Clinical factors associated with outcome in solid tumor patients treated with immune-checkpoint inhibitors: a single institution retrospective analysis.

OBJECTIVES: Response to immune checkpoint inhibitor (ICI) remains limited to a subset of patients and predictive biomarkers of response remains an unmet need, limiting our ability to provide precision medicine. Using real-world data, we aimed to identify potential clinical prognosticators of ICI response in solid tumor patients. METHODS: We conducted a retrospective analysis of all solid tumor patients treated with ICIs at the Mount Sinai Hospital between January 2011 and April 2017. Predictors assessed included demographics, performance status, co-morbidities, family history of cancer, smoking status, cancer type, metastatic pattern, and type of ICI. Outcomes evaluated include progression free survival (PFS), overall survival (OS), overall response rate (ORR) and disease control rate (DCR). Univariable and multivariable Cox proportional hazard models were constructed to test the association of predictors with outcomes. RESULTS: We identified 297 ICI-treated patients with diagnosis of non-small cell lung cancer (N = 81, 27.3%), melanoma (N = 73, 24.6%), hepatocellular carcinoma (N = 51, 17.2%), urothelial carcinoma (N = 51, 17.2%), head and neck squamous cell carcinoma (N = 23, 7.7%), and renal cell carcinoma (N = 18, 6.1%). In multivariable analysis, good performance status of ECOG ≤ 2 (PFS, ORR, DCR and OS) and family history of cancer (ORR and DCR) associated with improved ICI response. Bone metastasis was associated with worse outcomes (PFS, ORR, and DCR). CONCLUSIONS: Mechanisms underlying the clinical predictors of response observed in this real-world analysis, such as genetic variants and bone metastasis-tumor microenvironment, warrant further exploration in larger studies incorporating translational endpoints. Consistently positive clinical correlates may help inform patient stratification when considering ICI therapy.

Combining immune checkpoint inhibition plus tyrosine kinase inhibition as first and subsequent treatments for metastatic renal cell carcinoma.

BACKGROUND: Immune checkpoint inhibitor/tyrosine kinase inhibitor (ICI/TKI) combinations are a new standard of care for the initial treatment of metastatic renal cell carcinoma (mRCC). Their efficacy and toxicity beyond the first-line setting remain poorly defined. METHODS: We retrospectively reviewed charts for 85 adults with mRCC of any histology receiving combination of ICI/TKI in any line of treatment at two academic centers as of 05/01/2020. We collected clinical, pathological, and treatment-related variables. Outcomes including objective response rate (ORR), progression-free survival (PFS), and toxicity were analyzed via descriptive statistics and the Kaplan-Meier method. RESULTS: Patients received pembrolizumab, nivolumab, avelumab, or nivolumab-ipilimumab, with concurrent use of sunitinib, axitinib, pazopanib, lenvatinib, or cabozantinib. Thirty-three patients received first-line ICI/TKI therapy, while 52 received ≥ second-line ICI/TKI. The efficacy of ICI/TKI therapy decreased with increasing lines of treatment (ORR: 56.7%, 37.5%, 21.4%, and 21%; median PFS [mPFS]: 15.2, 14.2, 10.1, and 6.8 months, for first, second, third, and ≥ fourth line therapy, respectively). In the ≥ second-line setting, ICI/TKI was most useful in patients who received ICI only, with an ORR of 50% and a mPFS of 9.1 months. Efficacy was limited in patients who received both TKI and ICI previously, with an ORR of 20% and a mPFS of 5.5 months. Overall, ≥ second-line ICI/TKI was tolerable with 25 of 52 (52%) patients developing grade ≥3 adverse events. CONCLUSIONS: ICI/TKI combination therapy is feasible and safe beyond the first-line setting. Prior treatment history appears to impact efficacy but has a lesser effect on safety/tolerability.

Salvage nivolumab and ipilimumab after prior anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma: A meta-analysis.

BACKGROUND: Salvage nivolumab and ipilimumab after prior anti-PD-1/PD-L1 therapy is frequently used off-label for clear cell metastatic renal cell carcinoma (mRCC). However, limited data are available to guide such therapy. We performed a meta-analysis to characterize further the safety and efficacy of salvage nivolumab and ipilimumab. METHODS: We conducted a systematic review in accordance with PRISMA. Studies of salvage nivolumab and ipilimumab in patients with mRCC published in English before June 1, 2021 were included. We also included patients treated at the Ohio State University from 2012 to 2020 through a retrospective chart review. The included studies were further stratified into adaptive and standard groups based on their designs. We calculated objective response rate (ORR) and adverse events (AEs) via pooled data and quantitative synthesis using the Stata metaprop procedure. A conservative random effect model was used to combine values. RESULTS: A total of 7 studies and 310 patients were included. Salvage nivolumab and ipilimumab had an ORR of 14% (95% CI, 0.09-0.21) and median progression-free survival ranged between 3.7 and 5.5 months. Four out of the seven studies were standard design, whereas the other three studies were adaptive. The ORR was numerically higher in the standard group compared with the adaptive group (21% and 9-10%, respectively). The responses to salvage nivolumab and ipilimumab did not correlate with the initial anti-PD-1/PD-L1 responses (odds ratio = 1.45; p = 0.5). Grade ≥3 AEs occurred in 26% of the patients (95% CI, 0.19-0.33). There were no new safety signals observed in this study. CONCLUSION: Salvage nivolumab and ipilimumab demonstrated moderate antitumor activity and a manageable safety profile in patients with mRCC who had prior anti-PD-1/PD-L1 therapy. IMPLICATION FOR PRACTICE: Patients with metastatic renal cell carcinoma have limited treatment options after progressive disease on anti-PD-1/PD-L1 therapy. The role of salvage nivolumab and ipilimumab in this patient population is poorly defined. The studies on this highly important and clinically relevant topic are limited by small sample sizes. The results from our meta-analysis suggest that nivolumab and ipilimumab are feasible in the salvage setting with moderate efficacy and acceptable toxicity profile. The response rates differ with different treatment designs. This information will be beneficial to guide clinical decision-making and accurately estimating toxicity.

Predicting toxicity-related docetaxel discontinuation and overall survival in metastatic castration-resistant prostate cancer: a pooled analysis of open phase 3 clinical trial data.

BACKGROUND: Docetaxel is widely used in metastatic castration-resistant prostate cancer (mCRPC), however its optimal use remains unclear in the current treatment landscape. Biomarkers to predict Docetaxel toxicity may help optimize treatment selection. We aimed to create a predictive model for toxicity-related Docetaxel discontinuation (TRDD). METHODS: Through Project Data Sphere, we accessed individual patient data from the control arms of three frontline mCRPC trials: ASCENT2, VENICE, and MAINSAIL. The inclusion criteria for these trials were all similar and included patients with chemotherapy-naïve mCRPC. The primary outcome was occurrence of TRDD. A competing risks regression (CRR) was used to predict TRDD, after accounting for the occurrence of competing events (death or progression). The output of the model was used as the dependent variable on a classification and regression tree (CART) to identify risk groups for TRDD. RESULTS: Overall, 1568 patients were considered. Pooled CI of TRDD was 19% after accounting for competing events (death: 474; progression: 59) within 12 months of starting treatment. To build a risk calculator we relied on a CRR that ultimately included age, ECOG performance status, AST, bilirubin, use of analgesics, and presence of diabetes and chronic kidney disease. The CART analysis identified three risk groups that were named: low (model-derived TRDD risk ≤24%), intermediate (25-64%), and high (≥65%) risk group. In each risk group, probability of TRDD during treatment was 14%, 58%, and 79%, and median OS was 24 months, 20 months, and 13 months, respectively (p < 0.001). CONCLUSIONS: Treatment selection in mCRPC remains a challenge. Our model can help clinicians balance Docetaxel toxicity and efficacy. The three risk categories that we identified correlated with OS and this is particularly useful for an optimal shared decision-making process.

Risk Factors for Emergency Room and Hospital Care Among Patients With Solid Tumors on Immune Checkpoint Inhibitor Therapy.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are being increasingly used across cancer types. Emergency room (ER) and inpatient (IP) care, common in patients with cancer, remain poorly defined in this specific population, and risk factors for such care are unknown. METHODS: We retrospectively reviewed charts for patients with solid tumors who received >1 ICI dose at 1 of 2 sites from January 1, 2011 to April 28, 2017. Demographics, medical history, cancer diagnosis/therapy/toxicity details, and outcomes were recorded. Descriptive data detailing ER/IP care at the 2 associated hospitals during ICI therapy (from first dose to 3 mo after last dose) were collected. The Fisher exact test and multivariate regression analysis was used to study differences between patients with versus without ER/IP care during ICI treatment. RESULTS: Among 345 patients studied, 50% had at least 1 ER visit during ICI treatment and 43% had at least 1 IP admission. Six percent of ER/IP visits eventually required intensive care. A total of 12% of ER/IP visits were associated with suspected or confirmed immune-related adverse events. Predictors of ER care were African-American race (odds ratio [OR]: 3.83, P=0.001), Hispanic ethnicity (OR: 3.12, P=0.007), and coronary artery disease (OR: 2.43, P=0.006). Predictors of IP care were African-American race (OR: 2.38, P=0.024), Hispanic ethnicity (OR: 2.29, P=0.045), chronic kidney disease (OR: 3.89, P=0.006), angiotensin converting enzyme inhibitor/angiotensin receptor blocker medication use (OR: 0.44, P=0.009), and liver metastasis (OR: 2.32, P=0.003). CONCLUSIONS: Understanding demographic and clinical risk factors for ER/IP care among patients on ICIs can help highlight disparities, prospectively identify high-risk patients, and inform preventive programs aimed at reducing such care.

On the Transition to Attendinghood.

Medical education and training consists of a series of stepped transitions, each marked by increasing autonomy and responsibility. Perhaps the most formidable transition begins upon the completion of one's training and stretches well into the first year of "attendinghood." This period is often defined by colossal changes that can extend far beyond the workplace and that are largely inconceivable beforehand. These changes can have important implications for job satisfaction, well-being, and resilience, especially in oncology, where rates of work-related burnout are particularly high. Unfortunately there is no "standard of care" or evidence-based guideline on how best to approach this period. However, it must be highlighted and deliberately discussed among current fellows and recent graduates not only to stimulate further study but also to provide support and community for those approaching or going through this transition.

Increased bleeding risk associated with concurrent vascular endothelial growth factor receptor tyrosine kinase inhibitors and low-molecular-weight heparin.

BACKGROUND: Some cancer patients who are diagnosed with thromboembolism may require dual treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and factor Xa inhibitors (low-molecular-weight heparin [LMWH] or direct oral anticoagulants [DOACs]). However, to the authors' knowledge, the safety of such combinations has not been well characterized. METHODS: Patients with advanced cancer who were treated with concurrent VEGFR TKIs and factor Xa inhibitors between 2010 and 2018 at The Ohio State University Comprehensive Cancer Center were included. Charts were reviewed retrospectively for clinically significant bleeding events occurring during concurrent treatment compared with those occurring during factor Xa inhibitor therapy alone, using each patient as their own control. The Fisher exact test was used to compare distribution of bleeding severities. The Cox proportional hazards model was used to compare bleeding risk between groups. RESULTS: Among 86 patients, there were 29 clinically significant bleeding events (including 8 major bleeding events) reported during concurrent treatment and 17 events (including 4 major bleeding events) reported during factor Xa inhibitor therapy alone over a median follow-up of 63 days. Concurrent treatment was associated with significantly higher risks of overall bleeding (hazard ratio, 2.45; 95% confidence interval, 1.28-4.69 [P = .007]) and first-onset bleeding (hazard ratio, 2.23; 95% confidence interval, 1.13-4.42 [P = .02]). Analysis of 6-month bleeding risk and the subgroups of patients treated with concurrent TKIs and LMWH versus LMWH alone demonstrated a similar trend. The sample size was inadequate for comparisons between treatment with concurrent TKIs and DOACs versus DOACs alone. CONCLUSIONS: Concurrent treatment with VEGFR TKIs and LMWH was found to be associated with a significantly increased risk of bleeding events when compared with LMWH therapy alone.

Estimating cost implications of potentially avoidable hospitalizations among Oncology Care Model patients with prostate cancer.

PURPOSE/OBJECTIVES: We sought to estimate the expected cost savings generated if a set of potentially avoidable hospitalizations (PAHs) among oncology care model (OCM) patients with prostate cancer were shifted to an acute care model in the outpatient setting. METHODS: We previously identified a set of 28 PAHs among OCM prostate cancer patients. Outpatient management costs for a characteristically similar cohort of cancer patients were obtained from our institution's ambulatory acute-care Oncology Care Unit (OCU). We excluded OCU visits resulting in hospitalization, involving non-cancer diagnoses, and those missing clinical/financial information. Exact-matching based on the strata of age, categorically-defined presenting complaint, and systemic disease was used to match PAHs to OCU acute care visits. PAH costs obtained from OCM data were compared to costs from matched OCU visits. RESULTS: We identified 130 acute care OCU visits, of which 47 met inclusion criteria. Twenty-four PAHs (89%) matched to 26 of these OCU visits. PAHs accounted for 5.8% of OCM expenditures during our study period. The mean inpatient cost among matched PAHs was $15,885 compared to $6,227 for matched OCU visits. Boot strapping within each match stratum produced a mean estimated cost savings of $12,151 (95% CI $10,488 to $13,814) per PAH. We estimate this per event savings to yield a 4.4% (95% CI 3.8% to 5.0%) an overall spending decrement for OCM prostate cancer episodes. CONCLUSIONS: PAHs contribute meaningfully to costs of care in oncology. Investment in specialized ambulatory acute care services for oncology patients could lead to substantial cost savings.

The Effect of Glucose Levels Prior to Hematopoietic Cell Transplantation on Post-Transplant Complications and Health Resource Utilization.

Background: Abnormal blood glucose (BG) levels during hematopoietic cell transplantation (HCT) are associated with increased infections, delayed engraftment, and prolonged hospitalization, though little is known about these associations. Materials and Methods: We retrospectively evaluated mean BG levels in the week prior to HCT and subsequent outcomes for 852 HCTs at our hospital from 1/2009 - 12/2013 pertaining to 745 patients. Outcomes included infections (pneumonia, C. difficile, positive cultures, administration of antimicrobials, or neutropenic fever), time-to-engraftment (TTE), and quality indicators (30- and 90-day readmission rates [RR] and median length-of-stay [LOS]). Results: 404 patients met the criteria for involvement in this study. The population was 55% male and was racially and ethnically mixed (White 38%, African American 23%, Hispanic 6%, Asian 7%, Other 21%). Mean age was 57+14 years. Significantly more patients in Group 2 were diagnosed with pneumonia (19%) compared with the Group 1 (7%) and Group 3 (10%) [p=.0054]. Patients in Group 2 also had significantly longer median LOS: Group 1-23 days, Group 2-26 days, Group 3-22 days [p = .0157]. No significant differences were noted in terms of the other infectious complications or in time-to-engraftment or readmissions. Conclusion: Pre-HCT BG trends may be a prognostic biomarker for adverse outcomes, and thus can help improve quality of care for HCT patients.

A pooled analysis of two phase II trials evaluating metformin plus platinum-based chemotherapy in advanced non-small cell lung cancer.

BACKGROUND: Despite a wealth of preclinical and observational data, prospective data regarding the use of metformin in lung cancer is extremely limited. METHODS: We pooled individualized data from two prospective trials evaluating metformin plus platinum-based chemotherapy, with or without bevacizumab, in non-diabetic patients with untreated advanced NSCLC. In addition to reporting on clinical efficacy and safety endpoints, we also explored metformin's activity in key molecular cohorts. RESULTS: 33 patients were included in the pooled analysis, of whom 70% were current or previous smokers. 82% had standard tissue molecular testing results available. KRAS, EGFR, and LKB1 mutation prevalence was 48%, 26%, and 8.3%, respectively. Composite median PFS was 6 months for all patients (95% CI: [1.36, 7.96]), 7.2 months for KRAS mutants (95% CI: [1.18, 9.21]), and 6.6 months for EGFR mutants (95% CI: [1.18, 15.29]). Composite median OS was 14.8 months for all patients (95% CI: [8.25, 19.99]), 17.5 months for KRAS mutants (95% CI: [8.86, 26.96]), and 13.3 months for EGFR mutants (95% CI: [2.60, 25.86]). Lymphopenia was the most common grade 3 AE (12%), followed by leukopenia, nausea, vomiting, and hypertension (9% each). There were 2 grade 4 AEs, neutropenia (21%) and sepsis (3%), and 1 grade 5 AE (colonic perforation) attributed to bevacizumab. CONCLUSION: Our results confirm the previously shown efficacy and tolerability of metformin in combination with chemotherapy and highlight encouraging activity in key molecular cohorts. Future efforts should build on this work by prospectively studying metformin in these molecular subgroups.

Identifying Potentially Avoidable Hospitalizations in Medicare Patients With Prostate Cancer: A Retrospective Analysis.

PURPOSE:: If identifiable, potentially avoidable hospitalizations (PAHs) can serve as an important target for cost containment efforts in oncology. METHODS:: PAHs among a cohort of Medicare patients with prostate cancer were identified using a two-stage consensus-driven review process. In stage 1, two clinicians independently evaluated admissions records using a case review form, which we modified from a previous study to assess for PAHs. In stage 2, any admissions that the reviewers disagreed on or were unsure of were re-examined in a larger group of clinicians to yield a consensus determination regarding avoidability. Univariable and multivariable regression analyses were performed to identify factors predictive of PAH. RESULTS:: There were 160 admissions among this cohort of 210 patients from January 2012 to June 2015, of which 99 were evaluable. Consensus-driven clinical review yielded an overall PAH rate of 28.3%. Factors associated with increased PAH risk were admission for symptoms related to cancer (odds ratio [OR], 7.33; P < .001), presence of a social contributor to admission (OR, 4.40; P = .014), and history of alcohol or drug abuse (OR, 4.93; P = .025). Admission for a noncancer condition was associated with decreased PAH risk (OR, 0.32; P = .011). On multivariable analysis, presence of a social contributor to admission (OR, 9.35; P = .002) and admission as a result of a noncancer condition (OR, 0.16; P = .038) remained predictive of PAH risk. CONCLUSION:: A significant proportion of hospitalizations among patients with prostate cancer are potentially avoidable. Understanding factors predictive of risk for PAH can help inform programs aimed at avoiding such admissions to improve overall care quality and value.

Interpreting Oncology Care Model Data to Drive Value-Based Care: A Prostate Cancer Analysis.

PURPOSE:: The Oncology Care Model (OCM) must be clinically relevant, accurate, and comprehensible to drive value-based care. METHODS:: We studied OCM data detailing observed and expected expenses for 6-month-long episodes of care for patients with prostate cancer. We constructed seven disease state-treatment dyads into which we grouped each episode on the bases of diagnoses, procedures, and medications in OCM claims data. We used this clinical-administrative stratification model to facilitate a comparative cost analysis, and we evaluated emergency department and hospital utilization and drug therapy as potential drivers of cost. RESULTS:: We examined 377 episodes of care, pertaining to 210 patients, that took place within our health system from January 2012 to June 2015. Ninety-six percent of episodes were assigned to clinically meaningful dyads. Excessive expenses were seen in metastatic, castration-resistant dyads containing second-line hormone therapy (ratio of observed to expected expenses [O/E], 2.66), chemotherapy (O/E, 2.09), and radium-223/sipuleucel-T (O/E, 3.01). An OCM update correcting for castration-resistant prostate cancer led to small differences in observed expenses (0% to +2%) but large changes in expected expenses (-17% to -27% for hormone-sensitive dyads and +136% to +141% for castration-resistant dyads). O/E increased up to 38% for hormone-sensitive dyads and decreased up to 58% for castration-resistant dyads. Emergency department and hospital utilization seems to drive cost for castration-resistant dyads but not for hormone-sensitive dyads. In the revised OCM model, overall O/E for all episodes improved by 22%, from 1.48 to 1.15. CONCLUSION:: Our experience with OCM highlights the limitations of administrative claims data within this model and illustrates a method of translating these data into clinically meaningful information to improve value.

Neoadjuvant Tyrosine Kinase Inhibition in Locally-advanced Non-small Cell Lung Cancer: Two Cases and a Brief Literature Review.

BACKGROUND: Despite their remarkable efficacy in metastatic non-small cell lung cancer (NSCLC), EGFR- and ALK-targeted therapies have not been shown to confer any survival benefit in stage III disease, even in subsets of patients with driver mutations. CASE STUDIES: Here, two patients with unresectable stage III NSCLC carrying mutations in the ALK (case 1) and EGFR (case 2) genes are presented. Treatment of the patient carrying an ALK mutation with an ALK inhibitor and the patient carrying an EGFR mutation with an EGFR inhibitor resulted in dramatic and durable responses. CONCLUSION: These cases demonstrated that ALK or EGFR mutation-positive stage III NSCLC patients can be treated with the corresponding inhibitors. They also highlight the urgent need for prospective data to assess their potential efficacy in order to improve patient outcomes.

Development and implementation of an academic cancer therapy stewardship program.

OBJECTIVES: Antibiotic stewardship is an integral aspect of hospital care, limiting the potential for resistance while working to minimize waste. A similar system is needed in oncology, given the rapid proliferation of new therapies and the challenges of navigating a complicated reimbursement environment. A "cancer therapy stewardship program" has never been described in the literature. Here, we detail our efforts to design and implement such a program and share lessons learned to inform future projects. STUDY DESIGN AND METHODS: For 1 year, a hematologist-oncologist (the "cancer therapy steward") at Mount Sinai Hospital was in charge of addressing all requests for nonformulary or off-label chemotherapeutic and supportive medications and regimens. Requests consisted of the rationale for use and supporting data from medical journal articles. This pilot initiative was focused mainly on inpatient malignant hematology. RESULTS: Sixty-seven requests were made by 23 physicians, and all requests were ultimately approved. Requests tended to fall into 3 categories: 1) use of a single drug in a setting not approved by the FDA, 2) use of multiple drugs in novel combinations not approved by the FDA, and 3) adding novel drugs to existing FDA-approved regimens. CONCLUSIONS: Our cancer therapy stewardship program yielded many useful insights into how our physicians face challenging clinical situations. It also helped to improve overall clinical quality and patient care by emphasizing the importance of value-based care and evidence-based medicine. Expanding this program will likely lead to many interesting experiments aimed at improving medical education and research, patient safety outcomes, and clinical quality.

Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial.

Background Metformin has been shown to have anti-neoplastic activity in non-small cell lung cancer (NSCLC) in both preclinical and observational studies, however this has never been prospectively evaluated. This single-arm phase II trial, while not fully accrued, is the first known prospective study evaluating the use of metformin with chemotherapy in advanced NSCLC. Methods Patients received carboplatin AUC 5 + pemetrexed 500 mg/m2 IV every 21 days for 4 cycles. For patients who achieved at least stable disease, maintenance pemetrexed was administered until progression or toxicity. Metformin was initiated at 1000 mg/day for week 1, 1500 mg/day for week 2, then 2000 mg/day thereafter, in divided doses. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and adverse events (AE). Tumor tissue was tested for LKB1/STK11 mutations, and non-fasting serum insulin levels were longitudinally assessed. Results Of a planned 50 patients, 14 were enrolled. ORR was 23% and median PFS was 3.9 months. Median OS was 11.7 months. No LKB1/STK11 mutations were identified. The most common AE were fatigue (42.9%), anemia, and nausea (28.6% each). The most common grade III AE was nausea (14.3%). No grade IV AE occurred. Mean duration of metformin treatment was 5.6 months. Conclusion Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed.