Neoadjuvant BRAF-targeted therapy for ameloblastoma of the mandible: an organ preservation approach.

BACKGROUND: Ameloblastoma is a rare odontogenic neoplasm frequently located in the mandible. Standard treatment involves radical bone resection and immediate reconstruction, causing functional, aesthetic, and psychological impairments. The BRAF V600E mutation is present in approximately 80% of mandible ameloblastomas, and BRAF inhibitors have demonstrated sustained responses in unresectable cases. METHODS: We identified ameloblastoma patients planned for ablative surgery and screened them for BRAF V600E mutation. Neoadjuvant BRAF inhibitors were offered to facilitate jaw preservation surgery. Retrospective data collection encompassed treatment regimens, tolerability, tumor response, and conversion to mandible preservation surgery. RESULTS: Between 2017 and 2022, a total of 11 patients received dabrafenib (n = 6) or dabrafenib with trametinib (n = 5). The median age was 19 (range = 10-83) years. Median treatment duration was 10 (range = 3-20) months. All (100%) patients achieved a radiological response. Ten (91%) patients successfully converted to mandible preservation surgery with residual tumor enucleation. One patient attained complete radiological response, and surgery was not performed. Among the 10 surgically treated patients, all exhibited a pathological response, with 4 achieving near complete response and 6 partial response. At a median follow-up of 14 (range = 7-37) months after surgery, 1 case of recurrence was observed. Grade 1-2 adverse effects were reported in 8 (73%) patients, with a single case of grade 3 (hepatitis). Dose modification was necessary for 3 patients, and 4 experienced treatment interruptions, while 1 patient permanently discontinued therapy. CONCLUSIONS: Neoadjuvant BRAF inhibition may offer a safe and effective strategy for organ preservation in mandible ameloblastoma treatment.

Incidence and Outcome of Neurologic Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in Patients With Melanoma.

BACKGROUND AND OBJECTIVES: Neurologic immune-related adverse events (n-irAEs) reportedly occur in up to 8% of patients treated with immune checkpoint inhibitors (ICIs) of all age groups. We investigated the association between age and n-irAEs in patients treated with ICIs and examined the effect of n-irAEs on survival outcomes in a large cohort of patients with melanoma. METHODS: We conducted a retrospective analysis of patients with advanced melanoma treated with ICIs at Ella Institute for Immuno-oncology and Melanoma between January 1, 2015, and April 20, 2022. The outcomes of interest were defined as the investigation of age-related frequency and severity of n-irAEs, the need for ICI interruption, the treatment required for n-irAE management, the safety of ICI reintroduction, and n-irAE's effect on survival. RESULTS: ICI was administered to 937 patients. At least one irAE occurred in 73.5% (n = 689) of them. Among the study population, 8% (n = 76) developed a n-irAE, with a median age of 66 years in female and 68 years in male patients at onset. The median follow-up after n-irAE was 1,147 days (IQR: 1,091.5 range: 3,938). Fewer irAEs occurred in patients older than 70 years (median: 3 events, p = 0.04, CI 2.5-4.7) while specifically colitis and pneumonitis were more common in the 18-60 age group (p = 0.03, 95% CI 0.8-0.38, p = 0.009, 95% CI 0.06-0.2). Grade ≥ 3 toxicity was seen in 35.5% of patients across age groups. The median time from ICI administration to n-irAE development was 48 days across age groups. Common n-irAE phenotypes were myositis (44.7%), encephalitis (10.5%), and neuropathy (10.5%). N-irAE required hospitalization in 40% of patients and steroids treatment in 46% with a median of 4 days from n-irAE diagnosis to steroids treatment initiation. Nine patients needed second-line immunosuppressive treatment. Rechallenge did not cause additional n-irAE in 71% of patients. Developing n-irAE (HR = 0.4, 95% CI 0.32-0.77) or any irAE (HR = 0.7195% CI 0.56-0.88) was associated with longer survival. DISCUSSION: N-irAEs are a relatively common complication of ICIs (8% of our cohort). Older age was not associated with its development or severity, in contrast with non-n-irAEs which occurred less frequently in the elderly population. Rechallenge did not result in life-threatening AEs. Development of any irAEs was associated with longer survival; this association was stronger with n-irAEs.

PET-CT underestimates the true pathological extent of disease at lymphadenectomy for melanoma patients after systemic therapy.

INTRODUCTION: Modern systemic therapy has revolutionized the treatment of melanoma. Currently, patients with clinically involved lymph nodes require lymphadenectomy with associated morbidities. Positron Emission Tomography - Computed Tomography (PET-CT) has demonstrated accuracy in melanoma detection and response to therapy. We aimed to identify whether a PET-CT directed lymphatic resection after systemic therapy is oncologically sound. MATERIALS AND METHODS: Retrospective review of patients who underwent lymphadenectomy after systemic therapy for melanoma with a preoperative PET-CT. Examined demographic, clinical, and perioperative parameters including extent of disease, systemic therapy and response, and PET-CT findings compared to pathological outcomes. We compared patients with "as or less than expected" outcomes on pathology against those with "more than expected" pathological outcomes. RESULTS: Thirty-nine patients met inclusion criteria. In 28 (71.8%), pathological outcomes were "as or less than expected" by PET-CT, and in 11 (28.2%) pathological outcome were "more than expected". "More than expected" occurred more frequently with advanced disease at presentation with 75% presenting with regional/metastatic disease versus only 42.9% in the "as or less than expected" group (p = 0.015). Poor response to therapy also trended towards the "more than expected" group with only 27.3% favorable response versus 53.6% favorable response in the "as or less than expected" group, not statistically significant. Extent of disease on imaging failed to predict pathological concordance. CONCLUSION: PET-CT underestimates pathological extent of disease in the lymphatic basin in 30% of patients after systemic therapy. We failed to identify predictors of more extensive disease and warn against limited PET-CT directed lymphatic resections.

Better Late Than Never: The Impact of Steroidal Treatment on the Outcome of Melanoma Patients Treated with Immunotherapy.

BACKGROUND: Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients concerning initiation timing and dosage. METHODS: A retrospective, single-center analysis of patients with advanced melanoma who underwent first-line ICI therapy during 2014-2020 was conducted. RESULTS: Among the 415 patients, two-hundred patients (48.3%) were exposed to steroids during the first line, most of them due to irAEs (n = 169, 84.5%). Nearly a quarter of them were exposed to steroids within the first four weeks of treatment. Surprisingly, steroidal exposure was associated with better progression-free survival (PFS; HR = 0.74, p = 0.015); however, early exposure (within four weeks of treatment) resulted in a significantly shorter PFS compared to late exposure (adjusted HR 3.2, p < 0.001). CONCLUSIONS: Early exposure to corticosteroids during the priming phase of ICI therapy could impede the establishment of an effective immune response. These results suggest that caution should be exercised when considering the use of steroids for the management of early-onset irAEs.

Real world evidence of Lenvatinib + anti PD-1 as an advanced line for metastatic melanoma.

Introduction: Immunotherapy has revolutionized the prognosis of patients with metastatic melanoma. To date, the most active regimen is the combination of ipilimumab + nivolumab (ipi-nivo) achieving a response rate of nearly 60% and a median survival (OS) of 6 years. However, approximately 40% of patients experience primary resistance, while around 50% experience secondary resistance, highlighting the need for an effective second-line treatment option The recently published results on the use of lenvatinib + pembrolizumab in the advanced line setting led to the adoption of this regimen at our institution. Here we present our experience with this regimen, focusing on efficacy and safety. Methods: Electronic medical records of patients treated at a tertiary referral melanoma center, with at least one cycle of anti PD-1 + lenvatinib from 2020 to 2023 were analyzed for baseline demographic characteristics, disease related characteristics and treatment outcomes. Results: Forty-two patients were identified. The Response rate (RR) was 28% and the disease control rate was 38%. Responses were seen across different melanoma subtypes, including 67% in acral melanoma, 20% in uveal melanoma, and 25% in mucosal melanoma. Patients with a more aggressive disease manifested by elevated lactate dehydrogenase (LDH) achieved a RR of 26%, while patients with active central nervous system (CNS) metastases had a RR of 31%, and an intra-cranial RR of 23%. Responses were seen across lines of treatment, with a 25% RR in the second and third lines, and a 36% RR in the fourth and fifth lines. The median progression free survival was 3 months, and the median survival was 11 months. The treatment was not easily tolerated with 31% of the patients experiencing grade 3-4 toxicity, which was manageable through dose interruptions and reductions. Only 7% of patients discontinued the treatment due to toxicity. Conclusion: Lenvatinib in combination with anti-PD1 had demonstrated both relative safety and efficacy in patients with metastatic melanoma of all subtypes in the advanced line setting. We are eagerly anticipating the mature results of the LEAP-004 study hoping that this regimen will receive regulatory approval, paving the way for its widespread adoption in daily practice worldwide.

MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2.

Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.

Radiotherapy may augment response to immunotherapy in metastatic uveal melanoma patients.

Introduction: Uveal melanoma (UM) is a subtype of melanoma arising from the ocular region. Despite various local therapies available, a significant portion of patients develop distant metastases, primarily to the liver. While cutaneous melanoma is very sensitive to immunotherapy, UM is known to be less responsive and patients were excluded from pivotal clinical trials. To date, there is no standard first line therapy for metastatic UM and clinical trial participation is encouraged. While UM is considered a radio-resistant tumor, there is a role for radiotherapy (RT) as palliative treatment and possibly for immune sensitization. This a retrospective analysis aimed at addressing the role of combination checkpoint inhibitors (ICI) with RT as a synergistic treatment in metastatic UM patient. We hypothesized that concurrent RT would improve the clinical response to immunotherapy. Methods: Retrospective chart review of patients with metastatic UM treated with ICI at Ella Lemelbaum Institute between 2015 and 2021. Patients' electronic medical records were analyzed for baseline characteristics, response rate and survival data. Patients were grouped according to receipt of concomitant RT. Study was approved by local IRB and statistical analyses done using Stata V.17. Results: Thirty-nine patients were treated with immunotherapy. Fifty percent were treated with anti-programmed cell death (PD)-1 and 50% with anti-PD1- anti CTLA4 combination therapy. Nine patients were treated concomitantly with immunotherapy and external beam RT or with stereotactic body RT (group A) and 29 patients were treated with immunotherapy alone (group B). Overall response rate was significantly higher in group A (44% versus 10%, p = 0.004). Median progression-free survival was longer for patients in group A (22 months versus 3 m, Hazard Ratio (HR) = 0.37, p = 0.036). Median overall survival was also longer for group A (26 months versus 7.5 m, HR = 0.34, p = 0.03). Toxicity was comparable between the groups. Conclusions: RT may improve response to immunotherapy with ICI in metastatic UM patients and may confer an advantage in survival. Further prospective, larger studies are warranted.

Efficacy and toxicity of Ipilimumab-Nivolumab combination therapy in elderly metastatic melanoma patients.

Introduction: Immunotherapy has revolutionized metastatic Melanoma therapy. The most active regimen is combination therapy of Ipilimumab-Nivolumab (Ipi-Nivo) with response rates (RR) of ~60% and median overall survival (OS) of ~6 years. Immune-related adverse events (irAE) are common (~60% develop grade 3-4) and pose a challenge when treating frail patients. We sought to examine whether Ipi-Nivo therapy is feasible in elderly metastatic melanoma patients. Methods: Electronic records of patients treated at the Ella Lemelbaum Institute with Ipi-Nivo between the years 2017-2021 were screened for age. Elderly patients were defined as age 75 and older (group A) and were matched with records of patients age <75 (group B). Records were analyzed for baseline parameters, immunotherapy regimen, RR, toxicity and progression-free survival (PFS). Results: Twenty-six relevant patients age >75 (median 77) were identified and were matched to 34 younger patients (median age 57). No statistically significant differences were noted in terms of baseline parameters except for BRAF mutation status (group A 15%, group B 47%, p=0.008). Response rate in group A was 38% and is consistent with previously published data. Median PFS was the same for both groups (A = 5.5 months, B= 7.5 months, p=NS). Treatment was similarly tolerated: 35% of group A patients completed 4 cycles of therapy compared to 28% for group B (p=NS). Grade 2-4 irAE were the same (A=58%, B=66%, p=NS) and there was no difference in the need for hospitalization for G3-4 events between the groups. (A=63%, B=69%, p=NS). Further division into 4 age groups (>80 vs 75-79 in group A and 65-74 vs <65 in group B) found no difference in terms of response rate or G3-4 toxicity. Conclusion: Ipilimumab-Nivolumab combination therapy in elderly metastatic Melanoma patients seems to be well tolerated and efficient in selected elderly patients based on performance status and comorbidities, just as in younger patients. This regimen seems to be a feasible treatment option for this age group.

The increasing role of abdominal metastesectomy for malignant melanoma in the era of modern therapeutics.

BACKGROUND: Metastatic spread of malignant melanoma to the abdomen presents a therapeutic challenge. Targeted and Immune-therapies dramatically improve patients' survival, yet some patients may still benefit from surgical intervention. This study investigates the outcomes of surgical treatment of abdominal metastatic melanoma in the era of modern therapy. METHODS: This is a retrospective study of all patients who underwent surgical resection for abdominal metastatic melanoma between the years 2009-2021 (n = 80). We examined the clinical, operative, perioperative, and oncological outcomes of these patients. RESULTS: The cohort included a therapeutic group (T, n = 43) and palliative group (P, n = 37). The rate of overall post-operative complications was lower in the T group (n = 3, 9.3%) compared to the P group (n = 10, 27.1%) (p = 0.04), but no difference in major complications rate (p = 0.41). The median follow-up was 13.4 months (range, 0.5-107), with an estimated 2- and 5-years survival of 66.5% and 45.3% respectively. The estimated 2- and 5-years survival of the T group was 76.61% and 69.65%, and 49.01% and 28.01% in the P group (p = 0.005). Univariate analysis identified Therapeutic resection (HR 3.2, p = 0.008), isolated lesions (HR 1.47, p = 0.033) and major complication score (HR 1.8, p=<0.001) to be correlated with survival. On multivariate analysis, Therapeutic resection (HR 2.53, p = 0.042) and major complication score (HR 1.62, p = 0.004) remained significant independent factors correlated with survival. In patients who progressed on treatment, and their progression was treated with surgical resection 46.1% where able to be maintained on the same preoperative treatment strategy. CONCLUSION: We have demonstrated that abdominal metastesectomy is a safe and oncologically efficacious therapy in selected patients. Especially in the era of modern therapeutics, patients with isolated disease site, limited resectable progression on therapy, or patients with symptomatic metastases should be considered for surgical resection.

Immunotherapy Discontinuation in Metastatic Melanoma: Lessons from Real-Life Clinical Experience.

BACKGROUND: Immunotherapy has revolutionized outcomes for melanoma patients, by significantly prolonging survival and probably even curing a fraction of metastatic patients. In daily practice, treatment for responding patients is often discontinued due to treatment-limiting toxicity, or electively, following a major tumor response. To date, the criteria for a safe stop and the optimal duration of treatment remain unclear. PATIENTS AND METHODS: This is a real-world single-site cohort of 106 advanced melanoma patients who were treated with immunotherapy and who discontinued treatments in the absence of disease progression. Here, we describe their long-term outcomes, and analyze the differential characteristics between patients who ultimately experienced progression and those who remained in unmaintained durable response. RESULTS: Patients were treated with anti-PD-1 monotherapy (81%) or in combination with ipilimumab (19%) for a median of 15.2 m (range, 0.7-42.3 m). Upon discontinuation, 75.5% had achieved a complete response (CR). After a median follow-up of 20.8 m (range, 6-58) from discontinuation, 32% experienced disease progression. Median time to progression was 8.5 m (range, 1.5-37). Response to re-induction with anti-PD-1 was observed in 47%. On multivariate analysis, achieving a non-CR response, immunotherapy given in advanced line, and shorter treatment duration were significantly associated with lesser progression-free survival. CONCLUSIONS: This is one of the few reports on real-world melanoma patients who discontinued immunotherapy while responding to treatment. This study reveals the key factors to bear in mind when considering an elective treatment cessation. Specifically, patients with non-CR as best response and patients treated in an advanced-line setting should be treated for longer periods, and elective discontinuation should not take place prior to 18 m.

Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy.

BACKGROUND: Adoptive 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. METHODS: In 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. RESULTS: We 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. CONCLUSIONS: Bone 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.

Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.

The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.

Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma.

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.

Comprehensive single institute experience with melanoma TIL: Long term clinical results, toxicity profile, and prognostic factors of response.

Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) mediates objective responses in 30% to 50% of patients with metastatic melanoma according to multiple, small phase 2 trials. Here we report the long-term clinical results, intent-to-treat analysis, predictors of response and toxicity profile in a large patient cohort. A total of 179 refractory melanoma patients were enrolled in the ACT trial. TIL were administered in combination with high-dose bolus interleukin-2 following preconditioning with cyclophosphamide and fludarabine. Patients were followed-up for a median of 7.2 years. A total of 107 (60%) of 179 enrolled patients were treated. The main reason for the drop out of the study was clinical deterioration. Of 103 evaluated patients, 29 patients (28%) achieved an objective response (OR), including complete remission (8%) or partial response (20%). Sixteen pateints exhibited stable disease. Predictors of response were performance status, time of TIL in culture and CD8 frequency in the infusion product. The absolute lymphocyte count 1 and 2 weeks after TIL infusion was the most predictive parameter of response. With a medium follow-up time of 7.2 years, OR patients reached a median overall survival (OS) of 58.45 months and a median progression-free survival (PFS) of 15.43 months, as compared with nonresponders, with 6.73 months OS and 2.60 months PFS. By 6 years, 50% of OR patients were alive and 43% had no documented progression. TIL ACT can yield durable objective responses, even as salvage therapy in highly advanced metastatic melanoma patients.

Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease.

PURPOSE: The risk of immune checkpoint inhibitor therapy-related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors. PATIENTS AND METHODS: We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events. RESULTS: Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn's disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event-related deaths were recorded. Anti-cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively). CONCLUSION: Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.

TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma.

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.

Recurrent Pneumonitis in Patients with Melanoma Treated with Immune Checkpoint Inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have changed the oncologic landscape in the past few years. Alongside impressive antitumor responses, new novel immune-related adverse events (irAEs) have emerged; pneumonitis is an irAE that can potentially be fatal and necessitates a proper management. No consensus exists regarding steroid treatment duration or drug rechallenge options. Our study describes the clinical and radiological course of melanoma patients diagnosed with immune-related pneumonitis that has recurred because of rechallenge attempt or despite complete treatment discontinuation (unprovoked). MATERIALS AND METHODS: The study population was composed of patients with metastatic melanoma who were treated with anti-programmed cell death 1 (PD-1) as monotherapy or in combination with anti-cytotoxic T lymphocyte antigen-4 and who were diagnosed with immune-related pneumonitis. For recurrent cases after clinical and radiological resolution, we explored the differences from cases with no recurrence. RESULTS: Nineteen out of 386 (4.8%) patients treated with ICI were diagnosed with pneumonitis. Median age was 66 years, and 53% were male. Compared with single-agent nivolumab, patients treated with ipilimumab-nivolumab combination presented with an earlier onset (27.5 vs. 10.3 weeks, respectively, p = .015) and had higher grades of severity. After complete resolution, rechallenge was attempted in seven patients; three of them had recurrent pneumonitis. Three other patients experienced recurrent pneumonitis despite complete discontinuation of the drug (unprovoked by rechallenge). The latter were characterized with an earlier onset of the first pneumonitis compared with those who did not experience recurrence (median, 12.4 vs. 26.4 weeks) and a shorter course of steroid treatment at first episode (median, 5.1 vs. 10 weeks). Recurrent cases were generally more severe than the first episode. CONCLUSION: Unprovoked recurrent pneumonitis is a new, poorly reported entity that requires further investigation. Our observations suggest that cases of pneumonitis that present early in the course of immunotherapy treatment may recur despite treatment discontinuation, thus necessitating closer monitoring and a longer course of steroid treatment. IMPLICATIONS FOR PRACTICE: This article sheds light on a poorly described immune-related adverse event: recurrent pneumonitis despite complete discontinuation of immunotherapy (unprovoked), in patients with advanced melanoma.

Immunotherapy comes of age in octagenarian and nonagenarian metastatic melanoma patients.

Immunotherapy with anti-programmed cell death-1 (PD-1) agents is an effective treatment for metastatic melanoma. Recent data hint at better response to therapy for patients over age 65 years. Patients with metastatic melanoma in their 80's and 90's pose a clinical challenge. We describe a cohort of 144 patients ≥65 years and analyse the efficacy and toxicity of anti-PD-1 therapy in ages 80-100 years compared with ages 65-79 years. Records of metastatic melanoma patients aged 65-100 years treated with anti-PD-1 were collected retrospectively. Baseline parameters, response rate (overall response rate [ORR]), best response, progression-free survival (PFS) and overall survival (OS) and immune-related adverse events were analysed. Cox regression, t test, and chi-square test were used for statistical analysis. Five hundred patients were treated with anti-PD-1 agents between 2013 and 2018.Eighty-two patients were aged 65-79 years (group A, median 71.5 years), and 62 patients were aged 80-100 years (group B, median 84 years, range 80-97 years). Baseline parameters were comparable except for worse PS in group B (p = 0.001). One hundred twenty-four patients were evaluable for analysis of response (76 group A, 48 group B). A trend was noted for higher ORR in the older group with 62.3% for group A and 73.9% for group B (p = 0.09). Complete response was significantly higher in group B versus group A (47.9% versus 20%, p = 0.001). No significant difference was found in PFS or OS between the groups. Toxicity for all patients was similar at 22.8%-25.6% G2-4 adverse events. Elderly patients show enhanced response to anti-PD-1 therapy. Increasing age within the elderly patients group may predict an even better response to therapy and comparable survival in patients of very old age.

Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case-Control Study.

Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients (n = 403) treated with anti-PD-1 (n = 356) or anti-CTLA-4 (n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls (P = 0.006). Four patients developed EPI, all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements.

Possible immune adverse events as predictors of durable response to BRAF inhibitors in patients with BRAF V600-mutant metastatic melanoma.

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are among the cornerstones of metastatic melanoma therapy demonstrating excellent response rates with duration of 7-12 m. Long-term benefit from these agents was reported in patients with normal lactate dehydrogenase (LDH) and less than three disease sites. However, a treatment-dependent marker for long-term efficacy is lacking. Data suggest that immune-related adverse events (irAEs) are associated with clinical benefit in patients treated with immunotherapy and that response to BRAF/MEK therapy may have an underlying immune mechanism. We hypothesised that AEs with an underlying immune mechanism may be associated with a durable response to targeted therapy. We retrospectively identified a cohort of 78 BRAF V600-mutant metastatic melanoma patients treated with BRAFi or BRAFi + MEKi between November 2010 and November 2013. Four treatment-related AEs including vitiligo, uveitis, erythema nodosum and keratitis sicca were defined as irAEs of interest. Retrospective analysis of AEs in relationship to progression-free survival (PFS), disease burden and LDH levels was performed. Median PFS (mPFS) for all patients was 7.5 months with responses ongoing in eight patients as of April 2017. Ten patients were identified with the AEs defined previously. Cox regression analysis revealed a very strong association between those AEs and PFS; mPFS was 42.8 m in patients with at least one AE versus 6.1 m in those without an AE (hazard ratio [HR] 0.22, p = 0.002). This association was independent of LDH levels and disease burden (HR 0.24, p = 0.035). This analysis demonstrates a strong association between immune AEs and durable response to targeted therapy and may provide a treatment-related biomarker to estimate the outcome of therapy.