Cytotoxic T lymphocyte associated antigen (CTLA-4) blockade is being explored in numerous clinical trials as an immune-based therapy for different malignancies. Our group conducted the first ...preoperative clinical trial with the anti-CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder.
Six patients were treated with 3 mg/kg/dose of anti-CTLA-4 and six patients were treated with 10 mg/kg/dose of antibody. Primary end points of the study were safety and immune monitoring.
Most drug-related adverse events consisted of grade 1/2 toxicities. All patients had measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. To determine if CD4+ICOShi T cells could be a correlative marker for clinical outcome after treatment with anti-CTLA-4, a cohort of metastatic melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells and survival. Data from this small cohort of patients indicated that an increased frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy, correlates with increased likelihood of clinical benefit consisting of overall survival.
Our trial shows that anti-CTLA-4 therapy has a tolerable safety profile in the presurgical setting and that a preoperative model can be used to obtain biological data on human immune responses, which can efficiently guide the monitoring of patients treated in the metastatic disease setting.
Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic ...factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO.
We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient's histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology.
The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node (n = 58), liver (n = 40), lung (n = 37), bone (n = 24), and brain (n = 8). Most patients (80.7%) were RMH good risk. Most patients (n = 62) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17-0.84, p = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41-1.19, p = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p = 0.0048).
Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.
Objective
To evaluate the safety and efficacy of epidermal growth factor receptor (EGFR)‐targeted therapy in patients with advanced penile or scrotal cancer.
Patients and Methods
We retrospectively ...reviewed the charts of patients with penile or scrotal squamous cell carcinoma who had visited our tertiary cancer centre between 2002 and 2009, including their subsequent treatment and follow‐up.
We collected details of EGFR‐targeted therapy and clinical outcomes. Treatment‐associated time‐to‐disease‐progression (TTP), overall survival (OS), responses to therapy and toxicity were evaluated.
Results
A total of 24 patients had received EGFR‐targeted therapies, including cetuximab, erlotinib and gefitinib. The most common treatment given (to 67% of patients) was cetuximab combined with one or more cytotoxic drugs.
The most common adverse effect was skin rash (71%). The median (range) TTP and OS were 11.3 (1–40) and 29.6 (2–205) weeks, respectively. The OS time for patients with visceral or bone metastases was significantly shorter than it was for those without (24.7 vs 49.9 weeks, P = 0.013).
Among 17 patients treated with cetuximab alone or in combination with cisplatin, there were four partial responses (23.5%) including two patients with apparently chemotherapy‐resistant tumours.
Conclusions
Our results suggest that cetuximab has antitumour activity in metastatic penile cancer, and may enhance the effect of cisplatin‐based chemotherapy.
Prospective studies of EGFR‐targeted therapies in men with these tumours are warranted.
Background
Optimal prognostic and predictive biomarkers for patients with advanced‐stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the ...neutrophil‐to‐lymphocyte ratio (NLR), the monocyte‐to‐lymphocyte ratio (MLR), and the platelet‐to‐lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced‐stage cancer who received IO.
Methods
A retrospective review was conducted of 90 patients with advanced cancer who received treatment on phase 1 clinical trials of IO‐based treatment regimens. NLR, MLR, and PLR values were log‐transformed and treated as continuous variables for each patient. Overall survival (OS), progression‐free survival (PFS), and clinical benefit were used to measure clinical outcomes. For univariate associations and multivariable analyses, Cox proportional‐hazards models or logistic regression models were used.
Results
The median patient age was 63 years, and most were men (59%). The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). High baseline NLR, MLR, and PLR values were associated significantly with worse OS and PFS (P < .05) and a lower chance of benefit (NLR and PLR; P < .05). Increased NLR, MLR, and PLR values 6 weeks after baseline were associated with shorter OS and PFS (P ≤ .052).
Conclusions
Baseline and early changes in NLR, MLR, and PLR values were strongly associated with clinical outcomes in patients who received IO‐based treatment regimens on phase 1 trials. Confirmation in a homogenous patient population treated on late‐stage trials or outside of trial settings is warranted. These values may warrant consideration for inclusion when risk stratifying patients enrolled onto phase 1 clinical trials of IO agents.
High baseline and early increases in the neutrophil‐to‐lymphocyte, monocyte‐to‐lymphocyte, and platelet‐to‐lymphocyte ratios are significantly associated with poor outcomes in patients with advanced‐stage cancer who receive immunotherapy. These markers of inflammation may warrant consideration in updated prognostic models for patients enrolled on phase 1 clinical trials.
Background
Advanced penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy with limited success of immune‐checkpoint inhibitors (ICIs). Approximately half of pSCC cases are ...associated with human papillomavirus (HPV) infection.
Methods
Evaluation was done retrospectively of the landscape of somatic alterations and ICI‐related biomarkers in pSCC by using the Caris Life Sciences data set with the aim to establish signatures for HPV‐dependent oncogenesis. The pSCC tumors were analyzed by using next‐generation sequencing (NGS) of DNA and RNA. Programmed death ligand 1 (PD‐L1) expression was evaluated by immunohistochemistry (IHC). Microsatellite instability (MSI) was tested by fragment analysis, IHC (SP142; ≥1%), and NGS. Tumor mutational burden (TMB)–high was defined as ≥10 mutations/Mb. HPV16/18 status was determined by using whole‐exome sequencing (WES) when available. Significance was adjusted for multiple comparisons (q value < .05).
Results
NGS of the overall cohort (N = 108) revealed TP53 (46%), CDKN2A (26%), and PIK3CA (25%) to be the most common mutations. Overall, 51% of tumors were PD‐L1+, 10.7% had high TMB, and 1.1% had mismatch repair–deficient (dMMR)/MSI‐high status. Twenty‐nine patients had their HPV status made available by WES (HPV16/18+, n = 13; HPV16/18−, n = 16). KMT2C mutations (33% vs. 0%) and FGF3 amplifications (30.8% vs. 0%) were specific to HPV16/18+ tumors, whereas CDKN2A mutations (0% vs. 37.5%) were exclusive to HPV16/18− tumors. TMB‐high was exclusively found in the HPV16/18+ group (30.8%). The two groups had comparable PD‐L1 and dMMR/MSI‐H status.
Conclusions
In a large and comprehensive NGS‐based evaluation of somatic alterations in pSCC, HPV16/18+ versus HPV16/18− pSCCs were molecularly distinct tumors. Our finding that TMB‐high is exclusive to HPV16/18+ tumors requires confirmation in larger data sets.
Plain Language Summary
Penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy in the advanced setting, with poor prognosis and little success with immune‐checkpoint inhibitors (ICIs) in an unselected patient approach. Human papillomavirus (HPV) infection is a known risk factor for pSCC; its impact on genomic tumor profiling is less defined.
Using next‐generation sequencing, we explored the genetic landscape and ICI‐related biomarkers of pSCC and HPV‐driven oncogenic molecular signatures.
Our results indicate that HPV‐positive and HPV‐negative pSCCs are molecularly distinct tumors. Increased tumor mutational burden is associated with HPV‐positive tumors, and could serve as a biomarker for predicting therapeutic response to ICI‐based therapies.
Our results support the growing literature indicating that HPV status in pSCC can be used to guide patient stratification in ICI‐based clinical trials.
This study reports on the genetic landscape of immune‐checkpoint inhibitor (ICI) biomarkers in penile squamous cell carcinoma (pSCC) and shows that HPV‐positive and HPV‐negative tumors are molecularly distinct, which is consistent with prior studies. Tumor mutational burden–high status was associated with HPV‐positive tumors. These results support that HPV status in pSCC can be used to guide patient stratification in ICI‐based clinical trials.
Biomarkers to guide treatment in metastatic renal-cell carcinoma (mRCC) are lacking. Neutrophil-to-lymphocyte ratio (NLR) predicts prognosis for mRCC patients receiving targeted therapy. After ...retrospective chart review of 38 patients with mRCC treated with nivolumab, we found that pretreatment NLR ≤ 5.5 is associated with superior progression-free survival and overall survival, supporting the notion that NLR is a prognostic biomarker for mRCC.
Biomarkers to guide treatment in metastatic renal-cell carcinoma (mRCC) are lacking. We aimed to investigate the association between pretreatment neutrophil-to-lymphocyte ratio (NLR) and outcome of patients with mRCC receiving nivolumab.
Through retrospective chart review, we identified 38 patients with mRCC treated with standard-of-care nivolumab between 2015 and 2016 at Winship Cancer Institute of Emory University. NLR was determined from complete blood count collected before starting treatment, and imaging was performed to assess progression. The NLR cutoff value of 5.5 was determined by log-rank test, and the univariate association with overall survival (OS) or progression-free survival (PFS) was assessed by the Cox proportional hazard model and Kaplan-Meier method.
The 38 patients had a median age of 69 years. The PFS and OS for all patients at 12 months was 54% and 69%, respectively. The median PFS was 2.6 months in the high NLR group but not reached in the low NLR group. Low NLR was strongly associated with increased PFS with hazard ratio of 0.20 (95% confidence interval, 0.07-0.64; P = .006). The median OS was 2.7 months in the high NLR group but not reached in the low NLR group. Low NLR was significantly associated with a prolonged OS with hazard ratio of 0.06 (95% confidence interval, 0.01-0.55; P = .012).
Pretreatment NLR < 5.5 is associated with superior PFS and OS. NLR is a biomarker that can inform prognosis for patients with mRCC and should be further validated in larger cohorts and in prospective studies.
Abstract Background Bladder cancer with divergent differentiation (BCDD) comprises a heterogenous group of tumors with a poor prognosis, and differential expression of nectin‐4 and programmed death ...ligand‐1 (PD‐L1) has been reported in BCDD. Importantly, nectin‐4 expression in bladder cancer is associated with response to enfortumab vedotin, and PD‐L1 expression is associated with responses to immune checkpoint inhibitors (ICIs). Methods The authors conducted a retrospective review identifying 117 patients with advanced or metastatic BCDD who were treated at Winship Cancer Institute from 2011 to 2021. They performed immunohistochemistry staining for nectin‐4 and PD‐L1 expression by histologic subtype as well as genomic analysis of these patients, including RNA sequencing, whole‐exome sequencing, and fusion detection analysis as well as a subgroup genomic analysis of patients with BCDD who received ICIs. Results The results indicated that nectin‐4 expression was highest in the groups who had the squamous and plasmacytoid subtypes, whereas the group that had the sarcomatoid subtype (70.8%) had the highest proportion of PD‐L1–positive patients. Genomic analysis yielded several key findings, including a 50% RB1 mutation rate in patients who had small cell BCDD, targetable PIK3CA mutations across multiple subtypes of BCDD, and significantly higher expression of TEC in responders to ICIs. Conclusions In this study, the authors identified clinically relevant data on nectin‐4 and PD‐L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis‐generating data.
In this study, the authors performed a retrospective analysis focused on the histologic and genomic characterization of bladder cancer with divergent differentiation. The results indicated that nectin‐4 expression was highest in patients with squamous and plasmacytoid differentiation, whereas patients who had sarcomatoid differentiation (70.8%) had the highest proportion of programmed death ligand‐1–positive disease, and several novel findings were identified in the genomic analysis that have potential clinical implications for these patients with rare tumors.
Immune-oncologic (IO) therapy has revolutionized the treatment and management of oncologic disease. Immunotherapy functions by enhancing the host immune-systems ability to endogenously clear ...malignant cells, however, this activation can also lead to immune-mediated damage to healthy native tissues. These side effects are known as immune-related adverse events or irAEs and can even present with phenotypes similar to autoimmune diseases. IrAEs are the major consequence of checkpoint inhibitors and can have a significant impact on a patient's cancer treatment and long-term quality of life. The management of these irAEs follows a similar approach to autoimmune diseases. More specifically, the management is akin to that of autoimmune disease exacerbations. While there is an array of immune-suppressing agents that can be used, steroids, immunomodulators and IO discontinuation are cornerstones of irAE management. The exact approach and dosing are based on the severity and subtype of irAE presented. Within recent years, there has been a push to better prevent and manage irAEs when they arise. There has been an additional effort to increase the number of steroid-sparing agents available for irAE treatment given the consequences of long-term steroid therapy as well as patient contraindications to steroids. The goals of this review are to summarize irAE management, highlight significant advances made in recent years and emphasize the future directions that will optimize the use of IO therapy in oncology.
Introduction
Programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) blockade has changed the landscape of treatment for metastatic urothelial cancer, but single‐agent cytotoxic ...T‐lymphocyte–associated protein 4 (CTLA‐4) blockade in metastatic urothelial cancer has been underexplored. A prior phase 2 trial of tremelimumab in PD‐1/PD‐L1–blockade naive patients with metastatic urothelial cancer revealed activity comparable to that observed with PD‐1/PD‐L1 blockade raising the hypothesis that these classes of immune checkpoint inhibitors might be non‐cross‐resistant.
Methods
The current phase 2 trial treated patients with PD‐1/PD‐L1 blockade‐resistant metastatic urothelial cancer with single‐agent tremelimumab (750 mg intravenously every 28 days for up to 7 cycles). The primary end point was objective response rate.
Results
Twenty‐six patients were enrolled and 24 patients were evaluable for response. The objective response rate was 8.3%, composed of a total of two partial responses that lasted 10.9 and 24.0 months. Stable disease was observed in another 20.8% of patients, with a median duration of stable disease of 5.4 months. Diarrhea occurred in 15 patients (58%), elevated hepatic transaminases occurred in seven patients (27%), and adrenal insufficiency occurred in two patients (8%); one patient died after experiencing immune‐related hepatitis.
Conclusions
High dose CTLA‐4 blockade in patients with PD‐1/PD‐L1–resistant metastatic urothelial cancer has modest activity and is associated with treatment‐related toxicity similar to prior reports.
The current phase 2 trial sought to test that cytotoxic T‐lymphocyte–associated protein 4 blockade demonstrates anticancer activity in patients with metastatic urothelial cancer and is non‐cross‐resistant with programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) blockade. Tremelimumab in patients with PD‐1/PD‐L1–resistant metastatic urothelial cancer demonstrated modest activity and is associated with treatment‐related toxicity similar to prior reports.
Background
Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long‐term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 ...clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here.
Methods
Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune‐mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression‐free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others.
Results
After a minimum follow‐up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%‐53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression‐free survival was 9.0 months (95% CI, 2.9‐12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable).
Conclusions
In patients who had previously untreated aRCC and brain metastases—a population with a high unmet medical need that often is underrepresented in clinical trials—the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals.
CheckMate 920 is the first prospective, multicohort study of nivolumab plus ipilimumab as first‐line therapy for advanced renal cell carcinoma in patients who have a poor prognosis and a high unmet medical need. In cohort 3 (advanced renal cell carcinoma and brain metastases), nivolumab plus ipilimumab has a safety profile consistent with previous reports of this dosing regimen with encouraging antitumor activity.
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