Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis.

BACKGROUND: Recent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and non-small cell lung cancer. These data are in line with growing preclinical evidence that the adaptive immune response may be more effectively stimulated earlier in the day. We sought to determine the impact of time-of-day ICI infusions on outcomes among patients with metastatic renal cell carcinoma (mRCC). METHODS: The treatment records of all patients with stage IV RCC who began ICI therapy within a multicenter academic hospital system between 2015 and 2020 were reviewed. The associations between the proportion of ICI infusions administered prior to noon (denoting morning infusions) and PFS and OS were evaluated using univariate and multivariable Cox proportional hazards regression. RESULTS: In this study, 201 patients with mRCC (28% women) received ICIs and were followed over a median of 18 months (IQR 5-30). The median age at the time of ICI initiation was 63 years (IQR 56-70). 101 patients (50%) received ≥20% of their ICI infusions prior to noon (Group A) and 100 patients (50%) received <20% of infusions prior to noon (Group B). Across the two comparison groups, initial ICI agents consisted of nivolumab (58%), nivolumab plus ipilimumab (34%), and pembrolizumab (8%). On univariate analysis, patients in Group A had longer PFS and OS compared with those in Group B (PFS HR 0.67, 95% CI 0.48 to 0.94, Punivar=0.020; OS HR 0.57, 95% CI 0.34 to 0.95, Punivar=0.033). These significant findings persisted following multivariable adjustment for age, sex, performance status, International Metastatic RCC Database Consortium risk score, pretreatment lactate dehydrogenase, histology, and presence of bone, brain, and liver metastases (PFS HR 0.70, 95% CI 0.50 to 0.98, Pmultivar=0.040; OS HR 0.57, 95% CI 0.33 to 0.98, Pmultivar=0.043). CONCLUSIONS: Patients with mRCC may benefit from earlier time-of-day receipt of ICIs. Our findings are consistent with established mechanisms of chrono-immunology, as well as with preceding analogous studies in melanoma and lung cancer. Additional prospective randomized trials are warranted.

Changes in Prescribing Patterns in Stage III Colon Cancer.

BACKGROUND: For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used. PATIENTS AND METHODS: To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018. RESULTS: A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47). CONCLUSIONS: Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

The Impact of Poorly Differentiated Histology on Immunotherapy in Advanced Gastrointestinal Cancers.

INTRODUCTION: Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have shown a correlation between immune cell infiltration and poorly differentiated cancers. This study evaluated the impact of poorly differentiated histology on survival in patients with advanced gastrointestinal cancers treated with immunotherapy. METHODS: This study was a retrospective, single-center analysis of patients with gastrointestinal cancers treated with CPIs between 2016 and 2021. Univariate and multivariable analyses were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor and patient characteristics, progression-free survival, and overall survival. RESULTS: A total of 123 patients were eligible and included in the analysis. Median age was 66 years (23-88 years). Majority had stage IV disease (89%), were white (65.5%), and were male (64.5%). Most common diagnoses were hepatocellular carcinoma (30.5%), gastric adenocarcinoma (16.5%), esophageal adenocarcinoma (17%), and colorectal cancer (19.8%). About 32% of the tumors were microsatellite instability-high (MSI-High/dMMR), with BRAF V600E mutation rate of 10%. About 25% of the patients received CPIs as initial treatment, while 35.5% had received two or more prior lines of therapy. Compared with well and moderately differentiated histology, patients with poorly differentiated tumors had a shorter median overall survival (mOS) (not reached [NR] vs. NR vs. 9.3 months, p = 0.0264). There was no statistically significant difference in median progression-free survival (mPFS) between histology types (2.5 vs. 4.2 vs. 2 months, p = 0.1314). On univariate survival analysis, moderately differentiated tumors correlated with a significantly longer mOS (HR: 0.48, CI: 0.24-0.93, p = 0.030) and mPFS (HR: 0.62, 95% CI: 0.38-1.00, p = 0.048) compared to poorly differentiated histology. Female patients (HR: 0.55, 95% CI: 0.34-0.90, p = 0.018) and the Eastern Cooperative Oncology Group (ECOG) of 1 (vs. ≥2) had significantly longer mPFS (HR: 0.58, 95% CI: 0.35-0.97, p = 0.036). ECOG of 1 also correlated with longer mOS (HR: 0.47, 95% CI: 0.23-0.94, p = 0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, 95% CI: 2.41-13.63, p < 0.001) and mOS (HR: 5.45, 95% CI: 1.64-18.12, p = 0.006). The number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, 95% CI: 1.03-1.39, p = 0.022) and mOS (HR: 1.23, 95% CI: 1.01-1.50, p = 0.045). On multivariable analyses, ECOG status of 0/1 versus ≥2 and MSI-High/dMMR versus MSS remained significantly associated with longer mPFS and mOS. There was no correlation with histologic differentiation status, race, or mutations such as BRAF V600E or KRAS. CONCLUSION: Results from this study demonstrate that poorly differentiated histology was associated with shorter mOS but was not associated with improved PFS in patients treated with CPI. Treatment-naïve patients, moderately differentiated tumors, female gender, ECOG 1, and MSI-High/dMMR were most likely to benefit from CPI.

Successful Liver Transplantation of Recurrent Fibrolamellar Carcinoma following Clinical and Pathologic Complete Response to Triple Immunochemotherapy: A Case Report.

INTRODUCTION: Fibrolamellar carcinoma (FLC) is a rare liver cancer that predominantly affects younger patients without a history of liver disease. Surgical resection is the cornerstone of therapy and represents the best potentially curative treatment option. Modest objective responses with cytotoxic chemotherapy alone or combined with immune checkpoint inhibitors (ICIs) have been reported; however, there are no established systemic therapy regimens for unresectable or metastatic FLC. CASE PRESENTATION: We report a case of a 23-year-old woman with FLC who presented with a 11.5 × 8.3 cm left liver mass and subsequently underwent resection as initial therapy. Molecular analysis of her surgical tissue revealed a DNAJB1-PRKACA fusion gene. The patient developed biopsy-proven recurrent FLC with multiple liver lesions but without any distant metastatic disease only 3 months after initial resection. In light of emerging data, the patient was treated with a novel triple therapy regimen including 5-fluorouracil (5-FU), interferon (IFN) alfa-2b, and nivolumab. Partial radiographic response was achieved after 4 treatments and complete response was achieved after 12 cycles with the combination. The patient received 2 more doses of 5-FU/IFN alfa-2b without nivolumab and underwent orthotopic liver transplantation (OLT) 6 months after the last dose of ICI. Pathological examination of the explanted liver remarkably confirmed pathologic complete response. She remains recurrence-free and is on active surveillance. DISCUSSION/CONCLUSION: For patients with unresectable/recurrent FLC with no distant disease, the combination of 5-FU, IFN alfa-2b, and nivolumab could be an effective systemic therapy option. The use of this chemoimmunotherapy regimen to downstage FLC prior to OLT may be worth investigating further.

Comparing Somatostatin Analogs in the Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: The 2 approved somatostatin analogs (SSAs) in the first-line treatment of advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are octreotide long-acting release (Sandostatin LAR) and somatuline depot (Lanreotide). The study's objective was to compare progression-free survival (PFS) and overall survival (OS) of patients (pts) with GEP-NETs treated with somatuline or octreotide LAR. Pts and Methods: Pts with advanced well-differentiated GEP-NET who received either SSA at Emory University between 1995 and 2019 were included after institutional review board approval. The primary end point was PFS, defined as time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.1, or clinical progression) or death. The secondary end point was OS. Kaplan-Meier curves were generated, and log-rank tests were conducted to compare the survival outcomes. RESULTS: A total of 105 pts were identified. The mean age was 62.1 years (SD ± 11.8). The male-to-female ratio was 51:54. The majority (N = 69, 65.7%) were white. Most pts had grade 2 (G2) disease (N = 44, 41.9%). Primary location was small bowel in 58 (55.2%), pancreas in 27 (25.7%), and other in 20 (19.0%). Functional tumors were defined in 32 pts distributed equally between the 2 groups. Distribution of treatment was similar in the 2 groups, with 54 receiving octreotide LAR and 51 receiving somatuline depot. The median PFS for the octreotide LAR and somatuline depot groups was 12 months (95% CI, 6-18 months) and 10.8 months (95% CI, 6-15.6 months), respectively, and the difference was not statistically significant (p = 0.2665). For pts with G1 disease, the median PFS for the octreotide LAR and somatuline depot was 8.4 versus 32.4 months, respectively, and the difference was not statistically significant (p = 0.159). For G2 disease, the difference in median PFS between octreotide LAR and somutaline depot groups was statistically significant (12 vs. 7.2 months, respectively; p = 0.0372). The mean follow-up time for octreotide LAR was 21.6 months versus 11.3 months for somatuline depot. CONCLUSIONS: Overall, there was no difference in PFS between octreotide LAR and somatuline depot for pts with well-differentiated, metastatic GEP-NETs. A prospective study is worth designing selecting for G.

Clinical Outcomes Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma Treated With Liposomal Irinotecan.

BACKGROUND: The NAPOLI-1 trial demonstrated that liposomal irinotecan in combination with fluorouracil (5-FU) and leucovorin (LV) prolonged survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. Real-world data on clinical outcomes associated with liposomal irinotecan in NAPOLI-1-based regimens is needed to further substantiate this. METHODS: This real-world, retrospective chart review study included patients with mPDAC who received NAPOLI-1-based regimens from six academic centers in the United States. Liposomal irinotecan initiation defined the index date. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier methodology. RESULTS: There were 374 patients evaluated; median age was 68 years, and 51% were female. Among 326 patients with baseline ECOG information, approximately 74% had ECOG score <2. Liposomal irinotecan was administered as a doublet with 5-FU in a NAPOLI-1-based regimen in the first line (1L; 16%), 2L (42%), and 3L+ (42%) of the metastatic setting. For patients treated in 1L, 2L, and 3L+, median [95% confidence interval (CI)] OS was 8.0 [5.1, 11.2], 7.3 [5.3, 8.8], and 4.6 [4.0, 5.7] months, and median [95% CI] PFS was 4.2 [2.2, 6.6], 3.0 [2.6, 3.7], and 2.0 [1.7, 2.2] months, respectively. CONCLUSIONS: Patients in a real-world setting treated with NAPOLI-1-based liposomal irinotecan doublet regimens at academic centers were older with poorer performance status compared to trial patients yet had similar outcomes and efficacy. Furthermore, liposomal irinotecan was frequently used in the 3L+ setting where no treatment has been approved and provided clinical benefit.

Safety and Efficacy of 7 Days on/7 Days off Versus 14 Days on/7 Days off Schedules of Capecitabine in Patients with Metastatic Colorectal Cancer: A Retrospective Review.

INTRODUCTION/BACKGROUND: The administration schedule of capecitabine for the treatment of metastatic colorectal cancer (mCRC) in clinical trials has been 14 days of drug with 7 days off in a 21 day cycle (14/7). In an effort to improve tolerability, an alternative every other week treatment (7/7) is often administered. The purpose of this study was to determine the safety and efficacy of administering 7/7 compared with 14/7 capecitabine dosing. MATERIALS AND METHODS: In this retrospective study, mCRC patients received capecitabine on a 7/7 or 14/7 schedule. The primary objective was to determine the tolerability of the respective dosing schedules, defined according to frequency of dose reductions and treatment delays. Secondary objectives included comparisons of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of dosing strategies. RESULTS: Of 175 included patients, 73 (41.7%) received the capecitabine 7/7 schedule and 102 (58.3%) received the 14/7 schedule. There was a statistically significant difference between the 7/7 and 14/7 groups with regard to dose reductions (4% vs. 29%; P < .001) and treatment delays (22% vs. 43%; P = .004). The incidence of any adverse effects (45% vs. 72%; P < .001) and specifically, palmar-plantar erythrodysesthesia (18% vs. 45%; P < .001), were significantly higher in the 14/7 group. No significant difference was seen with regard to ORR, PFS, or OS. CONCLUSION: Patients with mCRC who received the 7/7 schedule had significantly fewer dose reductions and treatment delays compared with patients who received the 14/7 schedule. Although no difference in efficacy outcomes were observed, prospective studies are needed to confirm these findings.

Mismatch Repair (MMR) Gene Alteration and BRAF V600E Mutation Are Potential Predictive Biomarkers of Immune Checkpoint Inhibitors in MMR-Deficient Colorectal Cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. MATERIALS AND METHODS: Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. RESULTS: A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). CONCLUSION: BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. IMPLICATIONS FOR PRACTICE: The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Retrospective study evaluating the safety of administering pegfilgrastim on the final day of 5-fluorouracil continuous intravenous infusion.

BACKGROUND: Pegfilgrastim, a long-acting granulocyte-colony-stimulating factor used to prevent neutropenia, is not indicated for administration within 24 h of completion of chemotherapy. The safety of administering pegfilgrastim in gastrointestinal cancer chemotherapy regimens containing continuous intravenous infusion of 5-fluorouracil (5-FUCI) on the day of completion of 5-fluorouracil has not been adequately studied. METHODS: An institutional review board-approved retrospective analysis of patients with a gastrointestinal malignancy receiving pegfilgrastim on the final day of 5-FUCI was conducted. The primary end point was to determine the incidence of grade 3 and grade 4 neutropenia and febrile neutropenia when pegfilgrastim was administered on the final day of 5-FUCI. The secondary endpoint was to determine rate of dose reductions and treatment delays. RESULTS: A total of 300 patients were reviewed from January 2010 to May 2017. The most common cancers were colorectal (25%) and pancreatic (60%), with 77% of patients having late stage disease. The risk of a patient developing grade 3 neutropenia was 0.010 (95% CI 0.002-0.029) and grade 4 neutropenia was 0.007 (95% CI 0.001-0.024). The risk of febrile neutropenia was 0.007 (95% CI 0.001-0.024). The risks of treatment delay and treatment reduction were 0.013 (95% CI 0.004-0.034) and 0.010 (95% CI 0.002-0.029), respectively. CONCLUSION: The low risk of grade 3 and grade 4 neutropenia, febrile neutropenia, as well as dose delays and/or reduction suggests that pegfilgrastim can be administered on the final day of 5-FUCI. Limitations of this study were that it was retrospective in nature and was conducted at a single institution.

Impact of Sarcopenia, BMI, and Inflammatory Biomarkers on Survival in Advanced Hepatocellular Carcinoma Treated With Anti-PD-1 Antibody.

BACKGROUND: Sarcopenia and inflammation are independently associated with worse survival in cancer patients. This study aims to determine the impact of sarcopenia, body mass index (BMI), and inflammatory biomarkers on survival in advanced hepatocellular carcinoma (HCC) patients treated with anti-PD-1 antibody-based immunotherapy. METHODS: A retrospective review of advanced HCC patients treated with immunotherapy at Winship Cancer Institute between 2015 and 2019 was performed. Baseline computed tomography and magnetic resonance images were collected at mid-L3 level, assessed for skeletal muscle density using SliceOmatic (TomoVision, version 5.0) and converted to skeletal muscle index (SMI) by dividing it by height (m2). Sex-specific sarcopenia was defined by the median value of SMI. The optimal cut for continuous inflammation biomarker was determined by bias-adjusted log-rank test. Overall survival (OS) was set as primary outcome and Cox proportional hazard model was used for association with survival. RESULTS: A total of 57 patients were included; 77.2% male, 52.6% Caucasian, 58.5% Eastern Cooperative Oncology Group performance status 0-1, 80.7% Child Pugh A. Treatment was second line and beyond in 71.9% of patients. The median follow-up time was 6 months. Sarcopenia cut-off for males and females was SMI of 43 and 39, respectively. 49.1% of patients had sarcopenia. Median OS was 5 versus 14.3 months in sarcopenic versus nonsarcopenic patients (Log-rank P=0.054). Median OS was 5 and 17.5 months in patients with BMI <25 and BMI ≥25, respectively (Log-rank P=0.034). Median OS was 3.6 and 14.3 months for patients with neutrophil-to-lymphocyte ratio (NLR) ≥5.15 versus NLR <5.15 (Log-rank P<0.001). In multivariable Cox regression model, higher baseline NLR was associated with worse OS (hazard ratio [HR]: 4.17, 95% confidence interval [CI]: 1.52-11.39, P=0.005). Sex-specific sarcopenia showed a trend of worse OS (HR: 1.71, 95% CI: 0.73-4.00, P=0.215) but was not statistically significant. BMI<25 was associated with worse OS (HR: 2.28, 95% CI: 0.92-5.65, P=0.076). In the association with progression free survival, neither baseline BMI nor sex-specific sarcopenia showed statistical significance. CONCLUSION: After controlling for baseline Child Pugh score and NLR, sex-specific sarcopenia does not predict OS. Baseline BMI and NLR together may predict OS in advanced HCC patients treated with anti-PD-1 antibody.

A concise review of the changing landscape of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related deaths in the United States, increasing by 2% to 3% annually, with a dismal 5-year survival rate of 18%. The Barcelona Clinic Liver Cancer criteria used to guide treatment considers performance status and assessment of liver function by Child-Pugh score in addition to tumor size and location. Curative therapies for HCC include surgical resection, liver transplantation, and tumor ablation. Patients with unresectable or inoperable lesions should be considered for arterially directed embolic therapy, systemic therapy, or radiation. Options for first-line systemic therapy of advanced HCC include sorafenib, lenvatinib, and atezolizumab plus bevacizumab. Nivolumab may be an option in patients with advanced HCC who are ineligible for tyrosine kinase inhibitors or other anti-angiogenic agents. Options for subsequent therapy following disease progression include regorafenib, cabozantinib, ramucirumab, lenvatinib, nivolumab, nivolumab plus ipilimumab, sorafenib, or pembrolizumab. Patients with advanced HCC are at a high risk of adverse effects because of baseline hepatic dysfunction, comorbidities associated with chronic liver disease, and potential drug-drug interactions. Improved tolerance of therapies for advanced HCC may lead to reduction in treatment discontinuation and contribute to better patient outcomes. Managed care pharmacists should understand the recent efficacy and safety data, guideline recommendations, and treatment algorithms for management of HCC.

Tacrolimus for the treatment of immune-related adverse effects refractory to systemic steroids and anti-tumor necrosis factor α therapy.

Immunotherapy treatments in oncology have garnered much attention and use throughout the past several years. With increased use and new approvals in many different types of solid tumors and hematological malignancies, practitioners in oncology should have an appreciation and understanding of the potential adverse effects of these unique treatment approaches. The most common adverse effects with immunotherapy treatment are immune-related adverse effects with activation of patients' immune systems against a wide array of tissues and organ systems. Immune-related adverse effects are typically treated first with high doses of immunosuppressive corticosteroids. Patients with immune-related adverse effects refractory to high dose corticosteroid treatment may receive anti-tumor necrosis factor α therapy in an attempt to halt the immune system from causing further organ dysfunction. However, these agents are not always successful and other immunomodulatory agents should be considered for refractory cases. Presented here are three patient cases supporting the use of the calcinuerin inhibitor tacrolimus to treat immune-related adverse effects refractory to corticosteroids and anti-tumor necrosis factor α.

Updates in pancreatic cancer: Modest gains and hopeful targets.

Pancreatic cancer is the twelfth most common cancer in the United States, representing 3.2% of all new cancer cases. While composing a small percentage of cancer diagnoses, pancreatic cancer is amongst the most lethal carcinomas, with an overall 5-year survival of 8.2% and incidence rates almost equivocal to death rates. By the time of diagnosis, a majority of patients will present with advanced stage disease. For patients with resectable disease, the estimated overall survival (OS) remains low at 20% as most will develop metastatic disease within 5 years. The lethality of this cancer is attributed to several factors including delayed presentation, lack of effective screening, and complex tumor biology and genetics. Data also suggest that even upon early presentation, pancreatic cancer is a systemic disease with micrometastasis present in the early stages. Traditional cytotoxic therapies have not been clinically impactful in pancreatic cancer, especially in advanced stages, and very little headway has been made in the development of new targeted therapies. As such, this review will discuss current advances in standard of care treatments and novel drug targets being researched.