Background
Immune‐related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is ...not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated.
Methods
This is a real‐world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n = 370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12‐week landmark sensitivity‐adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models.
Results
Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty‐seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached NR), shorter among those receiving only systemic steroids (SSs) (84.2 months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3 months; 95% CI, 6–20.1 months) (p < .001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable‐adjusted analysis (p < .001). Similar results were noted with anti–programmed death 1 (PD‐1) monotherapy and combination anti–PD‐1 plus anti–cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) therapy, and with 12‐week landmark sensitivity analysis (p = .01).
Conclusions
These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary.
This real‐world, multicenter, retrospective study of patients with advanced melanoma who received immune checkpoint inhibitors (ICIs) suggests that the use of systemic steroids (SSs) or immunosuppressive agents (ISAs) for the management of immune‐related adverse events (irAEs) is not associated with inferior ICI efficacy, which supports their use when necessary. These data further suggest that irAEs and their management with SSs or other ISAs are predictive biomarkers of ICI efficacy.
BackgroundImmune checkpoint inhibitors (ICIs), particularly the combination of anti-CTLA4 and anti-PD1, have demonstrated efficacy in treating patients with advanced melanoma. Although ICIs, whether ...administered individually or in combination, can lead to immune-related adverse events (irAEs), the clinical factors that predict the risk of irAEs are still uncertain. The objective of this study is to build machine learning (ML) models to predict whether patients will develop irAE(s) for melanoma patients receiving Immune-Oncology (IO) therapy and find the corresponding important factors.MethodsIn our single-center study utilizing electronic medical records, we identified patients with advanced melanoma who received anti-PD-1 and anti-CTLA4 between January 2011 and April 2018. Baseline demographics, laboratory parameters1 and derived ratios, treatment history, cancer-related mutations, and irAEs were collected. The evaluation of irAE types and grades was based on CTCAE V4.03. A total of 224 patients were included in the study cohort, comprising 138 patients who developed one or more irAEs and 86 patients who remained irAEs-free. Eight ML models were trained with 80% of the data with five-fold cross-validation and tested with the remaining 20% of data. The area under the receiver-operating curve (AUROC) was used to assess ML models. Important features affecting the model were analyzed based on the model with the best performance by SHAP value.2 ResultsWe employed eight machine learning models, including logistic regression, support vector machine, bagging k-nearest neighborhood (BKNN), random forest, Bernoulli Naive Bayes (BNB), etc. The BKNN and BNB models exhibited the highest AUROC score, achieving scores of 80.65% and 79.37%, respectively. According to the AUROC curve shown in (figure 1), BNB was chosen as the superior model for accurately predicting irAE development. The most important three features selected from the BNB model are the utilization of nivolumab and ipilimumab therapy in combination, pretreatment ECOG score of 0, and blood eosinophil count, as shown in (figure 2).ConclusionsOur study leverages comprehensive variables to predict irAE development for patients with melanoma treated with ICI. The findings demonstrate the predictive capability of ML models, with the BNB model exhibiting the highest performance. These outcomes underscore the promising prospects of ML techniques not only in melanoma but also in other cancer diseases treated with ICI. To address the limited sample size, we will involve more institutions in the data registry. Our future direction involves incorporating additional variables, like pre-treatment auto-antibodies, to predict irAE grade and type, enhancing irAE prediction.ReferencesHopkins AM, Rowland A, Kichenadasse G, Wiese MD, Gurney H, McKinnon RA, Karapetis CS, Sorich MJ. Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers. Br J Cancer. 2017 Sep 26;117(7):913–920. doi: 10.1038/bjc.2017.274. Epub 2017 Aug 24. PMID: 28950287; PMCID: PMC5625676.Singh R, Lanchantin J, Sekhon A, Qi Y. Attend and Predict: Understanding Gene Regulation by Selective Attention on Chromatin. Adv Neural Inf Process Syst. 2017 Dec;30:6785–6795. PMID: 30147283; PMCID: PMC6105294.Abstract 1317 Figure 1Abstract 1317 Figure 2
BackgroundEstrogen and progesterone influence the immune system and thus may also influence clinical outcomes for patients (pts) with cancer receiving immune checkpoint inhibitor (ICI) therapy. ...Hence, we investigated if gender, premenopausal (PREMENO), and postmenopausal (POSTMENO) female states influenced ICI-associated clinical outcomes.MethodsIn our multicenter study based on real-world data, we identified pts receiving anti-PD-1 or anti-PD-L1 PD(L)-1 ICI monotherapy between 1/2011 to 4/2018 with follow-up until 1/2021 using pharmacy records. Immune-related adverse events (irAEs) by CTCAE V4.03, and physician-assessed tumor responses and time to treatment failure (TTF) were collected. Women under the age of 55 years were considered PREMENO following the World Health Organization’s suggested average menopausal age.1 We further investigated the non-small cell lung cancer (NSCLC) cohort receiving PD(L)-1 ICI in the metastatic setting for ICI efficacy analysis. Univariate analysis, multivariable logistic regression models, and Kaplan-Meier analyses were used to assess differences between male vs. PREMENO vs. POSTMENO.ResultsWe identified 913 pts receiving PD(L)-1 ICI: 58% (n=528) nivolumab, 35% (320) pembrolizumab, 5% (47) atezolizumab, and 2% (18) others. The median age for the entire cohort (EC) was 68 years, 56% (514) were male, 36% (328) POSTMENO, 7% (67) PREMENO, 65% (591) White, and 21% (192) African American. The most common tumor types were NSCLC and melanoma in 46% (417) and 12% (109), respectively. Any grade and grade ≥3 irAEs were 32% (290) and 8% (76) for the EC. No difference among POSTMENO vs. PREMENO vs. male was noted for overall survival (OS) (p=0.2) or TTF (p=0.2). Similarly, no difference in any grade irAEs was noted among the study cohorts (p=0.24). Among 393 pts with NSCLC, 51% (202) were male, 44% (171) POSTMENO, and 5% (20) PREMENO. The NSCLC group consisted of 60% (239) White, 28% (109) African American, 15% (60) with a history of autoimmune disease, and 33% (128) with <2 sites of metastasis. Again, no difference in OS (p=0.6) or TTF (p=0.8) was observed among the three NSCLC study cohorts. Any grade irAEs were noted in 30% (115) and grade ≥3 irAEs in 7% of NSCLC patients (28). No difference in any grade irAEs was noted for the three NSCLC study cohorts (p=0.12).ConclusionsIn our study, gender, including female menopausal status, did not influence ICI safety or efficacy outcomes. While these findings are reassuring, further prospective studies, including pts with diverse cancer types and additional ICI regimens, are needed to universalize these findings.Ethics ApprovalThis study was approved by the Georgetown University Medical Center Institutional Review Board; approval number MODCR00002093
BackgroundPatients (pts) receiving immune checkpoint inhibitor (ICI) therapy can experience periods of prolonged disease control after treatment discontinuation. Previous studies have used ...treatment-free survival (TFS) to characterize this interval in pts with advanced melanoma (AM) and non-small cell lung cancer (NSCLC).1–3 To date, evaluation of TFS has largely been performed using clinical trial data. Here, we report TFS outcomes in patients with AM and NSCLC receiving ICI therapy over a 3-year timespan using real-world registry data.MethodsData were obtained using a multi-site immuno-oncology registry of pts receiving ICI therapy from Georgetown-MedStar Health and Hackensack Meridian Health between January 2011 and April 2018. Pts with AM and NSCLC were included and sub-stratified by line of therapy and treatment type for first-line therapy as follows: NSCLC: anti-PD-(L)1 monotherapy; AM: ICI monotherapy (anti-CTLA-4 or anti-PD-(L)1) or the combination. Survival functions were estimated using the Kaplan-Meier (KM) method. TFS was defined as the area between two KM curves for time from initiation to final dose of ICI therapy and time from ICI initiation to initiation of subsequent systemic therapy, death, or referral to hospice. The area between KM curves, including TFS, was estimated using (3-year) restricted mean survival time (RMST).ResultsTwo-hundred ninety pts with AM and 408 pts with NSCLC were included. The 3-year mean TFS was 9.2 months in the AM cohort and 4.0 months in the NSCLC cohort (table 1). Pts with AM who received ICI therapy first-line achieved a TFS of 10.58 months vs 8.43 in those who received it as second-line therapy or later. Among patients with AM receiving first-line therapy, the use of anti-CTLA-4, anti-PD-(L)1, and combination ICI was associated with mean TFS of 8.13, 8.56, and 15.04 months, respectively (figure 1). In the NSCLC cohort, ICI treatment as first-line, second-line, and later-line therapy was associated with mean TFS of 4.94, 4.25, and 1.98 months, respectively. NSCLC patients who received anti-PD-(L)1 monotherapy as first-line treatment had TFS of 4.43 months.ConclusionsTFS is emerging as a unique, clinically meaningful endpoint for treatment with ICIs. Marked mean TFS was seen in pts with AM and NSCLC over the 3-year period from first ICI initiation, comparable to the intervals observed in clinical trials.1–3 TFS generally decreased with later lines of therapy and was greater with combination therapy in AM. Future analysis will focus on identifying additional predictors of prolonged TFS in these cohorts.ReferencesRegan MM, Mantia CM, Werner L, Tarhini AA, Larkin J, Hodi FS, Wolchok J, Postow MA, Stwalley B, Moshyk A, Ritchings C. Treatment-free survival over extended follow-up of patients with advanced melanoma treated with immune checkpoint inhibitors in CheckMate 067. J Immunother Cancer. 2021;9:e003743.Peters S, Penrod J, Li J, Lubinga S, Gupta R, Bushong J, Rizzo J, Ramalingam S. Treatment-free survival (TFS) in metastatic non-small cell lung cancer (mNSCLC) patients (pts) treated with 1L nivolumab plus ipilimumab (NIVO+ IPI) or platinum doublet chemotherapy (PDC) in CheckMate (CM) 227. Ann Oncol. 2022;33:S32-S33.Brahmer JR, Lee JS, Ciuleanu TE, Bernabe Caro R, Nishio M, Urban L, Audigier-Valette C, Lupinacci L, Sangha R, Pluzanski A, Burgers J. Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer in CheckMate 227. J Clin Oncol. 2022;41:1200–1212Ethics ApprovalThis study was approved by the Georgetown University Medical Center Institutional Review Board; approval number MODCR00002093.Abstract 1418 Table 1Survival endpoints and states in patients with advanced melanoma and non-small cell lung cancerAbstract 1418 Figure 1Survival states for all patients with advanced melanoma (A) as well as those who received first-line therapy with anti-CTLA-4 (B), anti-PD-(L)1 (C), and combination (D) therapy. TFS treatment-free survival, SASSACD survival after subsequent anti-cancer drug
Background: Immunotherapy has drastically changed the outlook for melanoma patients over the past decade. Specifically, the dual blockade of immune checkpoints using ipilimumab and nivolumab has ...shown unprecedented response rates and survival outcomes. This immense achievement, though, is at the cost of toxicity, with 60% of the patients experiencing high-grade adverse events (AEs). Our study aims to report the efficacy and toxicity outcomes of an out-of-trial, real-life population. Methods: Data on metastatic melanoma patients treated with ipilimumab and nivolumab were retrieved from our melanoma database—a single-center prospectively updated, medical-records based oncologic registry. Data included demographics, clinical and pathological information, as well as tumor responses and survival. Associations between patient or treatment characteristics and outcomes were also evaluated. Results: We identified 172 metastatic melanoma patients, of whom 64% were treatment-naïve. The median follow-up was 12 months. The response rates for treatment-naïve and previously-treated patients were 61% and 25%, respectively; median progression-free survival (PFS) were 12.2 and 2.6 months, and median overall survival (OS) were not-reached (NR) and 6.1 months, respectively. The estimated three-year OS for treatment-naïve patients was 58% (95% CI 42–65). At data cutoff, 22% were still on-treatment. Grade 3–4 adverse events (AEs) were reported in 60% of the patients, almost all of whom were exposed to steroid treatments (59%); AEs were fatal in 4 patients, and led to permanent treatment discontinuation in 31%. Factors significantly associated with outcome were cutaneous histology, low lactate dehydrogenase (LDH), low number of metastatic sites, performance status, first line of treatment and number of combinations administered during the induction phase. Conclusions: Despite the profoundly different baseline patient characteristics, the combination of ipilimumab and nivolumab is as effective in the real-world population as it was in clinical trials, including long-term outcomes. In addition to confirming the significance of baseline prognostic factors, our study reveals that the number of combinations effectively administered may also be correlated with good outcome.
BackgroundAdoptive cell therapy with T cells genetically engineered to express a chimeric antigen receptor (CAR-T) or tumor-infiltrating T lymphocytes (TIL) demonstrates impressive clinical results ...in patients with cancer. Lymphodepleting preconditioning prior to cell infusion is an integral part of all adoptive T cell therapies. However, to date, there is no standardization and no data comparing different non-myeloablative (NMA) regimens.MethodsIn this study, we compared NMA therapies with different doses of cyclophosphamide or total body irradiation (TBI) in combination with fludarabine and evaluated bone marrow suppression and recovery, cytokine serum levels, clinical response and adverse events.ResultsWe demonstrate that a cumulative dose of 120 mg/kg cyclophosphamide and 125 mg/m2 fludarabine (120Cy/125Flu) and 60Cy/125Flu preconditioning were equally efficient in achieving deep lymphopenia and neutropenia in patients with metastatic melanoma, whereas absolute lymphocyte counts (ALCs) and absolute neutrophil counts were significantly higher following 200 cGyTBI/75Flu-induced NMA. Thrombocytopenia was most profound in 120Cy/125Flu patients. 30Cy/75Flu-induced preconditioning in patients with acute lymphoblastic leukemia resulted in a minor ALC decrease, had no impact on platelet counts and did not yield deep neutropenia. Following cell infusion, 120Cy/125Flu patients with objective tumor response had significantly higher ALC and significant lower inflammatory indexes, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Receiver-operating characteristics curve analysis 7 days after cell infusion was performed to determine the cut-offs, which distinguish between responding and non-responding patients in the 120Cy/125Flu cohort. NLR≤1.79 and PLR≤32.7 were associated with clinical response and overall survival. Cytokine serum levels did not associate with clinical response in patients with TIL. Patients in the 120Cy/125Flu cohort developed significantly more acute NMA-related adverse events, including thrombocytopenia, febrile neutropenia and cardiotoxicity, and stayed significantly longer in hospital compared with the 60Cy/125Flu and TBI/75Flu cohorts.ConclusionsBone marrow depletion and recovery were equally affected by 120Cy/125Flu and 60Cy/125Flu preconditioning; however, toxicity and consequently duration of hospitalization were significantly lower in the 60Cy/125Flu cohort. Patients in the 30Cy/75Flu and TBI/75Flu groups rarely developed NMA-induced adverse events; however, both regimens were not efficient in achieving deep bone marrow suppression. Among the regimens, 60Cy/125Flu preconditioning seems to achieve maximum effect with minimum toxicity.
Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented ...in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m2, autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%—smokers, 30.4%—non-White, 22.8%—elderly, 20.8%—ECOG PS ≥ 2, 15.7%—history of AIDs, and 4.7%—history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs.
Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for ...Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs.
A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs.
The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non-small cell lung cancer, 45% (n=50) were treated using an anti-PD-(L)1 ICI, and 33% (n=37) were treated using an anti-PD-1/anti-CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis n=4, nondisseminated varicella zoster infection n=2, PJP n=1, and Listeria monocytogenes endophthalmitis n=1) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia n=5 each). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs.
Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.
Electric bicycles and scooters have gained popularity among riders; studies assessing these device-related injuries have not specified ocular trauma. Our study examined the types and risk factors for ...ocular and periocular injuries associated with electric devices compared to motorcycle accidents. The study was conducted on the National Trauma Registry database from 20 trauma centers, including patients involved in accidents with electric bicycles, scooters, and motorcycles between 2014 to 2019. Injured riders were assigned into two groups: motorcycle group (M) and electric bicycle & scooter group (E). Data such as gender, age, protective gear use, ocular injury type, injury severity score (ISS), and ocular surgery were captured. Logistic regression models were conducted for injury types and the need for surgery. 8181 M-riders and 3817 E-riders were involved in an accident and hospitalized. E-riders suffered from ocular injury more than M-riders. Males were most vulnerable and the ages of 15-29. Orbital floor fracture was the most common injury, followed by ocular contusion, eyelid laceration, and other ocular wounds. Electric bicycle and scooter riders are more likely to suffer from ocular injury than motorcycle riders. Riders without helmets are at greater risk for injuries, specifically orbital floor fractures. ISS of 16 + was associated with injury demanding ocular surgery.
Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated ...cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit.
Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate.
Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none
3.7%), lung (6.7%
11.4%), colon (20.0%
46.2%), prostate (5.6%
10.5%), and cervical/uterine (none
8.5%) cancers. When compared with the average stage of detection in the United States, detection was earlier for breast, lung, prostate, and female reproductive cancers. Patient satisfaction rate was 8.35 ± 1.85 (scale 1-10).
We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings.Media: see text.
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