Advanced Cutaneous Squamous Cell Carcinoma: Italian Multicentric Retrospective Analysis of Patient Profiles and Therapeutic Approaches.

BACKGROUND: Advanced cutaneous squamous cell carcinoma (aCSCC) represents an area of unmet clinical need, with no standardized treatments until the recent approval of immune checkpoint inhibitors (ICIs). OBJECTIVES: The aim of the study was to describe clinical characteristics and therapeutic strategies of a real-life Italian cohort of aCSCC patients managed at the beginning of cemiplimab approval as compassionate use in Italy. METHODS: A multicenter retrospective study was performed by 10 Italian centers in the period January 1, 2018-May 31, 2020. Patients aged ≥18 years and diagnosed with aCSCC (locally aCSCC and metastatic CSCC) were eligible for the study. Analysis of patients' characteristics and treatment strategies was performed. RESULTS: 239 patients were initially recruited in the study: 19 patients were excluded due to incomplete data collection, yielding a final cohort of 220 patients, of which 191 and 220 were included for patients' clinical characteristics and therapeutic intervention analysis, respectively. Median age at the time of diagnosis was 81 years (range: 72-86); nodal metastases were detected in 64/220 (29%) patients, and distant metastatic spread was reported in 33/220 (15%) patients. Most of our patients referred chronic occupational and/or recreational sun exposure, experienced ≥1 sunburn during their lifetime, never wore hats or used photoprotective filters, and presented with signs of cumulative sun damage (solar lentigines and/or actinic keratosis). Majority of our cohort received at least one intervention directed to the primary tumor (n = 212, 96.3%); surgery and radiotherapy were the most common therapeutic choices. Immunotherapy was administered to a small number of patients as compassionate use, especially in the metastatic setting. CONCLUSIONS: Our study outlines the complex and heterogeneous clinical and therapeutic landscape of aCSCC patients at the beginning of ICI era, highlighting the need of a standardized care for this fragile and high-need patient population.

Cemiplimab in Advanced Cutaneous Squamous Cell Carcinoma: Real-World Experience in a Monographic Oncology Center.

Management of advanced cSCC is challenging, and many available systemic medications have modest efficacy. Cemiplimab has demonstrated efficacy in the treatment of advanced cSCC in clinical trials, but real-world data are still limited. With the objective of evaluating the efficacy of cemiplimab in a real-world clinical setting, we conducted a prospective observational study of 13 patients with advanced cSCC. Six patients (46%) had locally advanced disease, while 7 (54%) had metastatic disease. A total of 8 patients (62%) responded to cemiplimab. Five (38%) showed a partial response, while 3 (23%) showed a complete response. Four patients with an initial partial response presented subsequent disease progression during follow-up. Six patients (46%) developed AEs, most of which were mild (G1). PFS was 5.9 months, with a median follow-up was 9 months. In conclusion, cemiplimab demonstrated its utility in the treatment of advanced cSCC, with acceptable response rates, a remarkable number of complete responses, and a very good safety profile.

Cemiplimab in Advanced Cutaneous Squamous Cell Carcinoma: Real-World Experience in a Monographic Oncology Center. / [Artículo traducido] Cemiplimab en el carcinoma de células escamosas cutáneo avanzado: experiencia del mundo real en un centro oncológico monográfico.

Management of advanced cSCC is challenging, and many available systemic medications have modest efficacy. Cemiplimab has demonstrated efficacy in the treatment of advanced cSCC in clinical trials, but real-world data are still limited. With the objective of evaluating the efficacy of cemiplimab in a real-world clinical setting, we conducted a prospective observational study of 13 patients with advanced cSCC. Six patients (46%) had locally advanced disease, while 7 (54%) had metastatic disease. A total of 8 patients (62%) responded to cemiplimab. Five (38%) showed a partial response, while 3 (23%) showed a complete response. Four patients with an initial partial response presented subsequent disease progression during follow-up. Six patients (46%) developed AEs, most of which were mild (G1). PFS was 5.9 months, with a median follow-up was 9 months. In conclusion, cemiplimab demonstrated its utility in the treatment of advanced cSCC, with acceptable response rates, a remarkable number of complete responses, and a very good safety profile.

Assessing the Value of Cemiplimab for Adults With Advanced Cutaneous Squamous Cell Carcinoma: A Cost-Effectiveness Analysis.

OBJECTIVES: To evaluate the cost-effectiveness of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC) from a payer perspective in the United States. METHODS: A partitioned survival model was developed to assess the cost-effectiveness of cemiplimab versus historical standard of care (SOC). All inputs were identified based on a systematic literature review, supplemented by expert opinion where necessary. Clinical inputs for cemiplimab were based on individual patient data from a cemiplimab phase 2 single-arm trial (NCT27060498). For SOC, analysis was based on a pooled analysis of single-arm clinical trials and retrospective studies evaluating chemotherapy and epidermal growth factor receptor inhibitors (cetuximab, erlotinib, and gefitinib) identified via a systematic literature review (6 of the 27 included studies). Overall survival and progression-free survival were extrapolated over a lifetime horizon. Costs were included for drug acquisition, drug administration, management of adverse events, subsequent therapy, disease management, and terminal care. Unit costs were based on published 2019 US list prices. RESULTS: In the base case, cemiplimab versus SOC resulted in an incremental cost-effectiveness ratio of $99 447 per quality adjusted-life year (QALY), where incremental costs and QALYs were $372 108 and 3.74, respectively. At a willingness-to-pay threshold of $150 000/QALY, the probabilistic sensitivity analysis suggests a 90% probability that cemiplimab is cost-effective compared to SOC. Scenario analyses resulted in incremental cost-effectiveness ratios ranging from $90 590 to $148 738. CONCLUSIONS: Compared with historical SOC, cemiplimab is a cost-effective use of US payer resources for the treatment of advanced CSCC and is expected to provide value for money.

Treatment of advanced cutaneous squamous cell carcinoma: a Mohs surgery and dermatologic oncology perspective.

Locally advanced or metastatic cutaneous squamous cell carcinoma no longer amenable to surgical resection or primary radiation therapy requires an alternative approach to treatment. Until 2018, management consisted of limited systemic chemotherapies, which carried marginal clinical benefit. The introduction of immunotherapy with anti-PD-1 antibodies resulted in alternative treatment options for advanced cutaneous squamous cell carcinoma with substantial antitumor activity, durable response and acceptable safety profile. The field of immunotherapeutics continues to expand with adjuvant, neoadjuvant and intralesional studies currently in progress. Herein, the authors discuss their approach for the treatment of advanced cutaneous squamous cell carcinoma from the perspective of a Mohs surgeon and a dermatologic oncologist.

Update on the anti-programmed cell death-1 receptor antibodies in advanced cutaneous squamous-cell carcinoma.

Regarding the rising incidence and the not negligible mortality, the treatment of cutaneous squamous-cell carcinoma (cSCC) has a high clinical relevance. Immune checkpoint inhibitors (ICI), especially anti-programmed cell death-1 receptor (anti-PD-1) antibodies such as pembrolizumab and cemiplimab have shown promising results in Phase 2 studies for patients with locally advanced and/or metastatic cSCC. We are presenting a review of the latest results in the treatment of cSCC with ICI. Patients with locally advanced or metastatic cSCC have been treated with cemiplimab 3 mg/kg every 2 weeks. For locally advanced cSCC, an objective response was observed in 44% of patients, 13% patients with a complete response, and 31% with a partial response. For metastatic patients, the overall response rate was 49.2%. The approved dose for cemiplimab in the United States and Europe is 350 mg every 3 weeks. These ICI seem to achieve higher response rates compared with epidermal growth factor receptor (EGFR) inhibitors, with a durable response superior to both chemotherapy and EGFR inhibitors. The side effect profile of anti-PD-1 antibodies appears to be favorable compared to chemotherapy. In this way, PD-1 inhibitors are expected to become the new gold-standard treatment for patients with locally advanced and metastatic cSCC.

Review of systemic agents in the treatment of advanced cutaneous squamous cell carcinoma.

Advanced cutaneous squamous cell carcinoma (cSCC) accounts for only 5% of all cases of cSCC but up to 60% of disease related deaths. Historically, this disease has lacked effective treatment options due to a combination of poor response rate, poor response durability and significant treatment-associated morbidity. Autumn of 2018 marked the first time ever that an agent received US FDA approval for advanced cSCC and the future is looking much brighter for this previously neglected patient population. The purpose of this article is to review the various systemic treatment options for advanced cSCC moving from the past to the present, highlighting their relative merits and shortcomings, and to briefly speculate on future developments in the field of advanced cSCC.

Advanced Cutaneous Squamous Cell Carcinoma Is Associated with Suboptimal Initial Management in a Cohort of 109 Patients.

BACKGROUND: Little is known about the epidemiological characteristics of patients with advanced cutaneous squamous cell carcinoma (A-cSCC). OBJECTIVE AND METHOD: A retrospective study was conducted on a routine care cohort of 109 patients to identify the epidemiological factors associated with A-cSCC. RESULTS: The median age was 83 years (IQR: 73.9-89.8), and the median ECOG was 1 (IQR: 1-2). Sixty percent of the patients had a history of cardiac disease and 22% had cognitive disorders. Seventy-four percent of patients were from rural/semi-rural areas (towns of <15,000 residents) and 17% were living in nursing homes. The cSCC lesions were on the head and neck in 72% of cases. Thirty-seven percent of patients were not diagnosed until the disease was in an advanced stage, indicating a lack of cSCC identification. In the remaining 69 patients, 7% did not received treatment within 3 months of the cSCC being identified, 62% had an incomplete histological report, and 37% had incomplete treatment. CONCLUSION: A-cSCC is associated with incomplete initial treatment in an elderly and rural population with good general condition. We hypothesize that a lack of access to good dermatological expertise may have led to underestimation of the aggressiveness of cSCC and/or therapeutic mismanagement.

Improved survival over time with immunotherapy in locally advanced and metastatic cutaneous squamous cell carcinomas.

PURPOSE: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in white-skinned populations. There is little information on the epidemiology of cSCC, and even less on advanced cases (acSCC). Therefore, we analyzed acSCC patients to describe their characteristics, management, and outcomes over time. METHODS: A single-center retrospective study was conducted over a period of 5 years, including all patients who started systemic therapy for acSCC. The patient characteristics, cSCC management, response to therapy, and survival were recorded. Patients were stratified into equal chronological periods (periods 1 and 2). A subgroup analysis was performed to compare patients who received immunotherapy (group 1) with those who did not (group 2). RESULTS: The study included 127 patients, and patient numbers increased by an average of 19.7% per year. Most patients were male (88/127), elderly (mean 81.6 years), with comorbidities, and 27.6% were immunocompromised. The median overall survival (OS) was higher in period 2 (20 months) than in period 1 (10 months) (hazard ratio [95% confidence interval] = 0.62 [0.39; 0.98], p = 0.04). The risk of progression increased with age and immunosuppression. Of the 64 patients who received second-line therapy, 38 had immunotherapy (group 1) and 26 received other therapies (group 2). Immunotherapy reduced mortality and progression by 71% (p = 0.004) and 67% (p = 0.002), respectively. CONCLUSIONS: Patients with acSCC are usually very frail and elderly. OS increased over time, with a twofold improvement between periods 1 and 2, whereas progression-free survival (PFS) did not increase. Access to immunotherapy reduced mortality in a majority of patients in period 2. Immunosuppression and advanced age were associated with lower PFS.

Immunotherapy in advanced cutaneous squamous cell carcinoma: Sydney west cancer network experience.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in the Caucasian population. A minority of cases are inoperable at presentation, recur or develop metastatic disease with a historical 5-year overall survival of ~10%. Treatment options in this setting are generally palliative. Immunotherapy has emerged as a new paradigm in managing these patients. METHODS: Patients presenting to Sydney West Cancer Network with locally advanced or metastatic CSCC treated with the anti-PD1 agent cemiplimab were identified. Response to treatment was objectively assessed based on RECIST1.1 or PERCIST criteria. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), therapy toxicity, and predictors of treatment response. RESULTS: A total of 19 patients were identified with a median age of 76 (range 56-94) and 4 immunosuppressed. The longest follow up duration was 28 months. ORR, complete response (CR), and partial response (PR) were 68% (13/19), 53% (10/19), and 16% (3/19), respectively. Median PFS was 12 months (95% CI 9-14) whilst median OS was not reached by end of study. Responders (CR or PR) had significantly superior OS compared to those with no response (P < 0.01). A primary site of head and neck cancer was significantly associated with ORR (P = 0.04). A single patient experienced Grade 3 toxicity with the rest being Grades 0-1. CONCLUSION: This study confirms the clinical efficacy of cemiplimab in patients with advanced CSCC with many experiencing a durable response and an acceptable adverse effect profile.

Radical Resection of Locally Advanced Chest Wall cSCC With Muscle Flap Reconstruction.

Outcomes in those with advanced cutaneous squamous cell carcinoma (cSCC) are poor. Upon incidence of metastasis, the mortality rate has been shown to be >70% with median overall survival (OS) of less than 2 years. While there is no standardized combination and multimodal therapy recommendation for advanced cases, there is a significant necessity to include surgical intervention for improved locoregional control of disease and improved OS. Currently, Cisplatin as monotherapy or combination with Fluorouracil (5-FU), and radiotherapy followed by surgical intervention are the most likely regimens used in the treatment of advanced cSCC. Secondary chemotherapy options include carboplatin and paclitaxel. Here, we report the effectiveness of neoadjuvant chemoradiotherapy (CRT) using carboplatin and paclitaxel agents with intensity modulated radiation therapy (IMRT) followed by radical surgical resection, and later, muscle flap reconstruction with split-thickness skin grafting to treat a very high-risk Stage IV cSCC of the left chest wall.

Pembrolizumab as monotherapy in locally advanced cutaneous squamous cell carcinoma.

INTRODUCTION: Outcomes for patients with advanced cutaneous squamous cell carcinoma (cSCC) are poor, however recent approvals in programmed death-1 (PD-1) checkpoint inhibition have shown promise. Prior systemic treatments in this patient population included chemotherapy and anti-EGFR directed therapies, with limited long-term benefit. Studies investigating cemiplimab and pembrolizumab have recently revealed significant responses with many cases of sustained benefit in both locally advanced and recurrent and/or metastatic disease. While these treatments have shown improvement in outcomes, there are continued areas of need. AREAS COVERED: This review focuses on clinical evidence for PD-1 directed checkpoint inhibition in advanced cSCC. Excluded populations and new approaches involving immunotherapy are discussed. EXPERT OPINION: Immune checkpoint inhibition in advanced cSCC has shown impressive benefit. The clinical trials for both cemiplimab and pembrolizumab demonstrate similar responses and outcomes. Biomarkers for predicting response are an area of need. In addition, these trials excluded immunosuppressed patients due to hematological malignancies or prior organ transplant, which are populations with significantly increased risk of cSCC. Finally, a variety of novel approaches using checkpoint inhibition in cSCC are being investigated, with some encouraging preliminary results.

Response to First-Line Treatment with Immune-Checkpoint Inhibitors in Patients with Advanced Cutaneous Squamous Cell Carcinoma: A Multicenter, Retrospective Analysis from the German ADOReg Registry.

Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.

Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy.

Radiation therapy (RT) is an effective therapeutic option for small localized cutaneous squamous cell carcinoma (cSCC) among patients who are not eligible for or refuse surgery. RT also has a defined role as an adjuvant treatment in cases of adverse features that predispose to tumor recurrence after local excision. Since the development of cSCC is often a late consequence of chronic sun exposure, its occurrence is more common among elderly patients whose comorbidities may contraindicate surgical procedures. These could be impeded not only by frail medical conditions but also by technical issues. Indeed, an aggressive locoregional behavior of cSCC may culminate in unresectability due to widespread invasion of neighboring tissues. Moreover, cSCC could develop distant metastases. Both locally advanced and metastatic cSCCs carry a poor prognosis. In these scenarios, recent discoveries of tumor molecular targets are promoting the use of promising systemic therapies, especially immunotherapy, over RT. However, the results from using immunotherapy and, even more so, of chemotherapy are still not optimal. By contrast, advances in radiation delivery equipment can safely treat even large and complex-shaped cSCC targets in challenging body sites. In addition, RT could also have a role in metastatic cSCC settings by enhancing the effectiveness of concomitant immunotherapy. The aim of this review is to summarize and comment on the body of literature about the use of radiotherapy for operable and inoperable locally advanced cSCCs and for metastatic ones in an attempt to define its current and future role.

Risk Factors and Diagnosis of Advanced Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer affecting humans. The combination of the increasing incidence and high mortality in advanced stages of the disease, defines cSCC as an emerging public health problem. Advanced disease includes metastatic and locally advanced cSCC. Metastatic disease refers to the presence of locoregional metastasis (in transit or to regional lymph nodes) or distant metastasis. Locally advanced disease has been defined as non-metastatic cSCC that is unlikely to be cured with surgery, radiotherapy, or combination treatment. While metastatic cSCC is easily diagnosed, locally advanced disease lacks consensus definition and diagnosis is made after multidisciplinary board consultation. Identifying patients with aggressive cSCC at highest risk for relapse may prevent the occurrence of advanced disease. Prognostic factors suggested by most guidelines include tumor diameter (>2 cm), localization on temple/ear/lip/area, thickness (>6 mm), or invasion beyond subcutaneous fat, poor grade of differentiation, desmoplasia, perineural invasion, bone erosion, immunosuppression, undefined borders, recurrence, growth rate, site of prior radiotherapy, and lymphatic or vascular involvement. Although risk factors associated with worse outcomes are well known, there is still a gap of knowledge on the precise risk of each factor taken individually. The aim of this review is to summarize cSCC prognostic factors and encompass the various staging systems to guide management and follow-up in cSCC patients at higher risk for local recurrence and metastasis. Finally, we describe the hallmarks of the advanced disease. Advanced cSCC diagnosis should be made by a multidisciplinary board considering patients' performance status and disease characteristics.

Cemiplimab in an Elderly Frail Population of Patients With Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: A Single-Center Real-Life Experience From Italy.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer whose incidence is growing parallel to the lengthening of the average lifespan. Cemiplimab, an antiPD-1 monoclonal antibody, is the first approved immunotherapy for patients with locally advanced CSCC (laCSCC) or metastatic CSCC (mCSCC) thanks to phase I and II studies showing high antitumor activity and good tolerability. Nevertheless, at present, very few data are available regarding cemiplimab in real-life experience and in frail, elderly, and immunosuppressed patients as well as regarding biomarkers able to predict response so as to guide therapeutic choices. PATIENTS AND METHODS: We built a retroprospective cohort study including 30 non-selected patients with laCSCC (25) and mCSCC (five) treated with cemiplimab from August 2019 to November 2020. Clinical outcomes, toxicity profile, and correlations with disease, patients, and peripheral blood parameters are explored. RESULTS: The median age was 81 years (range, 36-95), with 24 males and five patients having an immunosuppressive condition, while the frailty prevalence was 83% based on index derived from age, Eastern Cooperative Oncology Group performance status, and Charlson Comorbidity Index. We reported 23 responses (76.7%) with nine complete responses (30%). A statistically significant higher response rate was observed in head and neck primary tumors and in patients with hemoglobin level >12 g/dl. No difference was observed with respect to frailty, median age, sex, and body mass index. The baseline low neuthophil/lymphocyte ratio and low platelet/lymphocyte ratio resulted to be also correlated with a better response. Moreover, lymphocyte, neutrophil, and monocyte behaviors had an opposite trend in responders and non-responders. An overall response was reported in four of five immunosuppressed patients. Seventeen patients (57.6%) have an ongoing response and are still alive. Six responders had interrupted treatment (two for toxicity and four for personal choice) but maintained their response. The treatment was well tolerated by the majority of patients. The most common adverse events were fatigue in seven patients (23.3%) and skin toxicity in 10 patients (33.3%), including pruritus in six patients, rash in three patients, and bullous erythema in one patient. CONCLUSIONS: In our real-life experience, cemiplimab showed a high antitumor activity with acceptable safety profile similar to those in trials with selected patients. Moreover, its antitumor activity resulted to be not impaired in very elderly patients and in those with immunocompromised status.

Anti-PD-1 therapy using cemiplimab for advanced cutaneous squamous cell carcinoma in HIV patient: A case report.

This is a case of a 60-year-old man living with HIV who presented with advanced cutaneous squamous cell carcinoma. After workup, medical and surgical treatment, and disease recurrence, he achieved a complete response with no unexpected toxicities after immunotherapy with cemiplimab.

Cemiplimab for locally advanced cutaneous squamous cell carcinoma: safety, efficacy, and position in therapy panel.

INTRODUCTION: Locally advanced cutaneous squamous cell carcinoma (lacSCC) is rare. Approximately one-fourth of the cases are observed among immunocompromised patients, in particular in solid organ transplant recipients (OTRs). LacSCC has a very poor prognosis. Surgery with or without radiotherapy remains the golden standard of treatment for cSCC. However, in advanced cases, there is a medical need for alternative treatment options. Classic systemic treatments include chemotherapy and/or EGFR inhibitors. Recently the effectiveness of programmed cell death protein-1 (PD-1) inhibitors has been demonstrated for lacSCC. Cemiplimab is a recombinant IgG4 human monoclonal antibody against the PD-1 protein for the intravenous treatment of lacSCC. AREAS COVERED: The principal studies evaluating the efficacy and safety of cemiplimab for lacSCC are presented. EXPERT OPINION: Cemiplimab is the first anti-PD-1 antibody that was FDA (2018) and EMA (2019) approved as a systemic treatment for lacSCC and/or metastatic cSCC when curative surgery or radiotherapy is no longer amenable. For this situation, experts currently recommend cemiplimab as a first-line systemic alternative. As cemiplimab therapy is potentially associated with a risk of organ graft rejection, pros and cons should be evaluated for every individual OTR patient with lacSCC.

Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma.

Introduction: In September of 2018, the United States Federal Drug Administration (FDA) approved cemiplimab-rwlc (Libtayo) for advanced cutaneous squamous cell carcinoma (CSCC). Cemiplimab is an intravenous human monoclonal antibody directed against programmed cell death-1 receptor (PD-1). Cemiplimab blocks T-cell inactivation and enhances the immune system's anti-tumor response. Areas Covered: We review CSCC and the studies leading to cemiplimab's approval, including common side effects and safety issues experienced during the clinical trials. Expert Opinion: Immunotherapy, specifically checkpoint inhibitors, represents an increasingly utilized class of medications that is proving to be an effective treatment option for those with certain cancers. Over time, immunotherapy is likely to be the standard of care for immune-sensitive tumors. There are many challenges that the field faces, including the identification of reliable biomarkers to better predict response, decreasing toxicity, and the potential treatment of organ transplant patients.