Cutaneous and Noncutaneous Adverse Effects in Patients with Advanced Melanoma Receiving Immunotherapy.

Relationships between cutaneous adverse effects (CAEs) and noncutaneous adverse effects (NCAEs) of melanoma immunotherapy may help identify patterns tied to distinct immunologic pathways. The objective of this study was to determine the associations between CAEs and NCAEs among patients with stages III-IV melanoma receiving immunotherapy and who were enrolled in a prospective cohort. Electronic medical record data were abstracted from the first immunotherapy infusion until 1 year later. CAEs were rash or itch. NCAEs were symptoms and/or laboratory abnormalities documented as immunotherapy related. NCAE onset and time to NCAE were compared between participants with and without CAEs using ORs and Wilcoxon rank sum tests. Of 34 participants, 11 (32.4%) developed no adverse effects, 7 (20.1%) developed CAEs only, 3 (8.8%) developed NCAEs only, and 13 (38.2%) developed both CAEs and NCAEs. After adjustment for age, sex, and immunotherapy regimen, CAE was associated with higher odds of NCAE development (OR = 9.72; 95% confidence interval = 1.2-76.8). Median NCAE onset was 63 days in those with CAEs and 168 days in those without CAEs (P = 0.41). Limitations included a small sample size, and larger prospective studies should be performed to confirm findings. CAE was associated with NCAE development. Early identification and treatment of NCAEs may reduce symptom burden and hospitalizations associated with NCAEs.

FcγRIIB expressed on CD8+ T cells limits responsiveness to PD-1 checkpoint inhibition in cancer.

Checkpoint inhibition using Fc-containing monoclonal antibodies has emerged as a powerful therapeutic approach to augment antitumor immunity. We recently showed that FcγRIIB, the only inhibitory IgG-Fc receptor, is expressed on a population of highly differentiated effector CD8+ T cells in the tumors of mice and humans, raising the possibility that CD8+ T cell responses may be directly modulated by checkpoint inhibitor binding to T cell-expressed FcγRIIB. Here, we show that despite exhibiting strong proliferative and cytokine responses at baseline, human FcγRIIBpos CD8+ T cells exhibited reduced responsiveness to both PD-1 and CTLA-4 checkpoint inhibition as compared with FcγRIIBneg CD8+ T cells in vitro. Moreover, frequencies of FcγRIIBpos CD8+ T cells were reduced after treatment of patients with melanoma with nivolumab in vivo. This reduced responsiveness was FcγRIIB dependent, because conditional genetic deletion of FcγRIIB on tumor-specific CD8+ T cells improved response to checkpoint blockade in B16 and LLC mouse models of cancer. The limited responsiveness of FcγRIIBpos CD8+ T cells was also dependent on an intact Fc region of the checkpoint inhibitor, in that treatment with Fc-devoid anti-PD-1 F(ab) fragments resulted in increased proliferation of FcγRIIBpos CD8+ T cells, without altering the response of FcγRIIBneg CD8+ T cells. Last, the addition of FcγRIIB blockade improved efficacy of PD-1 checkpoint inhibition in mouse models of melanoma, lung, and colon cancer. These results illuminate an FcγRIIB-mediated, cell-autonomous mechanism of CD8+ T cell suppression, which limits the efficacy of checkpoint inhibitors during antitumor immune responses in vivo.

Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma.

We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59-0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61-1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma. SIGNIFICANCE: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587.

Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study.

BACKGROUND: The dependence of the adaptive immune system on circadian rhythm is an emerging field of study with potential therapeutic implications. We aimed to determine whether specific time-of-day patterns of immune checkpoint inhibitor infusions might alter melanoma treatment efficacy. METHODS: Melanoma Outcomes Following Immunotherapy (MEMOIR) is a longitudinal study of all patients with melanoma who received ipilimumab, nivolumab, or pembrolizumab, or a combination of these at a single tertiary cancer centre (Winship Cancer Institute of Emory University, Atlanta, GA, USA). For this analysis, we collected deidentified participant-level data from the MEMOIR database for adults (age ≥18 years) diagnosed with stage IV melanoma between 2012 and 2020. Those who received fewer than four infusions were excluded. Standard of care doses were used, with modifications at the treating physicians' discretion. The primary outcome was overall survival, defined as death from any cause and indexed from date of first infusion of immune checkpoint inhibitor. We calculated the association between overall survival and proportion of infusions of immune checkpoint inhibitors received after 1630 h (a composite time cutoff derived from seminal studies of the immune-circadian rhythm to represent onset of evening) using Cox regression and propensity score-matching on age, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy. Treatment-related adverse events that led to change or discontinuation of immune checkpoint inhibitors were also assessed. FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 481 patients with melanoma received treatment with immune checkpoint inhibitors at the study centre, of whom 299 had stage IV disease and were included in this study; median follow-up was 27 months (IQR 14 to 47). In the complete unmatched sample, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR 51 to 72). Every additional 20% of infusions of immune checkpoint inhibitors received after 1630 h (among all infusions received by a patient) conferred an overall survival hazard ratio (HR) of 1·31 (95% CI 1·00 to 1·71; p=0·046). A propensity score-matched analysis of patients who did (n=73) and did not (n=73) receive at least 20% of their infusions of immune checkpoint inhibitors after 1630 h (54 [37%] of 146 patients were women and 92 [63%] were men, with a median age of 58 years [IQR 48 to 68]) showed that having at least 20% of infusions in the evening was associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [1·04 to 4·00; p=0·038]). This result remained robust to multivariable proportional hazards adjustment with (HR 1·80 [1·08 to 2·98; p=0·023]) and without (2·16 [1·10 to 4·25; p=0·025]) inclusion of the complete unmatched study sample. The most common adverse events were colitis (54 [18%] of 299 patients), hepatitis (27 [9%]), and hypophysitis (15 [5%]), and there were no treatment-related deaths. INTERPRETATION: Our findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening than if stimulated in the daytime. Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma. FUNDING: National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute.

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204).

BACKGROUND: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients. METHODS: Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months). RESULTS: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed. CONCLUSIONS: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.

Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017. METHODS: In this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months. RESULTS: Overall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies. CONCLUSIONS: This study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority. TRIAL REGISTRATION NUMBER: NCT02267603.

The Impact of Obesity on Surgically Treated Locoregional Melanoma.

BACKGROUND: The impact of obesity on early-stage melanoma is poorly understood. We examined the impact of overweight and obesity on clinical outcomes in locoregional melanoma. METHODS: Adults who underwent surgery at Emory University Healthcare between 2010 and 2017 for clinically stage I-II cutaneous melanoma, with known stage, height, and weight at the time of presentation, were identified. The relationship between body mass index (BMI) and clinicopathologic characteristics was assessed. RESULTS: Of 1756 patients, 584 were obese (33.2%; BMI ≥ 30), 658 were overweight (37.5%; BMI ≥ 25 and < 30), and 514 were normal weight (29.3%; BMI < 25). Demographics associated with obesity included male sex (odds ratio [OR] 2.6, 95% confidence interval [CI] 2.1-3.3; p < 0.001) and lower income (OR 1.5, 95% CI 1.2-1.9; p = 0.003). Melanomas in obese patients were thicker (2.0 ± 0.2 mm) than in overweight (1.7 ± 0.1 mm) or normal-weight patients (1.4 ± 0.1 mm; p = 0.002). Ulceration, mitoses, BRAF status, and sentinel lymph node (SLN) status were not affected by obesity. In multivariable analysis, obesity independently predicted increased odds of pathologic stage II melanoma (vs. stage 0 or I; OR 1.9, 95% CI 1.4-2.7, p = 0.001), but not pathologic stage III melanoma (p > 0.05). At 33 months' median follow-up, obesity was not an independent predictor of stage-specific overall survival (p > 0.05). CONCLUSION: Obese patients are nearly twice as likely as their normal-weight peers to present with thicker melanomas, but they have similar stage-specific overall survival and SLN positivity. Obesity may promote more aggressive growth of the primary tumor, and barriers to preventive care in obese patients may exacerbate later-stage presentation.

The evolving landscape of immunotherapy in solid tumors.

While surgical resection, local and cytotoxic therapies have long formed the basis of cancer care, immunotherapy now plays a key role in supplementing and even replacing these agents in the first line. Here we review the early success of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 blockade and discuss biomarkers of therapeutic response. We next highlight a select group of novel targets in Phase III trials both as monotherapies and in combination with PD-1 inhibitors. Finally, we discuss innovations which seek to improve outcomes in therapy-resistant solid tumors.

Neoadjuvant Therapy for Melanoma.

With the universal adoption of immune checkpoint blockade and agents targeting BRAF-mutated melanomas in the metastatic setting, numerous clinical trials have evaluated these agents in the neoadjuvant setting. These smaller trials have shown promising results with high pathologic response rates and acceptable safety. Larger prospective randomized trials are under way to determine if all patients with resectable metastatic disease should be receiving neoadjuvant therapy.

Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial.

PURPOSE: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti-PD-1 in the neoadjuvant setting for resectable MCC. METHODS: In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies. RESULTS: Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation. CONCLUSION: Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.

Changing Therapeutic Landscape for Melanoma With Multiple Brain Metastases.

Over 90 000 people are expected to be diagnosed with melanoma in the United States this year. The development of brain metastases is particularly difficult to manage. Over the past few years, melanoma patients with multiple unresectable brain metastases for which stereotactic surgery might also not be a viable option have fortunately experienced a dramatic expansion in available management options given improvements made to targeted agents, immunotherapy, and radiotherapy. Whole-brain radiation therapy (WBRT) is a long-standing radiation technique that has become increasingly sophisticated. In this review, we summarize retrospective and prospective studies on individual advances in targeted agents, immunotherapy, and WBRT, highlighting important variables such as overall survival, intracranial progression-free survival, control and response rates, and toxicities. We also discuss the recent integration of these therapies into a multimodality approach, which has shown promise in the clinical setting although toxicities have not been insignificant. Finally, we describe ongoing prospective trials relevant to melanoma with brain metastases, and we conclude with our own thoughts on the optimal approach for these patients.

Combined Effect of Sarcopenia and Systemic Inflammation on Survival in Patients with Advanced Stage Cancer Treated with Immunotherapy.

BACKGROUND: Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy. METHODS: We performed a retrospective review of 90 patients enrolled on immunotherapy-based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias-adjusted log-rank test. A four-level risk stratification was used to create low-risk (PLR <242 and nonsarcopenic), intermediate-risk (PLR <242 and sarcopenic), high-risk (PLR ≥242 and nonsarcopenic), and very-high-risk (PLR ≥242 and sarcopenic) groups with subsequent association with survival. RESULTS: Most patients (59%) were male, and the most common cancers were melanoma (33%) and gastrointestinal (22%). Very high-risk, high-risk, and intermediate-risk patients had significantly shorter overall survival (hazard ratio [HR], 8.46; 95% confidence interval [CI], 2.65-27.01; p < .001; HR, 5.32; CI, 1.96-14.43; p = .001; and HR, 4.01; CI, 1.66-9.68; p = .002, respectively) and progression-free survival (HR, 12.29; CI, 5.15-29.32; p < .001; HR, 3.51; CI, 1.37-9.02; p = .009; and HR, 2.14; CI, 1.12-4.10; p = .022, respectively) compared with low-risk patients. CONCLUSION: Baseline sarcopenia and elevated inflammatory biomarkers may have a combined effect on decreasing survival in immunotherapy-treated patients in phase I trials. These data may be immediately applicable for medical oncologists for the risk stratification of patients beginning immunotherapeutic agents. IMPLICATIONS FOR PRACTICE: Sarcopenia and inflammation have been associated with poor survival in patients with cancer, but it is unclear how to apply this information to patient care. The authors created a risk-stratification system that combined sarcopenia and platelet-to-lymphocyte ratio as a marker of systemic inflammation. The presence of sarcopenia and systemic inflammation decreased progression-free survival and overall survival in our cohort of 90 patients who received immunotherapy in phase I clinical trials. The data presented in this study may be immediately applicable for medical oncologists as a way to risk-stratify patients who are beginning treatment with immunotherapy.

Adiposity may predict survival in patients with advanced stage cancer treated with immunotherapy in phase 1 clinical trials.

BACKGROUND: Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy. METHODS: A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS. RESULTS: The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m2 , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P < .001]) and PFS (hazard ratio, 0.38; 95% CI, 0.20-0.72 [P = .003]) compared with patients at intermediate risk (those with an SFI <73 and IFI <3.4) and poor risk (those with an SFI <73 and IFI ≥3.4). The Uno concordance statistics were found to be higher for fat risk groups than BMI in predicting OS (0.603 vs 0.574; P = .581) and PFS (0.602 vs 0.586; P = .71). CONCLUSIONS: Increased BMI, increased SFI, and decreased IFI may be associated with prolonged survival in patients with cancer who are treated with immunotherapy. Further studies are needed to elucidate the effect of adiposity on the host immune response to immunotherapy.

Predictors of Overall and Progression-Free Survival in Patients with Ocular Melanoma Metastatic to the Liver Undergoing Y90 Radioembolization.

PURPOSE: To investigate predictors of overall survival (OS) and progression-free survival (PFS) in patients with ocular melanoma metastatic to the liver undergoing yttrium-90 (Y90) radioembolization, including the effect of concurrent immunotherapy. METHODS: An IRB-approved retrospective review of 24 patients with ocular melanoma metastatic to the liver who underwent Y-90 treatment between June 2003 and January 2018 was performed. Data regarding patients' performance status at the time of Y90, intra-/extrahepatic tumor burden, and treatment response were evaluated. RECIST was used to determine objective tumor response. Kaplan-Meier analysis was used to calculate OS and PFS from the first Y90 therapy. Log-rank analysis was used to determine predictors of prolonged OS and PFS. RESULTS: Median OS from primary diagnosis and diagnosis of liver metastases was 66 months (mo) and 26.3 mo, respectively. Median OS for those who received immunotherapy within 3 months of undergoing Y90 was prolonged at 26.0 mo versus 9.5 mo for others (p = 0.014). Median OS for patients with an ECOG performance status of 0 was prolonged at 26 mo versus 5.5 mo for others (p = 0.003). Median hepatic PFS was prolonged in patients treated with Y-90 on concurrent immunotherapy at 10.3 mo versus 2.7 mo for TARE only (p = 0.002). Patients with an ECOG performance status of 0 had prolonged PFS (p = 0.002). CONCLUSIONS: Concurrent immunotherapy and an ECOG performance status of 0 at the time of Y90 therapy appear to be predictors of prolonged OS and PFS in patients with ocular melanoma metastatic to the liver.

Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy.

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS: In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS: Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION: Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.

Clinical outcomes of advanced stage cancer patients treated with sequential immunotherapy in phase 1 clinical trials.

Background Given the increasing number of available immunotherapeutic agents, more patients are presenting after failing immunotherapy in need of new treatment options. In this study, we investigated the clinical outcomes of patients treated with sequential immunotherapy. Methods We performed a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute from 2009 to 2017. We included 49 patients with an immune checkpoint inhibitor (ICI)-indicated histology. Patients were analyzed based on whether they had received prior ICI. Clinical outcomes were overall survival (OS), progression-free survival (PFS), and clinical benefit (best response of complete response, partial response, or stable disease). Univariate analysis (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazard or logistic regression model. Covariates included age, liver metastases, number of prior lines of therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). More than half of patients (n = 27, 55%) received at least one ICI prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination, and ten received multiple ICI. In MVA, ICI-naïve patients had significantly longer OS (HR: 0.22, CI: 0.07-0.70, p = 0.010) and trended towards higher chance of CB (HR: 2.52, CI: 0.49-12.97, p = 0.268). Patients who received prior ICI had substantially shorter median OS (10.9 vs 24.3 months, p = 0.046) and PFS (2.8 vs. 5.1 months, p = 0.380) than ICI-naïve patients per Kaplan-Meier estimation. Within the ICI-naïve group, 78% (7 of 9) of patients who received prior interleukin (IL-2) or interferon gamma (IFNγ) experienced disease control for at least 6 months, compared to a disease control rate of 15% (2 of 13) in patients who had received chemotherapy, targeted therapy, or no prior treatment. Conclusions ICI-naïve patients may experience improved clinical outcomes on immunotherapy-based phase 1 clinical trials than patients who have received prior ICI. This may be particularly true for patients who received prior IL-2 or IFNγ. Further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. These results should be validated in a larger study.

Tuberculosis following PD-1 blockade for cancer immunotherapy.

Because of the well-established therapeutic benefit of boosting antitumor responses through blockade of the T cell inhibitory receptor PD-1, it has been proposed that PD-1 blockade could also be useful in infectious disease settings, including Mycobacterium tuberculosis (Mtb) infection. However, in preclinical models, Mtb-infected PD-1-/- mice mount exaggerated TH1 responses that drive lethal immunopathology. Multiple cases of tuberculosis during PD-1 blockade have been observed in patients with cancer, but in humans little is understood about Mtb-specific immune responses during checkpoint blockade-associated tuberculosis. Here, we report two more cases. We describe a patient who succumbed to disseminated tuberculosis after PD-1 blockade for treatment of nasopharyngeal carcinoma, and we examine Mtb-specific immune responses in a patient with Merkel cell carcinoma who developed checkpoint blockade-associated tuberculosis and was successfully treated for the infection. After anti-PD-1 administration, interferon-γ-producing Mtb-specific CD4 T cells became more prevalent in the blood, and a tuberculoma developed a few months thereafter. Mtb-specific TH17 cells, CD8 T cells, regulatory T cells, and antibody abundance did not change before the appearance of the granuloma. These results are consistent with the murine model data and suggest that boosting TH1 function with PD-1 blockade may increase the risk or severity of tuberculosis in humans.

The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy.

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.

Predictive and on-treatment monitoring biomarkers in advanced melanoma: Moving toward personalized medicine.

The treatment armamentarium for patients with metastatic melanoma has increased substantially over the past decade with the regulatory approval of targeted BRAF + MEK inhibitors and immune checkpoint inhibitors, which have vastly improved long-term outcomes. Recently, these advances have been rapidly translated to the high-risk adjuvant setting. Primary and acquired resistance to both immune and molecularly targeted agents, however, remains a challenge. Therefore, biomarkers predictive of response to therapy that can be assessed prior to initiation of treatment and early during the course of therapy are critical. Equally important is on-treatment biomarker monitoring that may predict the likelihood of treatment failure and disease relapse. This review will summarize recent advances in the understanding of biomarkers for patients with advanced melanoma, emphasizing emerging baseline predictive factors and on-treatment monitoring of biomarkers that aim to establish truly personalized treatment.