analysis. Primary end point was overall response rate by RECIST 1.1. Secondary end points included safety/toxicity, duration of response, progression-free survival), and overall survival. RESULTS: Between February 2018 and April 2021, 36 response-evaluable patients were enrolled. There was an equal split of platinum-refractory and cisplatin-ineligible patients. Confirmed overall response rate was 50.0% (18/36) including 3 complete and 15 partial responses; 31/36 patients experienced some tumor shrinkage. At a median follow-up of 19.7 months, median duration of response was 4.4 months (95% CI: 4.0-8.6), median progression-free survival 6.8 months (95% CI: 4.4-not reached), and median overall survival 18.2 months (95% CI: 10.6-not reached). Grade ≥3 adverse events occurred in 21/36 patients including fatigue (n=6) and anemia (n=4). Ten patients had immune-mediated adverse events. CONCLUSIONS: The combination of nab-paclitaxel and pembrolizumab exhibited promising activity in advanced urothelial cancer and warrants further study in this population. After reduction in nab-paclitaxel starting dose, no unanticipated or unexpected toxicities emerged.

Liver injury during durvalumab-based immunotherapy is associated with poorer patient survival: A retrospective analysis.

Background: Durvalumab is approved for the treatment of lung cancer, advanced biliary tract cancers, and is also being evaluated in many other solid organ tumors. The aim of our study is to define the incidence, etiology, and outcomes of liver injury in consecutive patients receiving durvalumab-based immunotherapy. Patients and methods: Durvalumab treated patients between 1/2016 - 7/2020 were identified from the electronic medical record. Liver injury was defined as serum AST or ALT ≥ 5x upper limit of normal (ULN), ALP ≥ 2x ULN, bilirubin ≥ 2.5 mg/dl, or INR ≥ 1.5. Potential drug induced liver injury (DILI) cases were adjudicated using expert opinion scoring and confirmed with Roussel Uclaf Causality Assessment Method (RUCAM). Results: Amongst 112 patients, 58 (52%) had non-small cell lung cancer, the median age was 65 years, and 60% were male. The 21 (19%) liver injury patients were significantly more likely to harbor hepatic metastases (52% vs 17%, p=<0.001), experience tumor progression (67% vs 32%, p=0.01) or die (48% vs 11%, p<0.001) during follow-up compared to the 91 without liver injury. Using multivariate regression analysis, the development of liver injury during treatment as well as baseline hepatic metastases were independently associated with mortality during follow-up. Six of the 21 (29%) liver injury cases were adjudicated as probable DILI with four attributed to durvalumab and two due to other drugs (paclitaxel, pembrolizumab). Durvalumab was permanently discontinued in two DILI patients, three received corticosteroids, and one was successfully rechallenged. Only one patient with DILI developed jaundice, and none required hospitalization. Liver biochemistries normalized in all 6 DILI cases, while they only normalized in 27% of the 15 non-DILI cases (p=0.002). The 6 DILI patients also had a trend towards improved survival compared to those with other causes of liver injury. Conclusion: Liver injury was observed in 19% of durvalumab-treated patients and is associated with a greater likelihood of tumor progression and death during follow-up. The four durvalumab DILI cases were mild and self-limited, highlighting the importance of causality assessment to determine the cause of liver injury in oncology patients receiving immunotherapy.

Infrequent liver injury from cemiplimab in patients with advanced cutaneous squamous cell carcinoma.

Aim: To describe the incidence and outcomes of liver injury in patients with advanced cutaneous squamous cell carcinoma (cSCC) receiving cemiplimab. Methods: Charts of cSCC patients receiving cemiplimab between 28 September 2018 and 14 July 2020 were reviewed. Liver injury was determined using laboratory criteria, and causality assessment was completed. Results: Of 39 cemiplimab-treated patients, four (10.3%) developed liver injury. Two cases of hepatotoxicity were attributed to immune-mediated liver injury caused by cemiplimab and the two other cases were attributed to other causes. The four patients with liver injury had tumor responses and survival similar to those of the patients without liver injury. Conclusion: Liver injury arising during cemiplimab therapy is mild and infrequent in cSCC patients. Due to its favorable safety profile, cemiplimab should be considered in patients with cSCC and pre-existing liver disease.

A new type of cancer treatment termed 'immunotherapy' alters a patient's own immune system to attack the cancer cells. However, cemiplimab and similar medications can sometimes inadvertently injure the liver or other organs due to off-target activation of the immune system. This study describes the frequency and outcomes of liver injury observed in 39 patients with advanced skin cancer who were treated with cemiplimab at a single center. The authors found that 10% of patients developed liver injury, but only half of the cases were due to immune-mediated liver injury. The liver injury in these four patients was generally mild and self-limited. This study suggests that cemiplimab may be a preferred immunotherapy agent for patients with underlying liver disease due to its generally favorable side-effect profile, but further studies are needed.

A Pilot Study of Checkpoint Inhibitors in Solid Organ Transplant Recipients with Metastatic Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are increasingly used in various solid organ malignancies. However, there are limited data regarding their safety and efficacy in solid organ transplant (SOT) recipients. The aim of this study was to review our experience with ICIs in SOT recipients with advanced head and neck cutaneous squamous cell carcinoma (cSCC). METHODS: A retrospective review of ICIs used in SOT recipients from April 2011 to September 2019 was undertaken. Patient clinical and demographic features, ICI regimen, immunosuppression, treatment efficacy, and adverse events were reviewed. RESULTS: The seven SOT recipients (four kidney, two liver, one lung) were diagnosed with metastatic head and neck cSCC. All had undergone prior locoregional surgery and adjuvant radiation therapy. At a median of 10.8 years (range, 6.6-18.1) post-transplant, six were treated with cemiplimab and one with pembrolizumab after minimizing calcineurin inhibitors (CNIs) or conversion of CNI to mammalian target of rapamycin (mTOR) inhibitors. During a median follow-up of 7.1 months, overall tumor response rate was 57.1% with one complete responder and three partial responders. Four patients died at a median of 135 days after starting ICI with two dying from tumor progression and two dying from other causes. Regarding adverse events, one lung transplant recipient developed severe pneumonitis that resolved with high-dose steroids, and one renal transplant patient developed progressive renal injury and died of unrelated causes. The three patients who received prophylactic prednisone all responded to cemiplimab with preserved allograft function and no adverse events. CONCLUSION: Our data suggest that minimization of CNI and conversion of CNI to mTOR inhibitors along with judicious use of prophylactic steroids may allow for the safe use of ICIs in SOT recipients with advanced cSCC. Short-term efficacy appears promising, but prospective studies with further follow-up and a standardized protocol for prophylactic steroids are needed. IMPLICATIONS FOR PRACTICE: Solid organ transplant (SOT) recipients are at increased risk of developing malignancy because of long-term post-transplant immunosuppression. Although immune checkpoint inhibitors (ICIs) are increasingly shown to be successful in treating multiple types of cancer, SOT recipients have been excluded from clinical trials because of concerns regarding potential allograft rejection. This pilot study provides evidence that ICIs along with prophylactic steroids may be a safe and efficacious treatment option for selected SOT recipients with advanced cutaneous squamous cell carcinoma. However, further prospective studies using ICIs in this high-risk patient population are needed.

Utility of a Computerized ICD-10 Algorithm to Identify Idiosyncratic Drug-Induced Liver Injury Cases in the Electronic Medical Record.

INTRODUCTION: Idiosyncratic drug-induced liver injury (DILI) is an important cause of liver injury that is difficult to diagnose and identify in the electronic medical record (EMR). OBJECTIVE: Our objective was to develop a computerized algorithm that can reliably identify DILI cases from the EMR. METHODS: The EMR was searched for all encounters with an International Classification of Diseases, Tenth Revision (ICD-10) T code for drug toxicity and a K-71 code for toxic liver injury between 1 October 2015 and 30 September 2018. Clinically significant liver injury was defined using predetermined laboratory values. An expert opinion causality score (1-3 = probable DILI, 4/5 = non-DILI), Roussel Uclaf Causality Assessment Method (RUCAM) score, and severity score was assigned to each case. RESULTS: Among the 1,211,787 encounters searched, 517 had both an ICD-10 T code and a K-71 code, with 257 patients meeting the laboratory criteria. After excluding 75 cases of acetaminophen hepatotoxicity, the final study sample included 182 cases of potential DILI, with antineoplastics and antibiotics being the most frequently implicated agents. Causality assessment identified probable DILI in 121 patients (66.5%), whereas 61 (33.5%) had an alternative cause of liver injury. Although age, sex, race, and suspect drugs were similar, the probable DILI cases were more likely to present with a hepatocellular injury profile and have more severe liver injury than the non-DILI cases (p < 0.05). CONCLUSION: A computerized algorithm based on a combination of ICD-10 codes identified 182 potential DILI cases with 121 true positives, 61 false positives, and a positive predictive value of 66.5%. Future studies incorporating natural language processing may further improve the utility of this algorithm in identifying high-causality idiosyncratic DILI cases.

Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy.

BACKGROUND: Pembrolizumab immunotherapy has been associated with hepatotoxicity in 1%-10% of oncology patients treated in clinical trials. AIM: To describe the incidence, phenotypes and outcomes of liver injury in a large cohort of solid organ tumour patients receiving pembrolizumab METHODS: Liver injury was defined by serum alanine aminotransferase, alkaline phosphatase, and/or total bilirubin levels exceeding threshold values. The likelihood of drug-induced liver injury was adjudicated by expert opinion. RESULTS: Seventy (14.3%) of the 491 pembrolizumab-treated patients developed liver injury at a median of 62 days (6-478) and 71.4% had a cholestatic injury profile at onset. The median age, gender and tumour types of liver injury patients were similar to those without, but hepatic metastases (53% vs 21%, P < 0.01) and prior systemic and liver-directed therapy (71% vs 53%, P < 0.01) were more commonly observed in liver injury patients. During follow-up, liver injury patients were less likely to experience tumour remission (10% vs 40.4%) and had higher mortality (67.1% vs 33.7%). Only 20 (28.6%) liver injury cases were adjudicated as probable drug-induced hepatotoxicity; these patients were significantly more likely to present with an hepatocellular/mixed injury pattern (65% vs 12%), to receive corticosteroids (55% vs 12%) and had lower mortality (45% vs 76%) during follow-up. CONCLUSIONS: Oncology patients treated with pembrolizumab who develop liver injury experience poorer outcomes during follow-up. The low incidence of confirmed drug hepatotoxicity highlights the need for thorough medical evaluation before initiating corticosteroids to optimise patient care.